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  • Cancer causes metabolic perturbations associated with reduced insulin-stimulated glucose uptake in peripheral tissues and impaired muscle microvascular perfusion
    Metabolism (IF 6.513) Pub Date : 2020-01-24
    Xiuqing Han; Steffen H. Raun; Michala Carlsson; Kim A. Sjøberg; Carlos Henriquez-Olguín; Mona Ali; Annemarie Lundsgaard; Andreas M. Fritzen; Lisbeth L.V. Møller; Zhen Li; Jinwen Li; Thomas E. Jensen; Bente Kiens; Lykke Sylow

    Background Redirecting glucose from skeletal muscle and adipose tissue, likely benefits the tumor’s energy demand to support tumor growth, as cancer patients with type 2 diabetes have 30% increased mortality rates. The aim of this study was to elucidate tissue-specific contributions and molecular mechanisms underlying cancer-induced metabolic perturbations. Methods Glucose uptake in skeletal muscle and white adipose tissue (WAT), as well as hepatic glucose production, were determined in control and Lewis lung carcinoma (LLC) tumor-bearing C57BL/6 mice using isotopic tracers. Skeletal muscle microvascular perfusion was analyzed via a real-time contrast-enhanced ultrasound technique. Finally, the role of fatty acid turnover on glycemic control was determined by treating tumor-bearing insulin-resistant mice with nicotinic acid or etomoxir. Results LLC tumor-bearing mice displayed reduced insulin-induced blood-glucose-lowering and glucose intolerance, which was restored by etomoxir or nicotinic acid. Insulin-stimulated glucose uptake was 30-40% reduced in skeletal muscle and WAT of mice carrying large tumors. Despite compromised glucose uptake, tumor-bearing mice displayed upregulated insulin-stimulated phosphorylation of TBC1D4Thr642 (+18%), AKTSer474 (+65%), and AKTThr309 (+86%) in muscle. Insulin caused a 70% increase in muscle microvascular perfusion in control mice, which was abolished in tumor-bearing mice. Additionally, tumor-bearing mice displayed increased (+45%) basal (not insulin-stimulated) hepatic glucose production. Conclusions Cancer can result in marked perturbations on at least six metabolically essential functions; i) insulin’s blood-glucose-lowering effect, ii) glucose tolerance, iii) skeletal muscle and WAT insulin-stimulated glucose uptake, iv) intramyocellular insulin signaling, v) muscle microvascular perfusion, and vi) basal hepatic glucose production in mice. The mechanism causing cancer-induced insulin resistance may relate to fatty acid metabolism.

  • Twelve weeks of exenatide treatment increases [18F]fluorodeoxyglucose uptake by brown adipose tissue without affecting oxidative resting energy expenditure in nondiabetic males
    Metabolism (IF 6.513) Pub Date : 2020-01-23
    Laura G.M. Janssen; Kimberly J. Nahon; Katrien F.M. Bracké; Dennis van den Broek; Renée Smit; Aashley S.D. Sardjoe Mishre; Lisa L. Koorneef; Borja Martinez-Tellez; Jedrzej Burakiewicz; Hermien E. Kan; Floris H.P. van Velden; Lenka M. Pereira Arias-Bouda; Lioe-Fee de Geus-Oei; Jimmy F.P. Berbée; Ingrid M. Jazet; Mariëtte R. Boon; Patrick C.N. Rensen

    Aims/hypothesis Brown adipose tissue (BAT) improves energy metabolism by combusting glucose and lipids into heat. Agonism of the glucagon-like peptide-1 receptor (GLP-1R) within the central nervous system activates BAT in mice. Moreover, in patients with type 2 diabetes, GLP-1R agonism lowers body weight and improves glucose and lipid levels, possibly involving BAT activation. Interestingly, people from South Asian descent are prone to develop cardiometabolic disease. We studied the effect of GLP-1R agonism on BAT in humans, specifically in South Asians and Europids without obesity or type 2 diabetes. Methods Twelve Dutch South Asian and 12 age- and BMI-matched Europid nondiabetic men received 12 weeks extended-release exenatide (Bydureon) in this single-arm prospective study. Before and after treatment, BAT was visualized by a cold-induced [18F]FDG-PET/CT scan and a thermoneutral MRI scan, and resting energy expenditure (REE), substrate oxidation, body composition and fasting plasma glucose and serum lipids were determined. Appetite was rated using a visual analogue scale. Results Since the effect of exenatide on metabolic parameters did not evidently differ between ethnicities, data of all participants were pooled. Exenatide decreased body weight (−1.5 ± 0.4 kg, p < .01), without affecting REE or substrate oxidation, and transiently decreased appetite ratings during the first weeks. Exenatide also lowered triglycerides (−15%, p < .05) and total cholesterol (−5%, p < .05), and tended to lower glucose levels. Notably, exenatide increased BAT metabolic volume (+28%, p < .05) and mean standardized uptake value (+11%, p < .05) ([18F]FDG-PET/CT), without affecting supraclavicular adipose tissue fat fraction (MRI). Conclusions/interpretation We show for the first time that GLP-1R agonism increases [18F]FDG uptake by BAT in South Asian and Europid men without obesity or type 2 diabetes. Trial registry. Clinicaltrials.gov NCT03002675

  • Normalization of metabolic flux data during clamp studies in humans
    Metabolism (IF 6.513) Pub Date : 2020-01-23
    Kasper W. ter Horst; Mireille J. Serlie

    Background There is no consensus in the field regarding the optimal method for the expression of metabolic flux data, such as glucose disposal rates during hyperinsulinemic-euglycemic clamp experiments. Several normalization methods are in use today, but their impact on study outcomes is rarely discussed. Methods We illustrate this issue using clamp data from 92 lean and 66 obese subjects. Glucose kinetics and insulin sensitivity were determined during hyperinsulinemic-euglycemic clamp studies using [6,6-2H2]glucose. From this single dataset, we calculated 21 expression methods for the glucose disposal rate during hyperinsulinemic conditions. Results and discussion With most normalization methods, the obese subjects demonstrated reduced insulin-stimulated glucose disposal as compared to the lean subjects. However, depending on the normalization method, glucose disposal rates in obese subjects ranged from 26 ± 1% to 207 ± 10% of glucose disposal rates in lean subjects. We conclude that data normalization methods greatly impacted metabolic flux outcomes in our dataset of lean and obese subjects. There is no compelling evidence to select one method over the other, but we encourage authors in the metabolic arena to think about, and provide a rationale for, the best normalization method for their specific research questions.

  • Metabolic flexibility is impaired in women who are pregnant and overweight/obese and related to insulin resistance and inflammation.
    Metabolism (IF 6.513) Pub Date : 2020-01-10
    Rachel A. Tinius; Maire M. Blankenship; Karen E. Furgal; W. Todd Cade; Kevin J. Pearson; Naomi S. Rowland; Regis C. Pearson; Donald L. Hoover; Jill M. Maples

    Context. Maternal obesity is a significant public health concern that contributes to unfavorable outcomes such as inflammation and insulin resistance. Women with obesity may have impaired metabolic flexibility (i.e. an inability to adjust substrate metabolism according to fuel availability). Impaired metabolic flexibility during pregnancy may mediate poor pregnancy outcomes in women with obesity. Purpose The purposes of this study were to: 1) compare metabolic flexibility between overweight/obese and lean women; and 2) determine the relationships between metabolic flexibility, inflammation following a high-fat meal, and maternal metabolic health outcomes (i.e. gestational weight gain and insulin resistance). Procedures. This interventional physiology study assessed lipid oxidation rate via indirect calorimetry before and after consumption of a high-fat meal. The percent change in lipid metabolism was calculated to determine ‘metabolic flexibility’. Maternal inflammatory profiles (CRP, IL-6, IL-8, IL-10, IL-12, TNF-α) and insulin resistance (HOMA-IR) were determined via plasma analyses. Main Findings. 64 women who were pregnant (lean = 35, overweight/obese = 29) between 32 and 38 weeks gestation participated. Lean women had significantly higher metabolic flexibility compared to overweight/obese women (lean 48.0 ± 34.1% vs overweight/obese 29.3 ± 34.3%, p = .035). Even when controlling for pre-pregnancy BMI, there was a negative relationship between metabolic flexibility and percent change in CRP among the overweight/obese group (r = −0.526, p = .017). Metabolic flexibility (per kg fat free mass) was negatively correlated with postprandial HOMA-IR (2 h: r = −0.325, p = .016; 4 h: r = −0.319, p = .019). Conclusions Overweight and obese women who are pregnant are less ‘metabolically flexible’ than lean women, and this is related to postprandial inflammation and insulin resistance.

  • Far-infrared radiation prevents decline in β-cell mass and function in diabetic mice via the mitochondria-mediated Sirtuin1 pathway
    Metabolism (IF 6.513) Pub Date : 2020-01-10
    Yung-Ho Hsu; Yen-Cheng Chen; Yu-Wei Chen; Tzu-Hsuan Chiu; Yung-Ting Kuo; Cheng-Hsien Chen

    Insulin deficiency in type 2 diabetes mellitus (DM) involves a decline in both pancreatic β-cell mass and function. Enhancing β-cell preservation represents an important therapeutic strategy to treat type 2 DM. Far-infrared (FIR) radiation has been found to induce promyelocytic leukemia zinc finger protein (PLZF) activation to protect the vascular endothelium in diabetic mice. The influence of FIR on β-cell preservation is unknown. Our previous study reveals that the biologically effective wavelength of FIR is 8–10 μm. In the present study, we investigated the biological effects of FIR (8–10 μm) on both survival and insulin secretion function of β-cells. FIR reduced pancreatic islets loss and increased insulin secretion in nicotinamide-streptozotocin-induced DM mice, but only promoted insulin secretion in DM PLZF−/− mice. FIR-upregulated PLZF to induce an anti-apoptotic effect in a β cell line RIN-m5 f. FIR also upregulated mitochondrial function and the ratio of NAD+/NADH, and then induced Sirtuin1 (Sirt1) expression. The mitochondria Complex I inhibitor rotenone blocked FIR-induced PLZF and Sirt1. The Sirt1 inhibitor EX527 and Sirt1 siRNA inhibited FIR-induced PLZF and insulin respectively. Sirt1 upregulation also increased CaV1.2 expression and calcium influx that promotes insulin secretion in β-cells. In summary, FIR-enhanced mitochondrial function prevents β-cell apoptosis and enhances insulin secretion in DM mice through the Sirt1 pathway.

  • Epigenetic silencing of microRNA-125b-5p promotes liver fibrosis in nonalcoholic fatty liver disease via integrin α8-mediated activation of RhoA signaling pathway
    Metabolism (IF 6.513) Pub Date : 2020-01-09
    Qingxian Cai; Fengjuan Chen; Fen Xu; Ke Wang; Ka Zhang; Guojun Li; Jun Chen; Hong Deng; Qing He

    Background Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases that may progress to liver fibrosis or cancer. The present study aimed to investigate the role of microRNA-125b-5p (miR-125b-5p) in NAFLD and to further explore underlying molecular mechanisms. Methods A mouse model of NAFLD was constructed by high cholesterol diet feeding and a cell-model was developed by treating the mouse liver cell line NCTC1469 with palmitic acid. Gain- and loss-of-function experiments were performed to determine the effects of miR-125b-5p, integrin α8 (ITGA8), and the RhoA signaling pathway on liver fibrosis in NAFLD. After the expression levels of miR-125b-5p, ITGA8, and RhoA were determined, liver fibrosis was evaluated in vivo and in vitro. The binding relationship of miR-125b-5p and ITGA8 was then validated. Finally, miR-125b-5p promoter methylation in NAFLD liver tissues and cells was determined. Results In NAFLD clinical samples, mouse model, and cell-model, miR-125b-5p expression was reduced, while ITGA8 expression was increased. Moreover, miR-125b-5p targeted and downregulated ITGA8, leading to inhibition of the RhoA signaling pathway. In NAFLD liver tissues and cells, the CpG island in the miR-125b-5p promoter was methylated, causing epigenetic silencing of miR-125b-5p. Both miR-125b-5p silencing and ITGA8 overexpression promoted in vitro and in vivo liver fibrosis in NAFLD via activation of the RhoA signaling pathway. Conclusions Collectively, epigenetic silencing of miR-125b-5p upregulates ITGA8 expression to activate the RhoA signaling pathway, leading to liver fibrosis in NAFLD.

  • High-density lipoprotein cholesterol efflux capacity and cardiovascular risk in autoimmune and non-autoimmune diseases
    Metabolism (IF 6.513) Pub Date : 2020-01-08
    Anouar Hafiane; Elda Favari; Stella S. Daskalopoulou; Nicolas Vuilleumier; Miguel A. Frias

    Functional assessment of cholesterol efflux capacity (CEC) to high-density lipoprotein (HDL) is an emerging tool for evaluating morbidity and mortality associated with cardiovascular disease (CVD). By promoting macrophage reverse cholesterol transport (RCT), HDL-mediated CEC is believed to play an important role in atherosclerotic lesion progression in the vessel wall. Furthermore, recent evidence indicates that the typical inverse associations between various forms of CEC and CV events may be strongly modulated by environmental systemic factors and traditional CV risk factors, in addition to autoimmune diseases. These factors influence the complex and dynamic composition of HDL particles, which in turn positively or negatively affect HDL-CEC. Herein, we review recent findings connecting HDL-CEC to traditional CV risk factors and cardiometabolic conditions (non-autoimmune diseases) as well as autoimmune diseases, with a specific focus on how these factors may influence the associations between HDL-CEC and CVD risk.

  • Time Trends and Predictors of Hypovitaminosis D Across the Life Course: 2009–2016
    Metabolism (IF 6.513) Pub Date : 2020-01-07
    Randa K. Saad; Vanessa C. Akiki; Maya Rahme; Sara Ajjour; Mariam Assad; Ghada A. El-Hajj Fuleihan

    Purpose We investigated prevalence, determinants, seasonal changes, and time trends in hypovitaminosis D. We derived a desirable serum 25-hydroxy-vitamin D (25OHD) level in adults/elderly by evaluating the 25OHD-parathyroid hormone (PTH) exponential relationship. Methods We analyzed serum 25OHD data from a large laboratory database (N = 151,394), from a major academic medical center in Lebanon, from 2009 to 2016. We used cross calibration formulas to convert measured 25OHD levels to LC-MS/MS equivalents based on our external quality assurance protocols. Results 6% of the population were children (mean age 11 ± 5 years, 57% girls), 69% were adults (44 ± 13 years, 71% women), and 25% were elderly (74 ± 6 years, 58% women). The prevalence of hypovitaminosis D, in the entire population, was 39%, 28% and 22% at 25OHD cutoffs of 20 ng/ml, 15 ng/ml, and 12 ng/ml, respectively, across all years. Using multivariate analysis, predictors of 25OHD levels below 12, 15 and 20 ng/ml were younger age, male sex, winter months, and inpatient status both in adults and elderly. In children, older age, female sex, winter months, and inpatient status, predicted levels below 15 ng/ml, but only older age, female sex, and winter months predicted levels below 12 ng/ml and 20 ng/ml. There was a significant steady annual increase in 25OHD levels between 2009 and 2016 of 0.8 ng/ml/year (95% CI: 0.7, 1.0) in children, 1.2 ng/ml/year (1.2, 1.3) in adults and 2.6 ng/ml/year (2.6, 2.8) in the elderly. Using best fit non-linear regression models, on a subset of adults and elderly in whom concomitant 25OHD and PTH data was available (N = 5885), PTH levels plateaued at a serum 25OHD level of 23.4 ng/ml. Conclusion Secular increase in serum 25OHD levels is observed in Lebanon, but hypovitaminosis D is still prevalent. Our data provides basis for a desirable 25OHD level above 23.4 ng/ml in adult and elderly Lebanese individuals.

  • Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet Regeneration
    Metabolism (IF 6.513) Pub Date : 2020-01-02
    Nadia Cobo Vuilleumier; Benoit R. Gauthier

    Type 1 diabetes mellitus (T1DM) is an autoimmune disease that targets the destruction of islet beta-cells resulting in insulin deficiency, hyperglycemia and death if untreated. Despite advances in medical devices and longer-acting insulin, there is still no robust therapy to substitute and protect beta-cells that are lost in T1DM. Attempts to refrain from the autoimmune attack have failed to achieve glycemic control in patients highlighting the necessity for a paradigm shift in T1DM treatment. Paradoxically, beta-cells are present in T1DM patients indicating a disturbed equilibrium between the immune attack and beta-cell regeneration reminiscent of unresolved wound healing that under normal circumstances progression towards an anti-inflammatory milieu promotes regeneration. Thus, the ultimate T1DM therapy should concomitantly restore immune self-tolerance and replenish the beta-cell mass similar to wound healing. Recently the agonistic activation of the nuclear receptor LRH-1/NR5A2 was shown to induce immune self-tolerance, increase beta-cell survival and promote regeneration through a mechanism of alpha-to-beta cell phenotypic switch. This trans-regeneration process appears to be facilitated by a pancreatic anti-inflammatory environment induced by LRH-1/NR5A2 activation. Herein, we review the literature on the role of LRH1/NR5A2 in immunity and islet physiology and propose that a cross-talk between these cellular compartments is mandatory to achieve therapeutic benefits.

  • The combination of Linagliptin, Metformin and Lifestyle Modification to prevent Type 2 Diabetes (PRELLIM). A randomized clinical trial
    Metabolism (IF 6.513) Pub Date : 2019-12-28
    Rodolfo Guardado-Mendoza; Sara Stephania Salazar-López; Mildred Fátima de la Luz Álvarez-Canales; Diana Farfán Vázquez; Yoscelina Estrella Martínez-López; Lilia M. Jiménez-Ceja; Erick L. Suárez-Pérez; Fabiola Angulo-Romero; Maria Lola Evia-Viscarra; María Luisa Montes de Oca-Loyola; Edgar G. Durán-Pérez; Franco Follie; Alberto Aguilar-García

    Background Prediabetes is a highly prevalent health problem with a high risk of complications and progression to type 2 diabetes (T2D). The goals of this study were to evaluate the effect of the combination of lingaliptin + metformin + lifestyle on glucose tolerance, pancreatic β-cell function and T2D incidence in patients with prediabetes. Methods A single center parallel double-blind randomized clinical trial with 24 months of follow-up in patients with impaired glucose tolerance plus two T2D risk factors which were randomized to linagliptin 5 mg + metformin 1700 mg daily + lifestyle (LM group) or metformin 1700 mg daily + lifestyle (M group). Primary outcomes were regression to normoglycemia and T2D incidence; glucose levels and pancreatic β-cell function were secondary outcomes. Results Subjects were screened for eligibility by OGTT and 144 patients with prediabetes were randomized to LM group (n = 74) or M group (n = 70); 52 and 36 participants in the LM group and 52 and 27 participants in the M group, completed the 12 and 24 months of treatment, respectively; average follow-up was 17 ± 6 and 18 ± 7 months in M and LM group, respectively. Glucose levels during OGTT improved more in LM group. OGTT disposition index (DI) improved significantly better during the first months in LM group, increasing from 1·31 (95% CI: 1·14–1·49) to 2·41 (95% CI: 2.10–2.72) and to 2.07 (95% CI: 1.82–2.31) at 6 and 24 months in LM group vs from 1.21 (95% CI: 0.98–1.34) to 1.56 (95% CI: 1.17–1.95) and to 1.72 (95% CI: 1.45–1.98) at 6 and 24 months in M group (p < .05). T2D incidence was higher in M group in comparison to LM group (HR 4.0, 95% CI: 1.24–13.04, p = .020). The probability of achieving normoglycemia was higher in LM group (OR 3.26 CI 95% 1.55–6.84). No major side effects were observed during the study. Conclusions The combination of linagliptin, metformin and lifestyle improved significantly glucose metabolism and pancreatic β-cell function, and reduced T2D incidence in subjects with prediabetes as compared to metformin and lifestyle.

  • High-resolution metabolomics study revealing L-homocysteine Sulfinic acid, Cysteic acid, and Carnitine as novel biomarkers for high acute myocardial infarction risk
    Metabolism (IF 6.513) Pub Date : 2019-12-24
    Adnan Khan; Yoonjeong Choi; Joung Hwan Back; Sunmi Lee; Sun Ha Jee; Youngja H. Park
  • Management of X-linked hypophosphatemia in adults
    Metabolism (IF 6.513) Pub Date : 2019-12-18
    Anne-Lise Lecoq; Maria Luisa Brandi; Agnès Linglart; Peter Kamenický

    X-linked hypophosphatemia (XLH) is caused by mutations in the PHEX gene which result in Fibroblast Growth Factor-23 (FGF23) excess and phosphate wasting. Clinically, XLH children present with rickets, bone deformities and short stature. In adulthood, patients may still be symptomatic with bone and joint pain, osteomalacia-related fractures or pseudofractures, precocious osteoarthrosis, entesopathy, muscle weakness and severe dental anomalies. Besides these musculoskeletal and dental manifestations, adult XLH patients are also prone to secondary and tertiary hyperparathyroidism, cardiovascular and metabolic disorders. Pathophysiology of hyperparathyroidism is only partially understood, ….. Similarly, the pathophysiological mechanisms of potential cardiovascular and metabolic involvements are not clear, but FGF-23 excess may play an essential role. Treatment should be considered in symptomatic patients, patients undergoing orthopedic or dental surgery and women during pregnancy and lactation. Treatment with oral phosphate salts and active vitamin D analogs has incomplete efficacy and potential risks. Burosumab, a recombinant human monoclonal antibody against FGF 23, has proven its efficacy in phase 2 and phase 3 clinical trials in adult patients with XLH, but currently its position as first line or second line treatment differ among the countries.

  • Reversibility of cerebral blood flow in patients with Cushing's disease after surgery treatment
    Metabolism (IF 6.513) Pub Date : 2019-12-18
    Hewei Cheng; Lu Gao; Bo Hou; Feng Feng; Xiaopeng Guo; Zihao Wang; Ming Feng; Bing Xing; Yong Fan

    Background and objectives Cushing's disease (CD) patients have metabolic abnormalities in the brain caused by excessive exposure to endogenous cortisol. However, the reversibility of brain metabolism of CD patients after treatment remains largely unknown. Methods This study recruited 50 CD patients seeking treatment and 34 matched normal controls (NCs). The patients were treated with Transsphenoidal Adenomectomy (TSA) and reexamined 3 months later. Cerebral blood flow (CBF) of the patients were assessed using 3D pseudo-continuous arterial spin labelling (PCASL) imaging before the treatment and at the 3-month follow-up and were compared with CBF measures of the NCs using a whole-brain voxelwise group comparison method. For remitted patients, their CBF measures and hormone level measures, including adrenocorticotropic hormone (ACTH), 24-h urinary free cortisol (24hUFC) and serum cortisol, were compared before and after the treatment. Finally, a correlation analysis was carried out to explore the relationship between changes of CBF and hormone level measures of the remitted CD patients. Results After the treatment, 45 patients reached remission. Compared with the NCs, the CD patients before the treatment exhibited significantly reduced CBF in cortical regions, including occipital lobe, parietal lobe, superior/middle/inferior temporal gyrus, superior/middle/inferior frontal gyrus, orbitofrontal cortex, precentral gyrus, middle/posterior cingulate gyrus, and rolandic operculum, as well as significantly increased CBF in subcortical structures, including caudate, pallidum, putamen, limbic lobe, parahippocampal gyrus, hippocampus, thalamus, and amygdala (p < .01, false discovery rate corrected). For the remitted patients, the change in CBF before and after the treatment displayed a spatial pattern similar to the difference between the NCs and the CD patients before the treatment, and no significant difference in CBF was observed between the NCs and the remitted CD patients after the treatment. The changes of 24hUFC were significantly correlated with the changes of averaged CBF within the subcortical region in the remitted patients (p = .01). Conclusions Our findings demonstrate that the brain metabolic abnormalities of CD patients are reversible when their hormone level changes towards normal after surgery treatment.

  • Inhibition of XBP1s ubiquitination enhances its protein stability and improves glucose homeostasis
    Metabolism (IF 6.513) Pub Date : 2019-12-16
    Honglin Sun; Gang Wei; He Liu; Danrui Xiao; Jianbo Huang; Junxi Lu; Ji Miao; Junli Liu; Suzhen Chen

    Background Hepatic ER stress is a risk factor of insulin resistance and type 2 diabetes. X-box binding protein 1 spliced (XBP1s), a transcription factor, plays a key role in ameliorating insulin resistance and maintaining glucose homeostasis. Unfortunately, the short half-life of the protein dampens its clinical application, and the specific site of lysine residue that could be ubiquitinated and involved in the degradation of XBP1s remains elusive. Methods and Results Here, we identified K60 and K77 on XBP1s as two pivotal ubiquitin sites required for its proteasome-dependent degradation. We also constructed a double mutant form of XBP1s (K60/77R) and found that it showed higher capacity in resisting against ubiquitin-mediated protein degradation, increasing nuclear translocation, enhancing transcriptional activity, suppressing ER stress and promoting Foxo1 degradation, compared to that of wild type XBP1s (WT). Consistently, overexpression of the K60/77R XBP1s mutant in DIO mice increased the ability to reduce ER stress and decrease Foxo1 levels, thus contributed to maintaining glucose homeostasis. Conclusion Our results suggest that delaying the degradation of XBP1s by preventing ubiquitination might provide a strategic approach for reducing ER stress as an anti-diabetes therapy.

  • Angiotensin-(1-7) induces beige fat thermogenesis through the Mas receptor
    Metabolism (IF 6.513) Pub Date : 2019-12-13
    Ariana Vargas-Castillo; Sandra Tobon-Cornejo; Leonardo Del Valle-Mondragon; Ivan Torre-Villalvazo; Alejandro Schcolnik-Cabrera; Martha Guevara-Cruz; Edgar Pichardo-Ontiveros; Rebeca Fuentes-Romero; Michael Bader; Natalia Alenina; Antonio Vidal-Puig; Enrique Hong; Nimbe Torres; Armando R. Tovar
  • Perinatal programming of metabolic diseases: the role of glucocorticoids
    Metabolism (IF 6.513) Pub Date : 2019-12-11
    Júlia Cristina Facchi, Thalyne Aparecida Leite de Lima, Lucas Ryba de Oliveira, Hercules de Oliveira Costermani, Ginislene Dias de Souza Miranda, Júlio Cezar de Oliveira

    The worldwide increase in metabolic diseases has urged the scientific community to improve our understanding about the mechanisms underlying its cause and effects. A well supported area of studies had related maternal stress with early programming to the later metabolic diseases. Mechanisms upon origins of metabolic disturbances are not yet fully understood, even though stressful factors rising glucocorticoids have been put out as pivotal trigger by programming metabolic diseases as long-term consequence. Considering energy balance and glucose homeostasis, by producing and/or sensing regulator signals, hypothalamus-pituitary-adrenal axis and endocrine pancreas are directly affected by glucocorticoids excess. We focus on the evidences reporting the role of increased glucocorticoids due to perinatal insults on the physiological systems involved in the metabolic homeostasis and in the target organs such as endocrine pancreas, white adipose tissue and blood vessels. Besides, we review some mechanisms underlining the malprogramming of type 2 diabetes, obesity and hypertension. Studies on this field are currently ongoing and even there is a good understanding regarding the effects of glucocorticoids addressing metabolic diseases, few is known about the relationship between maternal insults rising glucocorticoids to pups’ metabolic disturbances, a thorough understanding about that may provide pivotal clinical clues regarding those disorders.

  • Differential indication for SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with established atherosclerotic heart disease or at risk for congestive heart failure
    Metabolism (IF 6.513) Pub Date : 2019-12-07
    Francesco Giorgino, Irene Caruso, Julia Moellmann, Michael Lehrke

    SGLT-2 inhibitors and most GLP-1 receptor agonists demonstrated cardiovascular superiority and reduction of cardiovascular and overall mortality. These results stand as a turning point in the management of diabetes, shifting the focus from controlling glucose levels to mastering the extra-glycemic effects of these new drugs. This narrative review will discuss recent CVOT with focus on SGLT-2 inhibitors and GLP-1 receptor agonists to distinguish relevant patients' characteristics as potential predictors for therapeutic efficacy. It will also examine their efficacy and safety, the differences in their cardiovascular and renal benefits, aiming to convey clinical suggestions for everyday practice.

  • Long acting GLP-1 analog liraglutide ameliorates skeletal muscle atrophy in rodents
    Metabolism (IF 6.513) Pub Date : 2019-12-05
    Anagha Ashok Gurjar, Sapana Kushwaha, Sourav Chattopadhyay, Nabanita Das, Subhashis Pal, Shyamsundar Pal China, Harish Kumar, Arun Kumar Trivedi, Rajdeep Guha, Naibedya Chattopadhyay, Sabyasachi Sanyal

    Background Skeletal muscle atrophy is characterized by muscle wasting with partial or complete functional loss. Skeletal muscle atrophy severely affects the quality of life and currently, there is no available therapy except for spinal muscular atrophy. Objective Drug repositioning is a promising strategy that reduces cost and time due to prior availability of safety and toxicity details. Here we investigated myogenic and anti-atrophy effects of glucagon-like peptide-1 (GLP-1) analog liraglutide. Methods We used several in vitro atrophy models in C2C12 cells and in vivo models in Sprague Dawley rats to study Liraglutide's efficacy. QPCR and western blotting were used to assess cAMP-dependent signaling pathways specifically activated by liraglutide. Therapeutic efficacy of liraglutide was investigated by histological analysis of transverse muscle sections followed by morphometry. Myogenic capacity was investigated by immunostaining for myogenic factors. Results Liraglutide induced myogenesis in C2C12 myoblasts through GLP-1 receptor via a cAMP-dependent complex network of signaling events involving protein kinase A, phosphoinositide 3-kinase/protein kinase B, p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. Liraglutide imparted protection against freeze injury, denervation, and dexamethasone -induced skeletal muscle atrophy and improved muscular function in all these models. In a therapeutic mode, liraglutide restored myofibrillar architecture in ovariectomy-induced atrophy. Anti-atrophy actions of liraglutide involved suppression of atrogene expression and enhancement in expression of myogenic factors. Conclusion Liraglutide imparted protection and restored myofybrillar architecture in diverse models of muscle atrophy. Given its potent anti-atrophy, and recently reported osteoanabolic effects, we propose liraglutide's clinical evaluation in skeletal muscle atrophy and musculoskeletal disorders associated with diverse pathologies.

  • Moderate intensity exercise training combined with inulin-propionate ester supplementation increases whole body resting fat oxidation in overweight women
    Metabolism (IF 6.513) Pub Date : 2019-11-29
    Dalia Malkova, Thelma Polyviou, Eleni Rizou, Konstantinos Gerasimidis, Edward S. Chambers, Tom Preston, Catriona M. Tedford, Gary Frost, Douglas J. Morrison

    Background Our previous work has shown that oral supplementation with inulin propionate ester (IPE) reduces intra-abdominal fat and prevents weight gain and that oral propionate intake enhances resting fat oxidation. The effects of IPE combined with exercise training on energy substrate utilisation are unknown. The aim of this study was to investigate the impact of 4-weeks IPE supplementation, in combination with a moderate intensity exercise training programme, on whole body fat oxidation and on plasma GLP-1 and PYY. Methods Twenty overweight healthy women participated in randomised parallel study and underwent 4 weeks of supervised exercise training either with IPE (EX/IPE group) or Placebo (EX/Placebo group) supplementation. Before and after the intervention participants conducted an experimental trial, which involved collection of expired gas and blood samples in the fasted state and during 7 h of the postprandial state. Results Within groups, the EX/IPE group significantly enhanced the amount of fat (Pre, 24.1 ± 1.2 g; Post, 35.9 ± 4.0 g, P < .05) oxidised and reduced CHO (Pre, 77.8 ± 6.0 g; Post, 57.8 ± 7.7 g, P < .05) oxidised, reduced body weight (Pre, 77.3 ± 4.2 kg; Post, 76.6 ± 4.1 kg, P < .05) and body fat mass (Pre, 37.7 ± 1.9%; Post, 36.9 ± 1.9%, P < .05). In EX/Placebo group, changes in amount of fat (Pre, 36.8 ± 3.9 g; Post, 37.0 ± 4.0 g) and CHO (Pre, 62.7 ± 6.5 g; Post, 61.5 ± 7.4 g) oxidised, body weight (Pre, 84.2 ± 4.3 kg; Post, 83.6 ± 4.3 kg) and body fat mass (Pre, 40.1 ± 1.9%; Post, 38.7 ± 1.5%) were not significant (P > .05). Comparing between groups, changes in the amount of fat oxidised were significantly (P < .05) different and a trend for difference was observed for amount of CHO oxidised (P = .06) and RER (P = .06). The interventions had no impact on fasting or postprandial plasma concentrations of GLP-1 and PYY. Conclusion Moderate intensity exercise training programmes when combined with daily oral IPE supplementation may help overweight women to achieve increase in fat oxidation. The study was registered at clinicaltrials.gov as NCT04016350.

  • Serum endotoxin, gut permeability and skeletal muscle metabolic adaptations following a short term High Fat Diet in humans
    Metabolism (IF 6.513) Pub Date : 2019-11-28
    Suzanne M. Bowser, Ryan P. McMillan, Nabil E. Boutagy, Michael D. Tarpey, Andrew T. Smithson, Kristin L. Osterberg, Andrew P. Neilson, Brenda M. Davy, Kevin P. Davy, Matthew W. Hulver

    Background Our previous work demonstrated that a short-term high fat diet (HFD) increased fasting serum endotoxin, and altered postprandial excursions of serum endotoxin, and led to metabolic and transcriptional responses in skeletal muscle in young, healthy male humans. Purpose The purpose of the present study was to determine if a short-term high fat diet: 1) increases intestinal permeability and, in turn, fasting endotoxin concentrations and 2) decreases postprandial skeletal muscle fat oxidation. Methods Thirteen normal weight young adult males (BMI 23.1 ± 0.8 kg/m2, age 22.2 ± 0.4 years) were fed a control diet (55% carbohydrate, 30% fat, 9% of which was saturated, 15% protein) for two weeks, followed by 5 days of an isocaloric HFD (30% carbohydrate, 55% fat, 25% of which was saturated, 15% protein, isocaloric to the control diet). Intestinal permeability (via four sugar probe test) was assessed in the fasting state. Both before and after the HFD, a high fat meal challenge (HFM, 820 kcal, 25% carbohydrate, 63% fat, 26% of which was saturated, and 12% protein) was administered. After an overnight fast, blood samples were collected before and every hour for four hours after the HFM to assess endotoxin, and other serum blood measures. Muscle biopsies were obtained from the vastus lateralis before and four hours after the HFM in order to assess substrate oxidation (glucose, fatty acid and pyruvate) using radiolabeled techniques. Insulin sensitivity was assessed via intravenous glucose tolerance test. Intestinal permeability, blood samples and muscle biopsies were assessed in the same manner before and following the HFD. Main Findings. Intestinal permeability was not affected by HFD (p > .05), but fasting endotoxin increased two fold following the HFD (p = .04). Glucose oxidation and fatty acid oxidation in skeletal muscle homogenates significantly increased after the HFM before the HFD (+97%, and + 106% respectively) but declined after the HFM following 5 days of the HFD (−24% and + 16% respectively). Fatty acid suppressibility of pyruvate oxidation increased significantly after the HFM (+32%) but this physiological effect was abolished following 5 days of the HFD (+7%). Insulin sensitivity did not change following the HFD. Conclusion These findings demonstrate that in healthy young men, consuming an isocaloric HFD for 5 days increases fasting endotoxin, independent of changes in gut permeability. These changes in endotoxin are accompanied by a broad effect on skeletal muscle substrate metabolism including increases in postprandial fat oxidation. Importantly, the latter occurs independent of changes in body weight and whole-body insulin sensitivity.

  • Bile acids associate with glucose metabolism, but do not predict conversion from impaired fasting glucose to diabetes
    Metabolism (IF 6.513) Pub Date : 2019-11-27
    Oscar Chávez-Talavera, Matthieu Wargny, Matthieu Pichelin, Amandine Descat, Emmanuelle Vallez, Mostafa Kouach, Edith Bigot-Corbel, Marielle Joliveau, Jean-Francois Goossens, Cédric Le May, Samy Hadjadj, Rémy Hanf, Anne Tailleux, Bart Staels, Bertrand Cariou

    Objective Bile acids (BAs) are signaling molecules controlling lipid and glucose metabolism. Since BA alterations are associated with obesity and insulin resistance, plasma BAs have been considered candidates to predict type 2 diabetes (T2D) risk. We aimed to determine (1) the association of BAs with glucose homeostasis parameters and (2) their predictive association with the risk of conversion from prediabetes to new-onset diabetes (NOD) in a prospective cohort study. Design 205 patients with impaired fasting glucose (IFG) were followed each year during 5 years in the IT-DIAB cohort study. Twenty-one BA species and 7α-hydroxy-4-cholesten-3-one (C4), a marker of BA synthesis, were quantified by LC/MS-MS in plasma from fasted patients at baseline. Correlations between plasma BA species and metabolic parameters at baseline were assessed by Spearman's analyses and the association between BAs and NOD was determined using Cox proportional hazards models. Results Among the analyzed BA species, total hyocholic acid (HCA) and the total HCA/total chenodeoxycholic acid (CDCA) ratio, reflecting hepatic BA 6α-hydroxylation activity, negatively correlated with BMI and HOMA-IR. The total HCA/total CDCA ratio also correlated negatively with HbA1C. Conversion from IFG to NOD occurred in 33.7% of the participants during the follow-up. Plasma BA species were not independently associated with the conversion to NOD after adjustment with classical T2D risk factors. Conclusions Fasting plasma BAs are not useful clinical biomarkers for predicting NOD in patients with IFG. However, an unexpected association between 6α-hydroxylated BAs and glucose parameters was found, suggesting a role for this specific BA pathway in metabolic homeostasis. IT-DIAB study registry number NCT01218061.

  • Acute hypoxia reduces exogenous glucose oxidation, glucose turnover, and metabolic clearance rate during steady-state aerobic exercise
    Metabolism (IF 6.513) Pub Date : 2019-11-26
    Lee M. Margolis, Marques A. Wilson, Claire C. Whitney, Christopher T. Carrigan, Nancy E. Murphy, Patrick N. Radcliffe, Jess A. Gwin, David D. Church, Robert R. Wolfe, Arny A. Ferrando, Andrew J. Young, Stefan M. Pasiakos

    Background Exogenous carbohydrate oxidation is lower during steady-state aerobic exercise in native lowlanders sojourning at high altitude (HA) compared to sea level (SL). However, the underlying mechanism contributing to reduction in exogenous carbohydrate oxidation during steady-state aerobic exercise performed at HA have not been explored. Objective To determine if alterations in glucose rate of appearance (Ra), disappearance (Rd) and metabolic clearance rate (MCR) at HA provide a mechanism for explaining the observation of lower exogenous carbohydrate oxidation compared to during metabolically-matched, steady-state exercise at SL. Methods Using a randomized, crossover design, native lowlanders (n = 8 males, mean ± SD, age: 23 ± 2 yr, body mass: 87 ± 10 kg, and VO2peak: SL 4.3 ± 0.2 L/min and HA 2.9 ± 0.2 L/min) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically-matched (SL: 1.66 ± 0.14 V̇O2 L/min 329 ± 28 kcal, HA: 1.59 ± 0.10 V̇O2 L/min, 320 ± 19 kcal) treadmill exercise in SL (757 mmHg) and HA (460 mmHg) conditions after a 5-h exposure. Substrate oxidation rates (g/min) and glucose turnover (mg/kg/min) during exercise were determined using indirect calorimetry and dual tracer technique (13C-glucose oral ingestion and [6,6-2H2]-glucose primed, continuous infusion). Results Total carbohydrate oxidation was higher (P < .05) at HA (2.15 ± 0.32) compared to SL (1.39 ± 0.14). Exogenous glucose oxidation rate was lower (P < .05) at HA (0.35 ± 0.07) than SL (0.44 ± 0.05). Muscle glycogen oxidation was higher at HA (1.67 ± 0.26) compared to SL (0.83 ± 0.13). Total glucose Ra was lower (P < .05) at HA (12.3 ± 1.5) compared to SL (13.8 ± 2.0). Exogenous glucose Ra was lower (P < .05) at HA (8.9 ± 1.3) compared to SL (10.9 ± 2.2). Glucose Rd was lower (P < .05) at HA (12.7 ± 1.7) compared to SL (14.3 ± 2.0). MCR was lower (P < .05) at HA (9.0 ± 1.8) compared to SL (12.1 ± 2.3). Circulating glucose and insulin concentrations were higher in response carbohydrate intake during exercise at HA compared to SL. Conclusion Novel results from this investigation suggest that reductions in exogenous carbohydrate oxidation at HA may be multifactorial; however, the apparent insensitivity of peripheral tissue to glucose uptake may be a primary determinate.

  • The Adiponectin receptor agonist AdipoRon normalizes glucose metabolism and prevents obesity but not growth retardation induced by glucocorticoids in young mice
    Metabolism (IF 6.513) Pub Date : 2019-11-26
    Sarah Nicolas, Nathalie Rochet, Nadine Gautier, Joëlle Chabry, Didier Pisani

    Objective Glucocorticoids (GCs) are highly effective anti-inflammatory and immunosuppressive drugs. However, prolonged GC therapy may cause numerous adverse effects leading to diabetes and obesity, as well as bone disorders such as osteoporosis in adults and growth retardation in children and adolescents. Prevention and care of the GC-induced adverse effects remain challenging. We have previously demonstrated the efficacy of a treatment with a non-peptidic agonist of adiponectin receptors, AdipoRon, to reverse behaviour disorders and fat mass gain induced by long-term GC treatment. In this work, we have established a relevant model of GC-induced growth and metabolic disorders and determined that AdipoRon is a potential therapeutic tool to reverse these metabolic disturbances. Methods 5-week-old mice were treated continuously with or without corticosterone (35 mg/L) in drinking water for seven consecutive weeks. Taking advantage of this mouse model displaying various growth and metabolic disorders, we assayed whether AdipoRon (daily intraperitoneal injection of 1 mg/kg/day for the last 20 days) might prevent the GC-induced adverse effects. The control group was treated with vehicle only. Nutritional behaviors and metabolic parameters were followed-up throughout the treatment. Serum insulin and leptin levels were measured by ELISA. Computed tomography and histological analysis of adipose tissue were assessed at the end of the experimental procedure. Results We found that GC treatment in young mice resulted in continuously increased body weight gain associated with a food intake increase. Compared to vehicle-, GC-treated mice displayed early major hyperleptinemia (up to 6-fold more) and hyperinsulinemia (up to 20-fold more) maintained throughout the treatment. At the end of the experimental procedure, GC-treated mice displayed bone growth retardation (e.g. femur length 15.1 versus 14.0mm, P< 0.01), higher abdominal adipose tissue volume (4.1 versus 2.3, P< 0.01) and altered glucose metabolism compared to control mice. Interestingly, AdipoRon prevented GC-induced effects on energy metabolism such as abdominal adiposity, insulinemia and leptinemia. However, AdipoRon failed to counteract bone growth retardation. Conclusion We characterized the very early pathological steps induced by long-term GC in young mice in a relevant model, including growth retardation, fat mass gain and glucose homeostasis dysregulation. The adiponectin system stimulation enabled normalization of the adipose tissue and metabolic features of GC-treated mice. Adiponectin receptor agonists such as AdipoRon might constitute a novel way to counteract some GC-induced adverse effects.

  • Low levels of total and high-molecular-weight adiponectin may predict non-alcoholic fatty liver in Korean adults
    Metabolism (IF 6.513) Pub Date : 2019-11-23
    Young-Sang Kim, Soo-Hyun Lee, Seung Geon Park, Bo Youn Won, Hyejin Chun, Doo-Yeoun Cho, Moon-Jong Kim, Ji Eun Lee, Ji-Hee Haam, Kunhee Han

    Objectives While weight gain is known as a predictor of non-alcoholic fatty liver disease (NAFLD) incidence, it remains controversial whether adipokine levels predict the development of NAFLD. We aimed to investigate the relationship of total adiponectin, high-molecular-weight (HMW) adiponectin, and leptin with the development and improvement of non-alcoholic fatty liver (NAFL) independent of sex and weight change over a maximum of 8.5 years. Methods This prospective study enrolled 2735 participants in a hospital health check-up setting. Adipokine levels were measured at baseline. NAFL was assessed with liver ultrasonography, and the development or improvement of NAFL was determined by repeated ultrasonography at follow-ups. Results Cross-sectional analyses revealed that total and HMW adiponectin levels were inversely associated with NAFL prevalence. In longitudinal analyses, the incidence of NAFL was 5.6 per 100-person-years during the observation period. The hazard ratios (HRs) per 1 μg/mL increase in the levels of total and HMW adiponectin were 0.900 (0.836–0.969) and 0.846 (0.754–0.948), respectively. Sex-stratified analyses showed that total and HMW adiponectin levels were significantly related to NAFL incidence only in women. In the subgroup of minimal weight change, only HMW adiponectin was a significant predictor for NAFL. Leptin predicted NAFL in the subgroup with weight gain. The improvement of NAFL was influenced by weight change, but not by adipokine levels. Conclusions Low levels of total and HMW adiponectin may predict the development of NAFL independent of pathophysiological factors including obesity and insulin resistance. This predictability was evident in women. Leptin was a significant predictor for NAFL in the subjects with weight gain.

  • Central Sfrp5 regulates hepatic glucose flux and VLDL- triglyceride secretion
    Metabolism (IF 6.513) Pub Date : 2019-11-23
    Yang Li, Mingyuan Tian, Mengliu Yang, Gangyi Yang, Jianrong Chen, Han Wang, Dongfang Liu, Hongyan Wang, Wuquan Deng, Zhiming Zhu, Hongting Zheng, Ling Li

    Objective Secreted frizzled-related protein 5 (Sfrp5) has been shown to be associated with energy homeostasis and insulin resistance in mouse models of obesity and diabetes. However, its central role in glucose and lipid metabolism is unknown. Methods HFD-fed rats received ICV infusions of vehicle or Sfrp5 during a pancreatic euglycemic clamp procedure. To delineate the pathway(s) by which ICV Sfrp5 modulates HGP and VLDL-TG secretion, we inhibited the hypothalamic KATP channel using glibenclamide, the DVC NMDA receptor with MK801, and selectively transected the hepatic branch of the vagal nerve while centrally infusing Sfrp5. Results ICV Sfrp5 in HFD-fed rats significantly increased the glucose infusion required to maintain euglycemia due to HGP inhibition during the clamp procedure; moreover, hepatic PEPCK and G6Pase expression was decreased, and InsR and Akt phosphorylation was increased in the liver. ICV Sfrp5 also decreased circulating triglyceride levels via inhibiting hepatic VLDL-TG secretion. These changes were accompanied by the inhibition of enzymes related to lipogenesis in the liver. ICV Sfrp5 significantly increased insulin-stimulated phosphorylation of InsR and Akt in the hypothalamus of HFD-fed rats, and insulin-stimulated immunodetectable PIP3 levels were higher in Sfrp5 group than in control group both in vitro and vivo. The glucose- and lipid-lowering effects of ICV Sfrp5 were eliminated by NMDA receptor or DVC KATP channel inhibition or HVAG. Conclusions The present study demonstrates that central Sfrp5 signaling activates a previously unappreciated InsR-Akt-PI3k-KATP channel pathway in the hypothalamus and brain-hepatic vagus neurocircuitry to decrease HGP and VLDL-TG secretion.

  • Irradiation impairs mitochondrial function and skeletal muscle oxidative capacity: significance for metabolic complications in cancer survivors
    Metabolism (IF 6.513) Pub Date : 2019-11-22
    Nadia Amorim, Anthony Kee, Adelle C.F. Coster, Christine Lucas, Sarah Bould, Sara Daniel, Jacquelyn M. Weir, Natalie A. Mellett, Jayne Barbour, Peter J. Meikle, Richard J. Cohn, Nigel Turner, Edna C. Hardeman, David Simar

    Background Metabolic complications are highly prevalent in cancer survivors treated with irradiation but the underlying mechanisms remain unknown. Methods Chow or high fat-fed C57Bl/6 J mice were irradiated (6Gy) before investigating the impact on whole-body or skeletal muscle metabolism and profiling their lipidomic signature. Using a transgenic mouse model (Tg:Pax7-nGFP), we isolated muscle progenitor cells (satellite cells) and characterised their metabolic functions. We recruited childhood cancer survivors, grouped them based on the use of total body irradiation during their treatment and established their lipidomic profile. Results In mice, irradiation delayed body weight gain and impaired fat pads and muscle weights. These changes were associated with impaired whole-body fat oxidation in chow-fed mice and altered ex vivo skeletal muscle fatty acid oxidation, potentially due to a reduction in oxidative fibres and reduced mitochondrial enzyme activity. Irradiation led to fasting hyperglycaemia and impaired glucose uptake in isolated skeletal muscles. Cultured satellite cells from irradiated mice showed decreased fatty acid oxidation and reduced glucose uptake, recapitulating the host metabolic phenotype. Irradiation resulted in a remodelling of lipid species in skeletal muscles, with the extensor digitorum longus muscle being particularly affected. A large number of lipid species were reduced, with several of these species showing a positive correlation with mitochondrial enzymes activity. In cancer survivors exposed to irradiation, we found a similar decrease in systemic levels of most lipid species, and lipid species that increased were positively correlated with insulin resistance (HOMA-IR). Conclusion Irradiation leads to long-term alterations in body composition, and lipid and carbohydrate metabolism in skeletal muscle, and affects muscle progenitor cells. Such changes result in persistent impairment of metabolic functions, providing a new mechanism for the increased prevalence of metabolic diseases reported in irradiated individuals. In this context, changes in the lipidomic signature in response to irradiation could be of diagnostic value.

  • Curcumin analog CUR5–8 ameliorates nonalcoholic fatty liver disease in mice with high-fat diet-induced obesity
    Metabolism (IF 6.513) Pub Date : 2019-11-20
    Eun Soo Lee, Mi-Hye Kwon, Hong Min Kim, Ho Bum Woo, Chan Mug Ahn, Choon Hee Chung

    Objective Nonalcoholic fatty liver disease (NAFLD) occurs when excess fat storage in the liver and it is strongly linked with metabolic syndrome including obesity, insulin resistance, dyslipidemia and hypertension. Curcumin5–8 (CUR5–8) is a synthetic derivative of naturally active curcumin (CUR) that has anti-oxidative and anti-inflammatory properties. In the present study, we investigated the effects of CUR5–8, a novel CUR analog, on hepatic steatosis in mice with high-fat diet (HFD)-induced obesity. Methods Based on their diets for 13 weeks, the mice were categorized into the following six groups: regular diet (RD, n = 10), RD with CUR (RD + CUR, 100 mg/kg/day, n = 10), RD with CUR5–8 (RD + CUR5–8, 100 mg/kg/day, n = 10), high-fat diet-induced obese mice (HFD, n = 10), HFD with CUR (HFD + CUR, 100 mg/kg/day, n = 10), and HFD with CUR5–8 (HFD + CUR5–8, 100 mg/kg/day, n = 10) for 13 weeks.). Hematoxylin and eosin (H&E) staining of the sections revealed hepatic steatosis. Results CUR5–8 administration prevented increase in body and liver weights in mice with HFD-induced obesity. Compared to the HFD group, insulin resistance was significantly improved in the HFD + CUR5–8 group. Serum alanine aminotransferase level, which is an indicator of liver damage, was also decreased after CUR5–8 administration. H&E staining revealed that CUR5–8 treatment decreased hepatic steatosis in mice with HFD-induced obesity. Interestingly, CUR5–8, and not CUR, decreased the elevated liver triglyceride level induced by the HFD. Conclusions These findings suggest that CUR5–8 ameliorates insulin resistance and hepatic steatosis in mice with HFD-induced obesity.

  • The homeobox factor Irx3 maintains adipogenic identity
    Metabolism (IF 6.513) Pub Date : 2019-11-18
    Jan-Inge Bjune, Laurence Dyer, Gro V. Røsland, Karl Johan Tronstad, Pål R. Njølstad, Jørn V. Sagen, Simon N. Dankel, Gunnar Mellgren

    Background Inhibition of Irx3 and Irx5 has been shown to reduce body weight and white adipose tissue (WAT) mass through cell-autonomous and sympathetic-induced increases in adipocyte beiging and thermogenesis in mice and humans. However, the underlying mechanisms of the Irx control over beiging are still largely unknown, as illustrated by recent reports showing divergent effects of Irx3 on adipocyte metabolism and function. Here, we investigated the role of Irx3 in controlling beige preadipocyte function and differentiation. Methods Stable knock out of Irx3 in ME3 mouse preadipocytes capable of beiging was performed using a CRISPR-Cas9 system, and the effect on cell differentiation was assessed by oil-red-O lipid staining, qPCR and RNA-seq. Changes in cell identities were validated using cell type enrichment analysis from RNA-seq data. Proliferation and cell cycle progression in undifferentiated cells was measured by WST-1 and flow cytometry, reactive oxygen species (ROS) generation was determined by fluorescence spectrometry and mitochondrial respiration was investigated by Seahorse assay. Results Irx3 was found to be essential for the identity, function and adipogenic differentiation of beige adipocyte precursors. Irx3-KO impaired proliferation, ROS generation and mitochondrial respiration in the preadipocytes. We further observed profound changes in numerous genes during both early and late stages of adipogenic differentiation, including genes important for cell cycle progression, oxidative phosphorylation (OXPHOS) and morphogenesis. Cell enrichment analysis revealed a loss of mesenchymal/embryonic fibroblast identity and a gain of chondrocyte-like identity in Irx3-KO cells during early differentiation. Conclusions Irx3 is required for preadipocyte identity and differentiation capacity. Our findings suggest that, while inhibition of Irx3 may be beneficial during later developmental stages to modulate adipogenesis in the beige direction, constitutive and complete absence of Irx3 in the embryonic fibroblast stage leads to detrimental loss of adipogenic differentiation capacity.

  • Deletion of Smad3 prevents renal fibrosis and inflammation in type 2 diabetic nephropathy
    Metabolism (IF 6.513) Pub Date : 2019-11-15
    Bi-Hua Xu, Jingyi Sheng, Yong-Ke You, Xiao-Ru Huang, Ronald C.W. Ma, Qingwen Wang, Hui-Yao Lan

    Background Transforming growth factor (TGF)-β/Smad3 signaling is highly activated in kidneys of patients with type 2 diabetic nephropathy (T2DN), however, the precise role of Smad3 in the pathogenesis of diabetic nephropathy remains unclear. Methods Smad3 knockout (KO)-db/db mice were generated by intercrossing of male and female double-heterozygous Smad3+/− db/m mice. Renal functions including urinary albumin excretion and serum creatinine were determined. Renal histological injury including renal fibrosis and inflammation were examined by periodic acid Schiff (PAS), periodic acid‑silver methenamine (PASM), and immunohistochemistry (IHC) staining. Results Smad3 knockout (KO)-db/db mice were protected from the development of diabetic kidney injury, characterized by the normal levels of urinary albumin excretion and serum creatinine without any evidence for renal fibrosis and inflammation. In contrast, Smad3 wild-type (WT) db/db and Smad3+/− db/db mice developed progressively decline in renal function over the 12 to 32-week time course, including increased microalbuminuria and elevated levels of serum creatinine. Pathologically, Smad3 WT db/db and Smad3+/− db/db mice exhibited a marked deposition of collagen-I (colI), collagen-IV(col-IV), and an increased infiltration of F4/80+ macrophages in kidney. Mechanistically, Smad3 deficiency decreased the lncRNA Erbb4-IR transcription, while increased miR-29b transcription and therefore protected the kidney from progressive renal injury in db/db mice. Conclusion Results from this study imply that Smad3 may represent as a novel and effective therapeutic target for T2DN.

  • Effects of preeclampsia and eclampsia on maternal metabolic and biochemical outcomes in later life: a systematic review and meta-analysis
    Metabolism (IF 6.513) Pub Date : 2019-11-15
    Vanesa Alonso-Ventura, Yangzhou Li, Vinay Pasupuleti, Yuani M. Roman, Adrian V. Hernandez, Faustino R. Pérez-López

    Objective To evaluate the association between preeclampsia (PE) and eclampsia (E) on subsequent metabolic and biochemical outcomes. Methods Systematic review and meta-analysis of observational studies. We searched five engines until November 2018 for studies evaluating the effects of PE/E on metabolic and biochemical outcomes after delivery. PE was defined as presence of hypertension and proteinuria at >20 weeks of pregnancy; controls did not have PE/E. Primary outcomes were blood pressure (BP), body mass index (BMI), metabolic syndrome (MetS), blood lipids and glucose levels. Random effects models were used for meta-analyses, and effects reported as risk difference (RD) or mean difference (MD) and their 95% confidence interval (CI). Subgroup analyses by time of follow up, publication year, and confounder adjustment were performed. Results We evaluated 41 cohorts including 3300 PE/E and 13,967 normotensive controls. Women were followed up from 3 months after delivery up to 32 years postpartum. In comparison to controls, PE/E significantly increased systolic BP (MD = 8.3 mmHg, 95%CI 6.8 to 9.7), diastolic BP (MD = 6.8 mmHg, 95%CI 5.6 to 8.0), BMI (MD = 2.0 kg/m2; 95%CI 1.6 to 2.4), waist (MD = 4.3 cm, 95%CI 3.1 to 5.5), waist-to-hip ratio (MD = 0.02, 95%CI 0.01 to 0.03), weight (MD = 5.1 kg, 95%CI 2.2 to 7.9), total cholesterol (MD = 4.6 mg/dL, CI 1.5 to 7.7), LDL (MD = 4.6 mg/dL; 95%CI 0.2 to 8.9), triglycerides (MD = 7.7 mg/dL, 95%CI 3.6 to 11.7), glucose (MD = 2.6 mg/dL, 95%CI 1.2 to 4.0), insulin (MD = 19.1 pmol/L, 95%CI 11.9 to 26.2), HOMA-IR index (MD = 0.7, 95%CI 0.2 to 1.2), C reactive protein (MD = 0.05 mg/dL, 95%CI 0.01 to 0.09), and the risks of hypertension (RD = 0.24, 95%CI 0.15 to 0.33) and MetS (RD = 0.11, 95%CI 0.08 to 0.15). Also, PE/E reduced HDL levels (MD = –2.15 mg/dL, 95%CI –3.46 to −0.85). Heterogeneity of effects was high for most outcomes. Risk of bias was moderate across studies. Subgroup analyses showed similar effects as main analyses. Conclusion Women who had PE/E have worse metabolic and biochemical profile than those without PE/E in an intermediate to long term follow up period.

  • Non-invasive diagnosis of non-alcoholic steatohepatitis and fibrosis with the use of omics and supervised learning: a proof of concept study
    Metabolism (IF 6.513) Pub Date : 2019-11-09
    Nikolaos Perakakis, Stergios A. Polyzos, Alireza Yazdani, Aleix Sala-Vila, Jannis Kountouras, Athanasios D. Anastasilakis, Christos S. Mantzoros

    Background Non-alcoholic fatty liver disease (NAFLD) affects 25–30% of the general population and is characterized by the presence of non-alcoholic fatty liver (NAFL) that can progress to non-alcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis leading to hepatocellular carcinoma. To date, liver biopsy is the gold standard for the diagnosis of NASH and for staging liver fibrosis. This study aimed to train models for the non-invasive diagnosis of NASH and liver fibrosis based on measurements of lipids, glycans and biochemical parameters in peripheral blood and with the use of different machine learning methods. Methods We performed a lipidomic, glycomic and free fatty acid analysis in serum samples of 49 healthy subjects and 31 patients with biopsy-proven NAFLD (15 with NAFL and 16 with NASH). The data from the above measurements combined with measurements of 4 hormonal parameters were analyzed with two different platforms and five different machine learning tools. Results 365 lipids, 61 glycans and 23 fatty acids were identified with mass-spectrometry and liquid chromatography. Robust differences in the concentrations of specific lipid species were observed between healthy, NAFL and NASH subjects. One-vs-Rest (OvR) support vector machine (SVM) models with recursive feature elimination (RFE) including 29 lipids or combining lipids with glycans and/or hormones (20 or 10 variables total) could differentiate with very high accuracy (up to 90%) between the three conditions. In an exploratory analysis, a model consisting of 10 lipid species could robustly discriminate between the presence of liver fibrosis or not (98% accuracy). Conclusion We propose novel models utilizing lipids, hormones and glycans that can diagnose with high accuracy the presence of NASH, NAFL or healthy status. Additionally, we report a combination of lipids that can diagnose the presence of liver fibrosis. Both models should be further trained prospectively and validated in large independent cohorts.

  • Diagnosis, treatment-monitoring and follow-up of children and adolescents with X-linked hypophosphatemia (XLH)
    Metabolism (IF 6.513) Pub Date : 2019-03-27
    Anya Rothenbuhler, Dirk Schnabel, Wolfgang Högler, Agnes Linglart

    Early diagnosis, optimal therapeutic management and regular follow up of children with X-linked hypophosphatemia (XLH) determine their long term outcomes and future quality of life. Biochemical screening of potentially affected newborns in familial cases and improving physician's knowledge on clinical signs, symptoms and biochemical characteristics of XLH for de novo cases should lead to earlier diagnosis and treatment initiation. The follow-up of children with XLH includes clinical, biochemical and radiological monitoring of treatment (efficacy and complications) and screening for XLH-related dental, neurosurgical, rheumatological, cardiovascular, renal and ENT complications. In 2018, the European Union approved the use of burosumab, a humanized monoclonal anti-FGF23 antibody, as an alternative therapy to conventional therapy (active vitamin D analogues and phosphate supplements) in growing children with XLH and insufficiently controlled disease. Diagnostic criteria of XLH and the principles of disease management with conventional treatment or with burosumab are reviewed in this paper.

  • Physiology of FGF23 and overview of genetic diseases associated with renal phosphate wasting
    Metabolism (IF 6.513) Pub Date : 2019-01-19
    Justine Bacchetta, Claire Bardet, Dominique Prié

    Phosphate is a cornerstone of several physiological pathways including skeletal development, bone mineralization, membrane composition, nucleotide structure, maintenance of plasma pH, and cellular signaling. The kidneys have a key role in phosphate homeostasis with three hormones having important functions in renal phosphate handling or intestinal absorption: parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1–25-dihydroxyvitamin D (1,25(OH)2D). FGF23 is mainly synthesized by osteocytes; it is a direct phosphaturic factor that also inhibits 1,25(OH)2D and PTH. In addition to crucial effects on phosphate and calcium metabolism, FGF23 also has ‘off-target’ effects notably on the cardiovascular, immune and central nervous systems. Genetic diseases may affect the FGF23 pathway, resulting in either increased FGF23 levels leading to hypophosphatemia (such as in X-linked hypophosphatemia) or defective secretion/action of intact FGF23 inducing hyperphosphatemia (such as in familial tumoral calcinosis). The aim of this review is to provide an overview of FGF23 physiology and pathophysiology in X-linked hypophosphatemia, with a focus on FGF23-associated genetic diseases.

  • LSD1 mediates microbial metabolite butyrate-induced thermogenesis in brown and white adipose tissue
    Metabolism (IF 6.513) Pub Date : 2019-11-15
    Dan Wang, Chu-Dan Liu, Hong-Fei Li, Meng-Li Tian, Jia-Qiang Pan, Gang Shu, Qing-Yan Jiang, Yu-Long Yin, Lin Zhang

    Objective The gut microbiota regulates thermogenesis to benefit metabolic homeostasis at least partially via its metabolite butyrate, and the underlying mechanisms of this regulation are still unclear. In this study, we aim to investigate the role of lysine specific demethylase (LSD1), a histone demethylase and important regulator of thermogenesis, in mediating gut microbial metabolite butyrate regulation of thermogenesis. Methods The antibiotic cocktail (ABX) was administrated to deplete gut microbiota. Adipose-specific LSD1 knockout mice (LSD1 aKO) were generated by crossing LSD1-lox/lox with adiponectin-cre mice and butyrate sodium and dietary fiber inulin was administrated through oral-gavage. Primary stromal vascular cells were isolated from adipose tissues and differentiated to adipocytes for studying adipocyte thermogenesis. Results The antibiotic cocktail (ABX)-mediated depletion of the gut microbiota in mice downregulated the expression of LSD1 in both brown adipose tissue (BAT) and subcutaneous white adipose tissue (scWAT) in addition to uncoupling protein 1 (UCP1) and body temperature. Gavage of the microbial metabolite butyrate in ABX-treated mice reversed the thermogenic functional impairment and LSD1 expression. The adipose-specific ablation of LSD1 in mice attenuated the butyrate-mediated induction of thermogenesis and energy expenditure. Notably, our results showed that butyrate directly increased the expression of LSD1 and UCP1 as well as butyrate transporter monocarboxylate transporter 1 (MCT1) and catabolic enzyme acyl-CoA medium-chain synthetase 3 (ACSM3) in ex vivo cultured adipocytes. The inhibition of MCT1 blocked the effects of butyrate in adipocytes. Furthermore, the butyrate-mediated prevention of diet-induced obesity (DIO) through increased thermogenesis was attenuated in LSD1 aKO mice. Moreover, after gavaging HFD-fed mice with the dietary fiber inulin, a substrate of microbial fermentation that rapidly produces butyrate, thermogenesis in both BAT and scWAT was increased, and DIO was decreased; however, these beneficial metabolic effects were blocked in LSD1 aKO mice. Conclusions Together, our results indicate that the microbial metabolite butyrate regulates thermogenesis in BAT and scWAT through the activation of LSD1.

  • Hepatic exosome-derived miR-130a-3p attenuates glucose tolerance via suppressing PHLPP2 gene in adipocyte
    Metabolism (IF 6.513) Pub Date : 2019-11-10
    Jiahan Wu, Tao Dong, Ting Chen, Jiajie Sun, Junyi Luo, Jiajian He, Limin Wei, Bin Zeng, Haojie Zhang, Weite Li, Jie Liu, Xingping Chen, Mei Su, Yuechun Ni, Qingyan Jiang, Yongliang Zhang, Qianyun Xi

    Objective Glucose and lipid metabolism disorder is a major risk factor for type II diabetes and cardiovascular diseases. Evidence has indicated that the interplay between the liver and adipose tissue is crucial in maintaining energy homeostasis. Recently, the interaction between two distant endocrine organs mainly focuses on the regulation of hormones and receptors. However, as a novel carrier in the inter-tissue communication, exosome plays a role in liver-fat crosstalk, but its effects on glucose and lipid metabolisms are still unclear. In this study, we sought to investigate the effects of hepatic exosome-derived miR-130a-3p in the regulation of glucose/lipid metabolism in adipose tissues. Measure In vivo, we constructed generalized miR-130a-3p knockout (130KO) and overexpressed (130OE) mice. Wild type (WT), 130KO and 130OE mice (n = 10) were assigned to a randomized controlled trial and were fed diets with either 10% (standard diet, SD) or 60% (high-fat diet, HFD) of total calories from fat (lard). Next, hepatic exosomes were extracted from WT-SD, 130KO-SD and 130OE-SD mice (WT-EXO, KO-EXO, OE-EXO), and 130KO mice were injected with 100 mg hepatic exosomes of different sources via tail-vein (once every 48 h) for 28 days, fed with HFD. In vitro, 3 T3-L1 cells were treated with miR-130a-3p mimics, inhibitor and hepatic exosomes. Growth performance and glucose and lipid metabolic profiles were examined. Results After feeding with HFD, the weights of 130KO mice were markedly higher than WT mice. Over-expression of miR-130a-3p in 130OE mice and intravenous injection of 130OE-EXO in 130KO mice contributed to a positive correlation with the recovery of insulin resistance. In addition, miR-130a-3p mimics and 130OE-EXO treatment of 3 T3-L1 cells exhibited decreasing generations of lipid droplets and increasing glucose uptake. Conversely, inhibition of miR-130a-3p in vitro and in vivo resulted in opposite phenotype changes. Furthermore, PHLPP2 was identified as a direct target of miR-130a-3p, and the hepatic exosome-derived miR-130a-3p could improve impaired glucose tolerance via suppressing PHLPP2 to activate AKT-AS160–GLUT4 signaling pathway in adipocytes. Conclusions We demonstrated that hepatic exosome-derived miR-130a regulated energy metabolism in adipose tissues, and elucidated a new molecular mechanism that hepatic exosome-derived miR-130a-3p is a crucial participant in organismic energy homeostasis through mediating crosstalk between the liver and adipose tissues.

  • Skeletal muscle adiponectin induction in obesity and exercise
    Metabolism (IF 6.513) Pub Date : 2019-11-09
    Sergio F. Martinez-Huenchullan, Charmaine S. Tam, Linda A. Ban, Pamela Ehrenfeld-Slater, Susan V. Mclennan, Stephen M. Twigg

    Recent scientific efforts have focused on the detrimental effects that obesity has on the metabolic function of skeletal muscles and whether exercise can improve this dysfunction. In this regard, adiponectin, with important metabolic functions (e.g. insulin-sensitizer and anti-inflammatory), has been recently described as a myokine that acts in an autocrine/paracrine manner. Earlier studies reported that muscle adiponectin could be induced by pro-inflammatory mediators (e.g. lipopolysaccharide), cytokines, and high-fat diets, providing a protective mechanism of this tissue against metabolic insults. However, when metabolic insults such as high-fat diets are sustained this protective response becomes dysregulated, making the skeletal muscle susceptible to metabolic impairments. Recent studies have suggested that exercise could prevent or even reverse this process. Considering that most scientific knowledge on adiponectin dysregulation in obesity is from the study of adipose tissue, the present review summarizes and discusses the literature available to date regarding the effects of obesity on skeletal muscle adiponectin induction, along with the potential effects of different exercise prescriptions on this response in an obesity context.

  • Protective effects of sulforaphane on type 2 diabetes-induced cardiomyopathy via AMPK-mediated activation of lipid metabolic pathways and NRF2 function
    Metabolism (IF 6.513) Pub Date : 2019-11-09
    Yike Sun, Shanshan Zhou, Hua Guo, Jian Zhang, Tianjiao Ma, Yang Zheng, Zhiguo Zhang, Lu Cai

    Background AMP-activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. It was reported that sulforaphane (SFN) prevented type 2 diabetes (T2D)-induced cardiomyopathy accompanied by the activation of AMPK; In this study, AMPK's pivotal role in SFN-mediated prevention against T2D-induced cardiomyopathy was tested using global deletion of AMPKα2 gene (AMPKα2-KO) mice. Methods and Results. T2D was established by feeding 3-month high-fat diet (HFD) to induce insulin resistance, followed by an intraperitoneal injection of streptozotocin (STZ) to induce mild hyperglycemia in both AMPKα2-KO and wild-type (WT) mice. Then both T2D and control mice were subsequently treated with or without SFN for 3 months while continually feeding HFD or normal diet. Upon completion of the 3-month treatment, five mice from each group were sacrificed as a 3-month time-point (3 M). The rest continued normal diet or HFD until terminating study at the sixth month (6 M) of diabetes. Cardiac function was examined with echocardiography before sacrifice at both 3 M and 6 M. SFN prevented T2D-induced progression of cardiac dysfunction, remodeling (hypertrophy and fibrosis), inflammation, and oxidative damage in wild-type diabetic mice, but not in AMPKα2-KO mice. Mechanistically, SFN prevented T2D-induced cardiomyopathy not only by improving AMPK-mediated lipid metabolic pathways, but also enhancing NRF2 activation via AMPK/AKT/GSK3β pathway. However, these improving effects of SFN were abolished in AMPKα2-KO diabetic mice. Conclusions AMPK is indispensable for the SFN-induced prevention of cardiomyopathy in T2D, and the activation of NRF2 by SFN is mediated by AMPK/AKT/GSK3β signaling pathways.

  • HFD refeeding in mice after fasting impairs learning by activating caspase-1 in the brain
    Metabolism (IF 6.513) Pub Date : 2019-11-05
    Albert E. Towers, Maci L. Oelschlager, Michal B. Juda, Sparsh Jain, Stephen J. Gainey, Gregory G. Freund

    Background Diets that include some aspect of fasting have dramatically increased in popularity. In addition, fasting reduces inflammasome activity in the brain while improving learning. Here, we examine the impact of refeeding a low-fat diet (LFD) or high-fat diet (HFD) after fasting. Methods Male wildtype (WT), caspase-1 knockout (KO) and/or IL-1 receptor 1 (IL-1R1) KO mice were fasted for 24 h or allowed ad libitum access to food (chow). Immediately after fasting, mice were allowed to refeed for 2 h in the presence of LFD, HFD or chow. Mouse learning was examined using novel object recognition (NOR) and novel location recognition (NLR). Caspase-1 activity was quantified in the brain using histochemistry (HC) and image analysis. Results Refeeding with a HFD but not a LFD or chow fully impaired both NOR and NLR. Likewise, HFD when compared to LFD refeeding increased caspase-1 activity in the whole amygdala and, particularly, in the posterior basolateral nuclei (BLp) by 2.5-fold and 4.6-fold, respectively. When caspase-1 KO or IL-1R1 KO mice were examined, learning impairment secondary to HFD refeeding did not occur. Equally, administration of n-acetylcysteine to fasted WT mice prevented HFD-dependent learning impairment and caspase-1 activation in the BLp. Finally, the free-fatty acid receptor 1 (FFAR1) antagonist, DC260126, mitigated learning impairment associated with HFD refeeding while blocking caspase-1 activation in the BLp. Conclusions Consumption of a HFD after fasting impairs learning by a mechanism that is dependent on caspase-1 and the IL-1R1 receptor. These consequences of a HFD refeeding on the BLP of the amygdala appear linked to oxidative stress and FFAR1.

  • Active pyruvate dehydrogenase and impaired gluconeogenesis in orthotopic hepatomas of rats
    Metabolism (IF 6.513) Pub Date : 2019-10-28
    Min Hee Lee, Ralph J. DeBerardinis, Xiaodong Wen, Ian R. Corbin, A. Dean Sherry, Craig R. Malloy, Eunsook S. Jin

    Background Therapies targeting altered activity of pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) have been proposed for hepatomas. However, the activities of these pathways in hepatomas in vivo have not been distinguished. Here we examined pyruvate entry into the tricarboxylic acid (TCA) cycle through PDH versus PC in vivo using hepatoma-bearing rats. Methods Hepatoma-bearing rats were generated by intrahepatic injection of H4IIE cells. Metabolism of 13C-labeled glycerol, a physiological substrate for both gluconeogenesis and energy production, was measured with 13C NMR analysis. The concentration of key metabolites and the expression of relevant enzymes were measured in hepatoma, surrounding liver, and normal liver. Results In orthotopic hepatomas, pyruvate entry into the TCA cycle occurred exclusively through PDH and the excess PDH activity compared to normal liver was attributed to downregulated pyruvate dehydrogenase kinase (PDK) 2/4. However, pyruvate carboxylation via PC and gluconeogenesis were minimal, which was linked to downregulated forkhead box O1 (FoxO1) by Akt activity. In contrast to many studies of cancer metabolism, lactate production in hepatomas was not increased which corresponded to reduced expression of lactate dehydrogenase. The production of serine and glycine in hepatomas was enhanced, but glycine decarboxylase was downregulated. Conclusions The combination of [U-13C3]glycerol and NMR analysis enabled investigation of multiple biochemical processes in hepatomas and surrounding liver. We demonstrated active PDH and other related metabolic alterations in orthotopic hepatomas that differed substantially not only from the host organ but also from many earlier studies with cancer cells.

  • Mannose is an insulin-regulated metabolite reflecting whole-body insulin sensitivity in man
    Metabolism (IF 6.513) Pub Date : 2019-11-01
    E. Ferrannini, M. Bokarewa, P. Brembeck, R. Baboota, S. Hedjazifar, K. Andersson, S. Baldi, B. Campi, E. Muscelli, A. Saba, I. Sterner, C. Wasen, U. Smith

    Mannose is a glucose-associated serum metabolite mainly released by the liver. Recent studies have shown several unexpected pleiotropic effects of mannose including increased regulatory T cells (Tregs), prevention of auto-immune disease and ability to reduce growth of human cancer cells. We have previously shown in large cohorts that elevated serum mannose levels are associated with future development of type 2 diabetes (T2D) and cardiovascular disease. However, potential direct effects of mannose on insulin sensitivity in vivo or in vitro are unknown. We here show that administration of mannose (0.1 g/kg BW twice daily) for one week in man did not elicit negative effects on meal-modified glucose tolerance, markers of inflammation or insulin levels. Tregs number and insulin signaling in human liver cells were unchanged. These data suggest that mannose is a marker, and not a mediator, of insulin resistance. To verify this, we examined serum mannose levels during long-term euglycemic hyperinsulinemic clamps in non-diabetic and T2D individuals. Mannose was reduced by insulin infusion in proportion to whole-body insulin sensitivity. Thus, mannose is a biomarker of insulin resistance which may be useful for the early identification of diabetic individuals with insulin resistance and increased risk of its complications.

  • Downregulation of PHGDH expression and hepatic serine level contribute to the development of fatty liver disease
    Metabolism (IF 6.513) Pub Date : 2019-10-31
    Woo-Cheol Sim, Wonseok Lee, Hyungtai Sim, Kang-Yo Lee, Seung-Hwan Jung, You-Jin Choi, Hyun Young Kim, Keon Wook Kang, Ji-Yoon Lee, Young Jae Choi, Sang Kyum Kim, Dae Won Jun, Won Kim, Byung-Hoon Lee

    Objective Supplementation with serine attenuates alcoholic fatty liver by regulating homocysteine metabolism and lipogenesis. However, little is known about serine metabolism in fatty liver disease (FLD). We aimed to investigate the changes in serine biosynthetic pathways in humans and animal models of fatty liver and their contribution to the development of FLD. Methods High-fat diet (HFD)-induced steatosis and methionine-choline-deficient diet-induced steatohepatitis animal models were employed. Human serum samples were obtained from patients with FLD whose proton density fat fraction was estimated by magnetic resonance imaging. 3-Phosphoglycerate dehydrogenase (Phgdh)-knockout mouse embryonic fibroblasts (MEF) and transgenic mice overexpressing Phgdh (Tg-phgdh) were used to evaluate the role of serine metabolism in the development of FLD. Results Expression of Phgdh was markedly reduced in the animal models. There were significant negative correlations of the serum serine with the liver fat fraction, serum alanine transaminase, and triglyceride levels among patients with FLD. Increased lipid accumulation and reduced NAD+ and SIRT1 activity were observed in Phgdh-knockout MEF and primary hepatocytes incubated with free fatty acids; these effects were reversed by overexpression of Phgdh. Tg-Phgdh mice showed significantly reduced hepatic triglyceride accumulation compared with wild-type littermates fed a HFD, which was accompanied by increased SIRT1 activity and reduced expression of lipogenic genes and proteins. Conclusions Human and experimental data suggest that reduced Phgdh expression and serine levels are closely associated with the development of FLD.

  • Ingestion of lean meat elevates muscle inositol hexakisphosphate kinase 1 protein content independent of a distinct post-prandial circulating proteome in young adults with obesity
    Metabolism (IF 6.513) Pub Date : 2019-10-31
    Richie D. Barclay, Joseph W. Beals, Jenny Drnevich, Brian S. Imai, Peter M. Yau, Alexander V. Ulanov, Neale A. Tillin, Martha Villegas-Montes, Scott A. Paluska, Peter W. Watt, Michael De Lisio, Nicholas A. Burd, Richard W. Mackenzie

    Background We have recently shown that a novel signalling kinase, inositol hexakisphosphate kinase 1 (IP6K1), is implicated in whole-body insulin resistance via its inhibitory action on Akt. Insulin and insulin like growth factor 1 (IGF-1) share many intracellular processes with both known to play a key role in glucose and protein metabolism in skeletal muscle. Aims We aimed to compare IGF/IP6K1/Akt signalling and the plasma proteomic signature in individuals with a range of BMIs after ingestion of lean meat. Methods Ten lean [Body mass index (BMI) (in kg/m2): 22.7 ± 0.4; Homeostatic model assessment of insulin resistance (HOMAIR): 1.36 ± 0.17], 10 overweight (BMI: 27.1 ± 0.5; HOMAIR: 1.25 ± 0.11), and 10 obese (BMI: 35.9 ± 1.3; HOMAIR: 5.82 ± 0.81) adults received primed continuous L-[ring-13C6]phenylalanine infusions. Blood and muscle biopsy samples were collected at 0 min (post-absorptive), 120 min and 300 min relative to the ingestion of 170 g pork loin (36 g protein and 5 g fat) to examine skeletal muscle protein signalling, plasma proteomic signatures, and whole-body phenylalanine disappearance rates (Rd). Results Phenylalanine Rd was not different in obese compared to lean individuals at all time points and was not responsive to a pork ingestion (basal, P = .056; 120 & 300 min, P > .05). IP6K1 was elevated in obese individuals at 120 min post-prandial vs basal (P < .05). There were no acute differences plasma proteomic profiles between groups in the post-prandial state (P > .05). Conclusions These data demonstrate, for the first time that muscle IP6K1 protein content is elevated after lean meat ingestion in obese adults, suggesting that IP6K1 may be contributing to the dysregulation of nutrient uptake in skeletal muscle. In addition, proteomic analysis showed no differences in proteomic signatures between obese, overweight or lean individuals.

  • Clinical usefulness of human serum nonmercaptalbumin to mercaptalbumin ratio as a biomarker for diabetic complications and disability in activities of daily living in elderly patients with diabetes
    Metabolism (IF 6.513) Pub Date : 2019-10-29
    Saki Fukuhara, Keiko Yasukawa, Masaya Sato, Hitoshi Ikeda, Yukihiro Inoguchi, Tomoaki Etoh, Mitsunori Masakado, Fumio Umeda, Yutaka Yatomi, Teruaki Yamauchi, Toyoshi Inoguchi

    Background Oxidative stress may play an important role in the development of diabetic complications. The ratio of human nonmercaptalbumin (HNA; oxidized form) to human mercaptalbumin (HMA; reduced form) has attracted attention as an indicator for systemic redox states. In this study, we measured the ratio in elderly patients with diabetes and evaluated its association with diabetic complications and disability in activities of daily living (ADL disability). Methods One hundred twenty-six elderly patients with diabetes, aged 70 years and older, under medical care at Yukuhashi Central Hospital from April 2018 to June 2018, were continuously recruited. HNA%, defined as HNA / (HNA + HMA) × 100, was measured by a high-performance liquid chromatography method. First, multivariate regression analysis was performed to evaluate which variables were significant determinants for HNA%. Next, to evaluate the association of HNA% with ADL disability, logistic regression analysis in various models was performed. Then we plotted the receiver operating characteristic (ROC) curve and calculated the under area the curve (AUC), sensitivity, and specificity in each model. Results In elderly patients with diabetes, multiple regression analysis showed that serum bilirubin levels and albumin levels, both of which are major endogenous anti-oxidants, and chronic renal failure (or proliferative nephropathy) were significantly associated with HNA%, suggesting that HNA% may be a good biomarker for oxidative stress in those patients. We then evaluated the association of HNA% with ADL disability in various logistic regression models. Model using only HNA% showed that it was a significant determinant for ADL disability (OR 1.158, 95% CI 1.077–1.244, P < .001). Model using HNA% and age showed that both variables were significant determinants for ADL disability (OR 1.160, 95% CI 1.069–1.258, P < .001; OR 1.258, 95% CI 1.110–1.427, P < .001, respectively). ROC analysis showed that the AUC of HNA% alone was 0.765. The AUC of model using HNA% and age was further increased to 0.866. Conclusions HNA% was significantly associated with diabetic complications and ADL disability, thereby may be clinically useful as an oxidative stress marker in elderly patients with diabetes.

  • Supervised lifestyle intervention for people with metabolic syndrome improves outcomes and reduces individual risk factors of metabolic syndrome: a systematic review and meta-analysis.
    Metabolism (IF 6.513) Pub Date : 2019-10-28
    Maria van Namen, Luke Prendergast, Casey Peiris

    Background Metabolic syndrome is characterised by a clustering of metabolic risk factors including abdominal obesity, raised triglycerides, lowered HDL cholesterol, hypertension and impaired glucose tolerance. Multifaceted lifestyle interventions including diet and exercise are recommended as the first-line treatment for the metabolic syndrome. Objective To investigate the effects of lifestyle interventions that include both diet interventions and supervised exercise on outcomes for people with metabolic syndrome. Methods A systematic review and meta-regression was conducted. PubMed, EMBASE, MEDLINE and CINAHL were searched from the earliest date possible until November 2018 to identify randomised controlled trials examining the effects of lifestyle interventions compared to usual care on patient health outcomes and components of metabolic syndrome. Post-intervention means and standard deviations were pooled using inverse variance methods and random-effects models to calculate mean differences (MD), standardised mean differences (SMD) and 95% confidence intervals (CI). Results Searching identified 2598 articles, of which 15 articles reporting data from 10 trials, with 1160 participants were included in this review. Compared to usual care, supervised lifestyle intervention demonstrated significant improvements in all but one of the components of metabolic syndrome. Reductions were seen in waist circumference (−4.9 cm, 95%CI -8.0 to −1.7), systolic blood pressure (−6.5 mmHg, 95%CI –10.7 to −2.3), diastolic blood pressure (−1.9 mmHg, 95%CI -3.6 to −0.2), triglycerides (SMD -0.46, 95%CI -0.88 to −0.04) and fasting glucose (SMD -0.68, 95%CI −1.20 to −0.15). Prevalence of metabolic syndrome was reduced by 39% in intervention group participants compared to control group participants (Risk Ratio 0.61, 95%CI 0.38 to 0.96). Improvements in quality of life were not statistically significant. Conclusion There is low to moderate quality evidence that supervised multifaceted lifestyle intervention improves multiple risk factors of metabolic syndrome, as well as reducing prevalence of the disease. Health services should consider implementing lifestyle intervention programs for people with metabolic syndrome to improve health outcomes and prevent progression to chronic disease.

  • The Rho GTPase RND3 regulates adipocyte lipolysis.
    Metabolism (IF 6.513) Pub Date : 2019-10-28
    Simon N. Dankel, Therese H. Røst, Agné Kulyté, Zina Fandalyuk, Thomas Skurk, Hans Hauner, Jørn V. Sagen, Mikael Rydén, Peter Arner, Gunnar Mellgren

    Background Adipose tissue plays a crucial role in diet- and obesity-related insulin resistance, with implications for several metabolic diseases. Identification of novel target genes and mechanisms that regulate adipocyte function could lead to improved treatment strategies. RND3 (RhoE/Rho8), a Rho-related GTP-binding protein that inhibits Rho kinase (ROCK) signaling, has been linked to diverse diseases such as apoptotic cardiomyopathy, heart failure, cancer and type 2 diabetes, in part by regulating cytoskeleton dynamics and insulin-mediated glucose uptake. Results We here investigated the expression of RND3 in adipose tissue in human obesity, and discovered a role for RND3 in regulating adipocyte metabolism. In cross-sectional and prospective studies, we observed 5-fold increased adipocyte levels of RND3 mRNA in obesity, reduced levels after surgery-induced weight loss, and positive correlations of RND3 mRNA with adipocyte size and surrogate measures of insulin resistance (HOMA2-IR and circulating triglyceride/high-density lipoprotein cholesterol (TAG/HDL-C) ratio). By screening for RND3-dependent gene expression following siRNA-mediated RND3 knockdown in differentiating human adipocytes, we found downregulation of inflammatory genes and upregulation of genes related to adipocyte lipolysis and insulin signaling. Treatment of adipocytes with tumor necrosis factor alpha (TNFα), lipopolysaccharide (LPS), hypoxia or cAMP analogs increased RND3 mRNA levels 1.5–2-fold. Functional assays in primary human adipocytes confirmed that RND3 knockdown reduces cAMP- and isoproterenol-induced lipolysis, which were mimicked by treating cells with ROCK inhibitor. This effect could partly be explained by reduced protein expression of adipose triglyceride lipase (ATGL) and phosphorylated hormone-sensitive lipase (HSL). Conclusion We here uncovered a novel differential expression of adipose RND3 in obesity and insulin resistance, which may at least partly depend on a causal effect of RND3 on adipocyte lipolysis.

  • Predictive value of gastrointestinal hormones on weight loss
    Metabolism (IF 6.513) Pub Date : 2019-10-28
    Nikolaos Perakakis, Alexander Kokkinos, Natia Peradze, Nikolaos Tentolouris, Wael Ghaly, Eleni Pilitsi, Jagriti Upadhyay, Andreas Alexandrou, Christos S. Mantzoros

    Aims Bariatric surgery leads to profound and sustainable weight loss. Gastrointestinal hormones are involved in energy and glucose homeostasis, thus postoperative changes of their circulating levels may be mediating future weight loss. To investigate how the circulating concentrations of gastrointestinal hormones change in response to the most common types of bariatric operation and whether these changes can predict future weight loss. Materials and Methods We measured circulating GLP-1, GLP-2, oxyntomodulin, glicentin, glucagon, major proglucagon fragment (MPGF), ghrelin, GIP, PYY after overnight fasting and/or after a mixed meal test (MMT) in: a) 14 subjects that have undergone either an adjustable gastric banding [AGB] (n = 9) or a Roux-en-Y bypass (RYGB) (n = 5) (Pilot study 1), b) 28 subjects that have undergone either a vertical sleeve gastrectomy (n = 17) or a RYGB (n = 11) before and three, six and twelve months after surgery. Results In addition to the expected associations with GLP-1, the most robust increases were observed in postprandial levels of oxyntomodulin and glicentin three months after VSG or RYGB (but not after AGB) and are associated with degree of weight loss. Oxyntomodulin and glicentin levels at the third and sixth month postoperative visit are positively associated with feeling of satiety which may be underlying the observed associations with future weight loss. Conclusion Beyond GLP-1, early postprandial changes in circulating oxyntomodulin and glicentin are predictors of weight loss after bariatric surgery, possibly through regulation of satiety. Further studies should focus on underlying mechanisms, and their potential as attractive therapeutic tools against obesity and related comorbidities.

  • FGF21 in NAFLD
    Metabolism (IF 6.513) Pub Date : 2019-10-28
    Bradley Tucker, Huating Li, Xiaoxue Long, Kerry-Anne Rye, Kwok Leung Ong

    Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies ranging from uncomplicated hepatic fat accumulation to a state of lobular inflammation and hepatocyte ballooning, known as non-alcoholic steatohepatitis (NASH). Currently, there are no reliable biomarkers or effective therapeutic options established for NAFLD. Nevertheless, there are several molecular targets in the pipeline, of which fibroblast growth factor 21 (FGF21) is one. FGF21 is secreted primarily from liver and has a plethora of metabolic functions. Pre-clinical and epidemiological studies indicate a relationship between circulating FGF21 levels and hepatic fat content in both mice and humans. Moreover, animal studies have clearly shown that aberrant FGF21 signalling is a key pathological step in the development and progression of NAFLD. A recent Phase II clinical trial demonstrated that administration of an FGF21 analogue significantly reduced hepatic fat in subjects with NASH. As such, FGF21 provides a novel target for future biomarker and therapeutic studies. This review appraises preclinical data to outline the current understanding of FGF21 function in both normal hepatic function and NAFLD. Epidemiological evidence is explored to delineate the relationship between circulating FGF21 levels and NAFLD in humans. Finally, we review the therapeutic effects of FGF21 in the treatment of NAFLD.

  • SIRT1 activation rescues the mislocalization of RNA-binding proteins and cognitive defects induced by inherited cobalamin disorders
    Metabolism (IF 6.513) Pub Date : 2019-10-28
    Rose Ghemrawi, Carole Arnold, Shyue-Fang Battaglia-Hsu, Grégory Pourié, Isabelle Trinh, Christine Bassila, Rashka Charif, Arnaud Wiedemann, Justine Flayac, Aurélie Robert, Natacha Dreumont, François Feillet, Jean-Louis Guéant, David Coelho

    Background The molecular consequences of inborn errors of vitamin B12 or cobalamin metabolism are far from being understood. Moreover, innovative therapeutic strategies are needed for the treatment of neurological outcomes that are usually resistant to conventional treatments. Our previous findings suggest a link between SIRT1, cellular stress and RNA binding proteins (RBP) mislocalization in the pathological mechanisms triggered by impaired vitamin B12 metabolism. Objectives and Methods The goal of this study was to investigate the effects of the pharmacological activation of SIRT1 using SRT1720 on the molecular mechanisms triggered by impaired methionine synthase activity. Experiments were performed in vitro with fibroblasts from patients with the cblG and cblC inherited defects of vitamin B12 metabolism and in vivo with an original transgenic mouse model of methionine synthase deficiency specific to neuronal cells. Subcellular localization of the RBPs HuR, HnRNPA1, RBM10, SRSF1 and Y14 was investigated by immunostaining and confocal microscopy in patient fibroblasts. RBPs methylation and phosphorylation were studied by co-immunoprecipitation and proximity ligation assay. Cognitive performance of the transgenic mice treated with SRT1720 was measured with an aquatic maze. Results Patient fibroblasts with cblC and cblG defects of vitamin B12 metabolism presented with endoplasmic reticulum stress, altered methylation, phosphorylation and subcellular localization of HuR, HnRNPA1 and RBM10, global mRNA mislocalization and increased HnRNPA1-dependent skipping of IRF3 exons. Incubation of fibroblasts with cobalamin, S-adenosyl methionine and okadaic acid rescued the localization of the RBPs and mRNA. The SIRT1 activating compound SRT1720 inhibited ER stress and rescued RBP and mRNA mislocalization and IRF3 splicing. Treatment with this SIRT1 agonist prevented all these hallmarks in patient fibroblasts but it also improved the deficient hippocampo-dependent learning ability of methionine synthase conditional knock-out mice. Conclusions By unraveling the molecular mechanisms triggered by inborn errors of cbl metabolism associating ER stress, RBP mislocalization and mRNA trafficking, our study opens novel therapeutic perspectives for the treatment of inborn errors of vitamin B12 metabolism.

  • Effects of newer antidiabetic drugs on nonalcoholic fatty liver and steatohepatitis: think out of the box!
    Metabolism (IF 6.513) Pub Date : 2019-10-28
    Golnaz Ranjbar, Dimitri P. Mikhailidis, Amirhossein Sahebkar

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western societies and a major cause of hepatic disease worldwide. Its more severe type, namely nonalcoholic steatohepatitis (NASH), may result in the development of cirrhosis and hepatocellular carcinoma. NAFLD, and especially NASH, are also associated with increased cardiovascular morbidity and mortality. Type 2 diabetes mellitus (T2DM) predisposes to NAFLD development and progression via insulin resistance and hyperglycemia. It has also been reported that the majority of T2DM patients have NAFLD/NASH, thus potentially further increasing their cardiometabolic risk. Current guidelines recommend to screen for NAFLD in all T2DM patients and vice-versa. Lifestyle remains the first-line therapeutic option for NAFLD/NASH. Among antidiabetic drugs, pioglitazone was shown to improve histological features of NASH. More recently, there is an increasing interest regarding the effects of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4i), sodium glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on NAFLD/NASH. The present narrative review considers the up-to-date data on the impact of DPP-4i, SGLT2i, and GLP-1 RAs on biochemical and/or histological markers of NAFLD/NASH. The potential clinical implications of these findings in daily practice are also discussed. Taking into consideration the global increasing prevalence of NAFLD/NASH, therapeutic options that can prevent or treat this disease will exert considerable benefits on human health.

  • Evidence mapping of recommendations on diagnosis and therapeutic strategies for diabetes foot: an international review of 22 guidelines
    Metabolism (IF 6.513) Pub Date : 2019-08-05
    Yue Sun, Ya Gao, Ji Chen, Hao Sun, Yi-tong Cai, Long Ge, Ya-nan Li, Junhua Zhang, Jin-hui Tian

    To systematically review clinical practice guidelines (CPGs) on diabetes foot and assess the consistency of recommendations, quality of CPGs and to present an evidence-map for explicating research trends and gaps. We performed a literature search on PubMed, Embase, and Web of Science, guideline databases and websites of diabetes society to include the diabetic CPGs. The basic information, recommendations for the diabetic foot, methodological quality and reporting quality of diabetic CPGs were exacted by the Excel. Four researchers evaluated the methodological and reporting quality of diabetic foot CPGs by AGREE II instrument and RIGHT checklist. R3.5.1 software was used to create all bubble plots. A total of 22 diabetic CPGs were included, eight CPGs were from different professional diabetes societies. Recommendations on diabetic foot complications involve Diabetic foot ulcer (DFU), Charcot neuropathy (CN) and Osteomyelitis (OM). Eight DFU diagnostic systems presented in 22 CPGs. According to the recommendations of diabetic CPGs, the treatment of DFU can be summarized in four major items; six recommendations on CN diagnosis and six recommendations on treatment of CN were consistent among studies. However, there were inconsistencies in three OM diagnosis recommendations and four OM treatment recommendations. Some recommendations in CPGs were not very specific and clear, and hence they were not reliable for OM diagnosis and treatment. Once these inconsistencies are resolved, validated, accurate and effective diagnosis and treatment of diabetes foot will lead to reduced costs and adverse complications. The results of this review add to our knowledge and promote the development of trustworthy CPGs on diabetes.

  • Adaptor protein APPL1 coordinates HDAC3 to modulate brown adipose tissue thermogenesis in mice
    Metabolism (IF 6.513) Pub Date : 2019-08-04
    Linling Fan, Hongying Ye, Yun Wan, Lang Qin, Lu Zhu, Jing Su, Xiaoming Zhu, Lv Zhang, Qing Miao, Qiongyue Zhang, Zhaoyun Zhang, Aimin Xu, Yiming Li, Xi Li, Yi Wang
  • Risk of coronary artery disease according to glucose abnormality status and prior coronary artery disease in Japanese men.
    Metabolism (IF 6.513) Pub Date : 2019-10-27
    Masaru Kitazawa, Kazuya Fujihara, Taeko Osawa, Masahiko Yamamoto, Mayuko Harada Yamada, Masanori Kaneko, Yasuhiro Matsubayashi, Takaho Yamada, Nauta Yamanaka, Hiroyasu Seida, Hirohito Sone

    Objective Although glucose abnormality status (GAS), prior coronary artery disease (CAD), and other traditional risk factors affect the incidence of subsequent CAD, their impact in the same cohort has been scantly studied. Research Design and Methods. We analyzed data from a nationwide claims database in Japan that was accumulated during 2008–2016 involving 138,162 men aged 18–72 years. Participants were classified as having normoglycemia, borderline glycemia, or diabetes mellitus (DM) with prior CAD (CAD+) or without prior CAD (CAD-). Cox regression model identified variables related to the incidence of CAD. Results Among CAD-, management of traditional risks differed from those with and without subsequent CAD events. On the other hand, such differences were weaker in borderline glycemia and DM CAD+, and the influence of traditional risk factors on subsequent CAD was not observed. Cox regression model showed that borderline glycemia and DM confer approximately 1.2- and 2.8-fold excess risks of CAD, respectively, compared with CAD- with normoglycemia. CAD+ confers approximately a 5- to 8-fold increased risk. The impacts of DM and prior CAD additively reached a hazard ratio (HR) of 15.74 (95% confidence interval [CI]: 11.82–21.00). However, the HR in those with borderline glycemia and CAD+ was 7.20 (95%CI: 5.01–10.34), which was not different from those with normoglycemia and CAD+. Conclusion Control status of traditional risk factors and impact on subsequent CAD differ among categories of glycemic status with and without prior CAD. Individualizing treatment strategies is needed in consideration of risk factors, such as GAS and CAD+.

  • Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance
    Metabolism (IF 6.513) Pub Date : 2019-10-27
    Chaitanya K. Gavini, Tyler M. Cook, David J. Rademacher, Virginie Mansuy-Aubert
  • Interleukin-1α leads to growth hormone deficiency in adamantinomatous craniopharyngioma by targeting pericytes: implication in pituitary fibrosis
    Metabolism (IF 6.513) Pub Date : 2019-10-27
    Jian Mao, Binghui Qiu, Fen Mei, Fan Liu, Zhanpeng Feng, Jun Fan, Jing Nie, Lijun Huang, Xixian Liao, Zhenhao Wang, Jiahui Zeng, Zelin Weng, Nailiang Zang, Songtao Qi, Yun Bao

    Background The incidence of growth hormone deficiency (GHD) in adamantinomatous craniopharyngioma (aCP) is significantly higher than in other sellar region tumors, but the possible mechanism is still elusive. A high level of inflammatory responses is another feature of aCP. We investigated the internal connection between interleukin-1α (IL-1α) and GHD, while focusing on its biological activities in pituitary fibrosis. Materials and Methods To diagnosis of GHD, the Body Mass Index (BMI), Insulin Like Growth Factor-1(IGF-1) and peak growth hormone (GH) values after insulin stimulation test of 15 aCP patients were recorded. Histological staining was performed on the aCP samples. Levels of 9 proinflammatory cytokines in tumor tissue and cell supernatant were detected using Millipore bead arrays. The effect of IL-1α on GH secretion was evaluated in vivo and in vitro. Western blot, qRT-PCR and cell functional assays were used to explore the potential mechanism through which IL-1α acts on GH secretion. The stereotactic ALZET osmotic pump technique was used to simulate aCP secretion of proinflammatory cytokines in rats. Recombinant IL-1α (rrIL-1α) and conditioned media (CM) prepared from the supernatant of aCP cells was infused directly into the intra-sellar at a rate of 1 ul/h over 28 days, and then the effects of IL-1α treatment on pathological changes of pituitary gland and GH secretion were measured. To further confirm whether IL-1α affects GH secretion through IL-1R1, an IL-1R1 blocker (IL-1R1a, 10 mg/kg body weight, once daily) was administered subcutaneously from the first day until day 28. Results There was a significant positive correlation between pituitary fibrosis and GHD (rS = 0.756, P = .001). A number of cytokines, in particular IL-1α, interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), were elevated in tumor tissue and cell supernatant. Only IL-1α showed a significant difference between the GHD group and the No-GHD group (P<0.001, F = 6.251 in tumor tissue; P = .003, F = 1.529 in cell supernatant). IL-1α significantly reduced GH secretion in coculture of GH3 and pericytes. The activation of pericytes induced by IL-1α was mediated by the IL-1R1 signaling pathway. In vivo, IL-1α induces pituitary fibrosis, further leading to a decreased level of GH. This pathological change was antagonized by IL-1R1a. Conclusion This study found that the cross talk between aCP cells and stroma cells in the pituitary, i.e. pericytes, is an essential factor in the formation of GHD, and we propose that neutralization of IL-1α signaling might be a potential therapy for GHD in aCP.

  • Preadipocyte factor 1 regulates adipose tissue browning via TNF-α-converting enzyme-mediated cleavage
    Metabolism (IF 6.513) Pub Date : 2019-10-23
    Marie Rhee, Ji-Won Kim, Min-Woo Lee, Kun-Ho Yoon, Seung-Hwan Lee

    Background Increasing adaptive thermogenesis in adipose tissue may be a potential therapeutic target for overcoming obesity and obesity-related disorders. Preadipocyte factor 1 (Pref-1), a preadipocyte secreted protein, plays an inhibitory role in adipogenic differentiation. However, the role of Pref-1 in adipose tissue browning remains unknown. We investigated whether Pref-1 regulates thermogenic program and beige fat biogenesis. Methods Pref-1 expression levels were examined in inguinal white adipose tissue (iWAT) and differentiated 3 T3-L1 adipocytes in thermogenic conditions induced by cold exposure or a beta-adrenergic stimulus (CL316,243). Overexpression and knockdown studies were performed both in vivo and in vitro to clarify the role of Pref-1 in iWAT browning. Results Cold exposure or CL316,243 induced a thermogenic program in adipose tissue of C57BL/6 N mice and in 3 T3-L1 adipocytes. Notably, Pref-1 levels were down-regulated in iWAT and adipocytes under these conditions. Overexpressing Pref-1 showed reduced thermogenic gene expressions in response to CL316,243 treatment, whereas depletion of Pref-1 augmented thermogenic program in 3 T3-L1 adipocytes. Correspondingly, treating C57BL/6 N mice with Pref-1 resulted in reduced expression of thermogenic and beige fat markers, a reduced rate of oxygen consumption, blunting of UCP1 expression and beige fat formation in iWAT in response to cold exposure or CL316,243 injection compared to the untreated mice. The opposite phenotype was observed in mice with inducible fat-specific knock-out of Pref-1. Mechanistically, these effects were regulated by modulation of TNF-α-converting enzyme activity and Pref-1 cleavage. Conclusion Our findings establish a novel role of Pref-1 that regulates adaptive thermogenesis. This offers a unique target for improving energy homeostasis and treating obesity.

  • Morphological and functional adaptations of pancreatic alpha-cells during late pregnancy in the mouse
    Metabolism (IF 6.513) Pub Date : 2019-10-05
    Cristina Quesada-Candela, Eva Tudurí, Laura Marroquí, Paloma Alonso-Magdalena, Ivan Quesada, Ángel Nadal

    Background Pregnancy represents a major metabolic challenge for the mother, and involves a compensatory response of the pancreatic beta-cell to maintain normoglycaemia. However, although pancreatic alpha-cells play a key role in glucose homeostasis and seem to be involved in gestational diabetes, there is no information about their potential adaptations or changes during pregnancy. Material and Methods Non-pregnant (controls) and pregnant C57BL/6 mice at gestational day 18.5 (G18.5) and their isolated pancreatic islets were used for in vivo and ex vivo studies, respectively. The effect of pregnancy hormones was tested in glucagon-secreting α-TC1.9 cells. Immunohistochemical analysis was performed in pancreatic slices. Glucagon gene expression was monitored by RT-qPCR. Glucagon secretion and plasma hormones were measured by ELISA. Results Pregnant mice on G18.5 exhibited alpha-cell hypertrophy as well as augmented alpha-cell area and mass. This alpha-cell mass expansion was mainly due to increased proliferation. No changes in alpha-cell apoptosis, ductal neogenesis, or alpha-to-beta transdifferentiation were found compared with controls. Pregnant mice on G18.5 exhibited hypoglucagonaemia. Additionally, in vitro glucagon secretion at low glucose levels was decreased in isolated islets from pregnant animals. Glucagon content was also reduced. Experiments in α-TC1.9 cells indicated that, unlike estradiol and progesterone, placental lactogens and prolactin stimulated alpha-cell proliferation. Placental lactogens, prolactin and estradiol also inhibited glucagon release from α-TC1.9 cells at low glucose levels. Conclusions The pancreatic alpha-cell in mice undergoes several morphofunctional changes during late pregnancy, which may contribute to proper glucose homeostasis. Gestational hormones are likely involved in these processes.

  • Endothelial senescence-associated secretory phenotype (SASP) is regulated by Makorin-1 ubiquitin E3 ligase
    Metabolism (IF 6.513) Pub Date : 2019-08-30
    Sivareddy Kotla, Nhat-Tu Le, Hang Thi Vu, Kyung Ae Ko, Young Jin Gi, Tamlyn N. Thomas, Carolyn Giancursio, Aldos J. Lusis, John P. Cooke, Keigi Fujiwara, Jun-ichi Abe

    Background Disturbed flow (d-flow)–induced senescence and activation of endothelial cells (ECs) have been suggested to have critical roles in promoting atherosclerosis. Telomeric repeat-binding factor 2 (TERF2)-interacting protein (TERF2IP), a member of the shelterin complex at the telomere, regulates the senescence-associated secretory phenotype (SASP), in which EC activation and senescence are engendered simultaneously by p90RSK-induced phosphorylation of TERF2IP S205 and subsequent nuclear export of the TERF2IP-TERF2 complex. In this study, we investigated TERF2IP-dependent gene expression and its role in regulating d-flow-induced SASP. Methods A principal component analysis and hierarchical clustering were used to identify genes whose expression is regulated by TERF2IP in ECs under d-flow conditions. Senescence was determined by reduced telomere length, increased p53 and p21 expression, and increased apoptosis; EC activation was detected by NF-κB activation and the expression of adhesion molecules. The involvement of TERF2IP S205 phosphorylation in d-flow–induced SASP was assessed by depletion of TERF2IP and mutation of the phosphorylation site. Results Our unbiased transcriptome analysis showed that TERF2IP caused alteration in the expression of a distinct set of genes, including rapamycin-insensitive companion of mTOR (RICTOR) and makorin-1 (MKRN1) ubiquitin E3 ligase, under d-flow conditions. In particular, both depletion of TERF2IP and overexpression of the TERF2IP S205A phosphorylation site mutant in ECs increased the d-flow and p90RSK-induced MKRN1 expression and subsequently inhibited apoptosis, telomere shortening, and NF-κB activation in ECs via suppression of p53, p21, and telomerase (TERT) induction. Conclusions MKRN1 and RICTOR belong to a distinct reciprocal gene set that is both negatively and positively regulated by p90RSK. TERF2IP S205 phosphorylation, a downstream event of p90RSK activation, uniquely inhibits MKRN1 expression and contributes to EC activation and senescence, which are key events for atherogenesis.

  • Assessing Causality Between Childhood Adiposity and Early Puberty: A Bidirectional Mendelian Randomization and Longitudinal Study.
    Metabolism (IF 6.513) Pub Date : 2019-08-15
    Yang-Ching Chen, Hsien-Yu Fan, Chen Yang, Rong-Hong Hsieh, Wen-Harn Pan, Yungling L. Lee

    Aims Obesity and early puberty have been reported to be mutually causative. We investigated the causal relationship between adiposity and early puberty by performing bidirectional Mendelian randomization (MR) and longitudinal data analyses. Methods We used information from the Taiwan Children Health Study (3109 adolescents aged 11–12 years) with 17 body mass index (BMI)- and 10 puberty-related single-nucleotide polymorphisms (SNPs) to produce genetic instrumental variables (IVs). The two-stage least squares (2SLS) method, MR sensitivity analysis, and survival analysis were used to explore and confirm causality. Results Regression estimates from IVs revealed that significantly increased association of BMI with early puberty was noted. (coefficients: 0.13, 0.10, and 0.09; 95% CI: 0.07–0.19, 0.02–0.19, and 0.02–0.16 for all participants, male adolescents, and female adolescents, respectively). Genetic IVs for puberty were not associated with BMI. MR sensitivity and two-sample MR analyses produced similar results. Longitudinal analysis results revealed that prepubertal overweight and obesity could predict early onset of puberty. However, after excluding children with a history of overweight and obesity at the age of 7–12 years, early puberty was not found to trigger new-onset of overweight and obesity at the age of 18 years in either sex. Conclusions Higher adiposity may lead to early puberty. However, the causal effects of early puberty on adiposity accumulation was not supported by our data. Targeted interventions to reduce childhood obesity are strongly recommended to prevent obesity-related comorbidities, as well as early puberty onset.

  • Will medications that mimic gut hormones or target their receptors eventually replace bariatric surgery?
    Metabolism (IF 6.513) Pub Date : 2019-08-11
    Alexander Kokkinos, Dimitrios Tsilingiris, Carel W. le Roux, Francesco Rubino, Christos S. Mantzoros

    Bariatric surgery is currently the most effective therapeutic modality through which sustained beneficial effects on weight loss and metabolic improvement are achieved. During recent years, indications for bariatric surgery have been expanded to include cases of poorly controlled type 2 (T2DM) diabetes mellitus in lesser extremes of body weight. A spectrum of the beneficial effects of surgery is attributed to robust changes of postprandial gut peptide responses that are observed post operatively. Consolidated knowledge regarding gut peptide physiology as well as emerging new evidence shedding light on the mode of action of previously overlooked gut hormones provide appealing potential obesity and T2DM therapeutic perspectives. The accumulation of evidence from the effect of exogenous administration of native gut peptides alone or in combinations to humans as well as the development of mimetic agents exerting agonistic effects on combinations of gut hormone receptors pave the way for future integrated gut peptide-based treatments, which may mimic the effects of bariatric surgery.

  • Placental proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and IGF-I and IGF–II: levels in umbilical cord blood and associations with birth weight and length
    Metabolism (IF 6.513) Pub Date : 2019-08-08
    Bridget DiPrisco, Ajay Kumar, Bhanu Kalra, Gopal V. Savjani, Zoe Michael, Olivia Farr, Aimilia Papathanasiou, Helen Christou, Christos Mantzoros

    Background A newborn's birth weight for gestational age provides important insights into his or her fetal growth and well-being. While the underlying mechanisms regulating fetal growth remain to be fully elucidated, the IGF-axis plays an important role. Some components of this axis have been well-characterized in umbilical cord blood, but others have not yet been studied. We measured the proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and the established molecules IGF-I and –II in umbilical cord blood to better characterize the IGF axis in relation to birth weight and length. Methods We performed a case-control study of 180 neonates born at a tertiary teaching hospital in Boston. To maximize power, infants were recruited in a 1:3:1 ratio with 37 SGA, 111 AGA, and 37 LGA infants matched by gestational age, sex, and delivery mode. IGFI, IGF-II, IGFBP-4, IGFBP-5, PAPP-A, and PAPP-A2 were measured in umbilical cord blood by ELISA. Associations between birth weight and birth length Z-scores and the Z-scores of the above molecules were analyzed using linear regression models and analysis of covariance. Results Birth weight and length Z-scores were positively associated with Z-scores of IGFI, IGF-II, total IGFBP-4, and IGFBP-5, with IGF-I having the strongest association. Birth weight and length Z-scores were negatively associated with Z-scores of intact IGFBP-4, and PAPP-A and PAPP-A2 levels. Conclusions We confirm previous findings of significant associations between the IGFs in cord blood and newborn size and for the first time show positive associations between cord blood total IGFBP-4 and -5 and birth weight and a negative association between intact IGFBP-4 and birth weight. We also show for the first time a reciprocal relationship between cord blood levels of PAPP-A and PAPP-A2 and newborn size. The implications of these findings need to be further examined in large longitudinal studies and likely have diagnostic and therapeutic potential.

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上海纽约大学William Glover