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Maternal Exercise Preserves Offspring Cardiovascular Health via Oxidative Regulation of the Ryanodine Receptor Mol. Metab. (IF 8.1) Pub Date : 2024-03-11 Kelsey M. Pinckard, Elisa Félix-Soriano, Shanna Hamilton, Radmila Terentyeva, Lisa A. Baer, Katherine R. Wright, Drew Nassal, Joao Victor Esteves, Eaman Abay, Vikram K. Shettigar, Mark T. Ziolo, Thomas J. Hund, Loren E. Wold, Dmitry Terentyev, Kristin I. Stanford
The intrauterine environment during pregnancy is a critical factor in the development of obesity, diabetes, and cardiovascular disease in offspring. Maternal exercise prevents the detrimental effects of a maternal high fat diet on the metabolic health in adult offspring, but the effects of maternal exercise on offspring cardiovascular health have not been thoroughly investigated. To determine the effects
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Adipose tissue peroxisomal lipid synthesis orchestrates obesity and insulin resistance through LXR-dependent lipogenesis Mol. Metab. (IF 8.1) Pub Date : 2024-03-07 Brian Kleiboeker, Anyuan He, Min Tan, Dongliang Lu, Donghua Hu, Xuejing Liu, Parniyan Goodarzi, Fong-Fu Hsu, Babak Razani, Clay F. Semenkovich, Irfan J. Lodhi
Adipose tissue mass is maintained by a balance between lipolysis and lipid storage. The contribution of adipose lipogenesis to fat mass, especially in the setting of high-fat feeding, is considered minor. Here, we report that adipose-specific knockout of the peroxisomal lipid synthetic protein PexRAP promotes diet-induced obesity and insulin resistance through activation of de novo lipogenesis. PexRAP
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Mustn1 is a smooth muscle cell-secreted microprotein that modulates skeletal muscle extracellular matrix composition Mol. Metab. (IF 8.1) Pub Date : 2024-03-06 Serge Ducommun, Paulo R. Jannig, Igor Cervenka, Marta Murgia, Melanie J. Mittenbühler, Ekaterina Chernogubova, José M. Dias, Baptiste Jude, Jorge C. Correia, Jonathan G. Van Vranken, Gabriel Ocana-Santero, Margareta Porsmyr-Palmertz, Sarah McCann Haworth, Vicente Martínez-Redondo, Zhengye Liu, Mattias Carlström, Matthias Mann, Johanna T. Lanner, Ana I. Teixeira, Lars Maegdefessel, Bruce M. Spiegelman
Skeletal muscle plasticity and remodeling are critical for adapting tissue function to use, disuse, and regeneration. The aim of this study was to identify genes and molecular pathways that regulate the transition from atrophy to compensatory hypertrophy or recovery from injury. Here, we have used a mouse model of hindlimb unloading and reloading, which causes skeletal muscle atrophy, and compensatory
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VCD-induced menopause mouse model reveals reprogramming of hepatic metabolism Mol. Metab. (IF 8.1) Pub Date : 2024-03-01 Roshan Kumari, Michael E. Ponte, Edziu Franczak, John C. Prom, Maura F. O'Neil, Mihaela E. Sardiu, Andrew J. Lutkewitte, Lane K. Christenson, Kartik Shankar, E. Matthew Morris, John P. Thyfault
Menopause adversely impacts systemic energy metabolism and increases the risk of metabolic disease(s) including hepatic steatosis, but the mechanisms are largely unknown. Dosing female mice with vinyl cyclohexene dioxide (VCD) selectively causes follicular atresia in ovaries, leading to a murine menopause-like phenotype. In this study, we treated female C57BL6/J mice with VCD (160 mg/kg i.p. for 20
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Role of human Kallistatin in glucose and energy homeostasis in mice Mol. Metab. (IF 8.1) Pub Date : 2024-02-29 Leontine Sandforth, Sebastian Brachs, Julia Reinke, Diana Willmes, Gencer Sancar, Judith Seigner, David Juarez-Lopez, Arvid Sandforth, Jeffrey D. McBride, Jian-Xing Ma, Sven Haufe, Jens Jordan, Andreas L. Birkenfeld
Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown. Kallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT)
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Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic mice Mol. Metab. (IF 8.1) Pub Date : 2024-02-28 Kanikkai Raja Aseer, Caio Henrique Mazucanti, Jennifer F. O’Connell, Isabel González-Mariscal, Anjali Verma, Qin Yao, Christopher Dunn, Qing-Rong Liu, Josephine M. Egan, Máire E. Doyle
Type 1 diabetes (T1D) occurs because of islet infiltration by autoreactive immune cells leading to destruction of beta cells and it is becoming evident that beta cell dysfunction partakes in this process. We previously reported that genetic deletion and pharmacological antagonism of the cannabinoid 1 receptor (CB1) in mice improves insulin synthesis and secretion, upregulates glucose sensing machinery
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Atlas of exercise-induced brain activation in mice Mol. Metab. (IF 8.1) Pub Date : 2024-02-28 Grethe Skovbjerg, Andreas Mæchel Fritzen, Charlotte Sashi Aier Svendsen, Johanna Perens, Jacob Lercke Skytte, Camilla Lund, Jens Lund, Martin Rønn Madsen, Urmas Roostalu, Jacob Hecksher-Sørensen, Christoffer Clemmensen
There is significant interest in uncovering the mechanisms through which exercise enhances cognition, memory, and mood, and lowers the risk of neurodegenerative diseases. In this study, we utilize forced treadmill running and distance-matched voluntary wheel running, coupled with light sheet 3D brain imaging and c-Fos immunohistochemistry, to generate a comprehensive atlas of exercise-induced brain
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Effects of chronic high fat diet on mediobasal hypothalamic satiety neuron function in POMC-Cre mice Mol. Metab. (IF 8.1) Pub Date : 2024-02-21 Özge Başer, Yavuz Yavuz, Deniz Öykü Özen, Hüseyin Buğra Özgün, Sami Ağuş, Cihan Civan Civaş, Deniz Atasoy, Bayram Yılmaz
The prevalence of obesity has increased over the past three decades. Proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC) play a vital role in induction of satiety. Chronic consumption of high-fat diet is known to reduce hypothalamic neuronal sensitivity to hormones like leptin, thus contributing to the development and persistence of obesity. The functional and morphological
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Acetyl-CoA synthetase (ACSS2) does not generate butyryl- and crotonyl-CoA Mol. Metab. (IF 8.1) Pub Date : 2024-02-16 Nour Zeaiter, Laura Belot, Valérie Cunin, Roland Abi Nahed, Malgorzata Tokarska-Schlattner, Audrey Le Gouellec, Carlo Petosa, Saadi Khochbin, Uwe Schlattner
Acetyl and other acyl groups from different short-chain fatty acids (SCFA) competitively modify histones at various lysine sites. To fully understand the functional significance of such histone acylation, a key epigenetic mechanism, it is crucial to characterize the cellular sources of the corresponding acyl-CoA molecules required for the lysine modification. Like acetate, SCFAs such as propionate
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Insulin at the intersection of thermoregulation and glucose homeostasis Mol. Metab. (IF 8.1) Pub Date : 2024-02-13 Nathan C. Winn, Michael W. Schleh, Jamie N. Garcia, Louise Lantier, Owen P. McGuinness, Joslin A. Blair, Alyssa H. Hasty, David H. Wasserman
Mammals are protected from changes in environmental temperature by altering energetic processes that modify heat production. Insulin is the dominant stimulus of glucose uptake and metabolism, which are fundamental for thermogenic processes. The purpose of this work was to determine the interaction of ambient temperature induced changes in energy expenditure (EE) on the insulin sensitivity of glucose
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Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer Mol. Metab. (IF 8.1) Pub Date : 2024-02-13 M. Rufaik Farook, Zack Croxford, Steffan Morgan, Anthony D. Horlock, Amy K. Holt, April Rees, Benjamin J. Jenkins, Carmen Tse, Emma Stanton, D. Mark Davies, Catherine A. Thornton, Nicholas Jones, I. Martin Sheldon, Emma E. Vincent, James G. Cronin
The pyruvate transporter MPC1 (mitochondrial pyruvate carrier 1) acts as a tumour-suppressor, loss of which correlates with a pro-tumorigenic phenotype and poor survival in several tumour types. In high-grade serous ovarian cancers (HGSOC), patients display copy number loss of in around 78% of cases and reduced mRNA expression. To explore the metabolic effect of reduced expression, we demonstrate that
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Letter-to-the-editor on “A low-carbohydrate diet induces hepatic insulin resistance and metabolic associated fatty liver disease in mice” Mol. Metab. (IF 8.1) Pub Date : 2024-02-13 Xin Wang, Bo Jiang
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Intermittent rapamycin feeding recapitulates some effects of continuous treatment while maintaining lifespan extension Mol. Metab. (IF 8.1) Pub Date : 2024-02-13 Maarouf Baghdadi, Tobias Nespital, Carolina Monzó, Joris Deelen, Sebastian Grönke, Linda Partridge
Rapamycin, a powerful geroprotective drug, can have detrimental effects when administered chronically. We determined whether intermittent treatment of mice can reduce negative effects while maintaining benefits of chronic treatment. From 6 months of age, male and female C3B6F1 hybrid mice were either continuously fed with 42 mg/kg rapamycin, or intermittently fed by alternating weekly feeding of 42
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Response-to Letter-to-the-editor: “A low-carbohydrate diet induces hepatic insulin resistance and metabolic associated fatty liver disease in mice” Mol. Metab. (IF 8.1) Pub Date : 2024-02-13 Christian Wolfrum, Tenagne D. Challa
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Treatment of infantile-onset Pompe disease in a rat model with muscle-directed AAV gene therapy Mol. Metab. (IF 8.1) Pub Date : 2024-02-10 Sergio Muñoz, Joan Bertolin, Veronica Jimenez, Maria Luisa Jaén, Miquel Garcia, Anna Pujol, Laia Vilà, Victor Sacristan, Elena Barbon, Giuseppe Ronzitti, Jihad El Andari, Warut Tulalamba, Quang Hong Pham, Jesus Ruberte, Thierry VandenDriessche, Marinee K. Chuah, Dirk Grimm, Federico Mingozzi, Fatima Bosch
Pompe disease (PD) is caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA), leading to progressive glycogen accumulation and severe myopathy with progressive muscle weakness. In the Infantile-Onset PD (IOPD), death generally occurs <1 year of age. There is no cure for IOPD. Mouse models of PD do not completely reproduce human IOPD severity. Our main objective was to generate the first
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The vagus nerve mediates the physiological but not pharmacological effects of PYY3-36 on food intake Mol. Metab. (IF 8.1) Pub Date : 2024-02-08 Aldara Martin Alonso, Simon C. Cork, Phyllis Phuah, Benjamin Hansen, Mariana Norton, Sijing Cheng, Xiang Xu, Kinga Suba, Yue Ma, Georgina KC. Dowsett, John A. Tadross, Brian YH. Lam, Giles SH. Yeo, Herbert Herzog, Stephen R. Bloom, Myrtha Arnold, Walter Distaso, Kevin G. Murphy, Victoria Salem
Peptide YY (PYY) is a post-prandially released gut hormone with potent appetite-reducing activity, the mechanism of action of which is not fully understood. Unravelling how this system physiologically regulates food intake may help unlock its therapeutic potential, whilst minimising unwanted effects. Here we demonstrate that germline and post-natal targeted knockdown of the PYY preferring receptor
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Dysfunction of Akt/FoxO3a/Atg7 regulatory loop magnifies obesity-regulated muscular mass decline Mol. Metab. (IF 8.1) Pub Date : 2024-02-06 Yang Yu, Jing Yang, Lixia Zheng, Han Su, Sunrun Cao, Xuehan Jiang, Xiyan Liu, Weiwei Liu, Zhuo Wang, Fang Meng, Hongde Xu, Deliang Wen, Chen Sun, Xiaoyu Song, Antonio Vidal-Puig, Liu Cao
Myoprotein degradation accelerates in obese individuals, resulting in a decline in muscular mass. Atg7 plays a crucial role in regulating protein stability and function through both autophagy-dependent and independent pathways. As obesity progresses, the expression of gradually rises in muscle tissue. Nonetheless, the precise impact and mechanism of Atg7 in promoting muscle mass decline in obesity
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β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects in obese mice Mol. Metab. (IF 8.1) Pub Date : 2024-02-03 Nina Suda, Alberto Bartolomé, Jiani Liang, Jinsook Son, Yoko Yagishita, Christian Siebel, Domenico Accili, Hongxu Ding, Utpal B. Pajvani
Notch signaling, re-activated in β cells from obese mice and causal to β cell dysfunction, is determined in part by transmembrane ligand availability in a neighboring cell. We hypothesized that β cell expression of Jagged1 determines the maladaptive Notch response and resultant insulin secretory defects in obese mice. We assessed expression of Notch pathway components in high-fat diet-fed (HFD) or
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The aryl hydrocarbon receptor in β-cells mediates the effects of TCDD on glucose homeostasis in mice Mol. Metab. (IF 8.1) Pub Date : 2024-02-02 Myriam P. Hoyeck, Ma. Enrica Angela Ching, Lahari Basu, Kyle van Allen, Jana Palaniyandi, Ineli Perera, Emilia Poleo-Giordani, Antonio A. Hanson, Peyman Ghorbani, Morgan D. Fullerton, Jennifer E. Bruin
Chronic exposure to persistent organic pollutants (POPs) is associated with increased incidence of type 2 diabetes, hyperglycemia, and poor insulin secretion in humans. Dioxins and dioxin-like compounds are a broad class of POPs that exert cellular toxicity through activation of the aryl hydrocarbon receptor (AhR). We previously showed that a single high-dose injection of 2,3,7,8-tetrachlorodibenzo--dioxin
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Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation Mol. Metab. (IF 8.1) Pub Date : 2024-02-01 Marissa N. Trujillo, Erin Q. Jennings, Emely A. Hoffman, Hao Zhang, Aiden M. Phoebe, Grace E. Mastin, Naoya Kitamura, Julie A. Reisz, Emily Megill, Daniel Kantner, Mariola M. Marcinkiewicz, Shannon M. Twardy, Felicidad Lebario, Eli Chapman, Rebecca L. McCullough, Angelo D'Alessandro, Nathaniel W. Snyder, Darren A. Cusanovich, James J. Galligan
Chronic, systemic inflammation is a pathophysiological manifestation of metabolic disorders. Inflammatory signaling leads to elevated glycolytic flux and a metabolic shift towards aerobic glycolysis and lactate generation. This rise in lactate corresponds with increased generation of lactoylLys modifications on histones, mediating transcriptional responses to inflammatory stimuli. Lactoylation is also
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The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis Mol. Metab. (IF 8.1) Pub Date : 2024-02-01 Gianmarco Villano, Erica Novo, Cristian Turato, Santina Quarta, Mariagrazia Ruvoletto, Alessandra Biasiolo, Francesca Protopapa, Monica Chinellato, Andrea Martini, Elisabetta Trevellin, Marnie Granzotto, Stefania Cannito, Laura Cendron, Silvia De Siervi, Maria Guido, Maurizio Parola, Roberto Vettor, Patrizia Pontisso
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NR2F6 is essential for brown adipocyte differentiation and systemic metabolic homeostasis Mol. Metab. (IF 8.1) Pub Date : 2024-02-01 Wei-yu Zhou, Pei Liu, Yi-fan Xia, Yi-jie Shi, Hong-yu Xu, Meng Ding, Qi-qi Yang, Shu-wen Qian, Yan Tang, Yan Lu, Qi-qun Tang, Yang Liu
Brown adipose tissue (BAT) development and function are essential for maintaining energy balance. However, the key factors that specifically regulate brown adipogenesis require further identification. Here, we demonstrated that the nuclear receptor subfamily 2 group F member 6 (NR2F6) played a pivotal role in brown adipogenesis and energy homeostasis. We examined the differentiation of immortalized
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Human ACVR1C missense variants that correlate with altered body fat distribution produce metabolic alterations of graded severity in knock-in mutant mice Mol. Metab. (IF 8.1) Pub Date : 2024-02-01 Pawanrat Tangseefa, Hong Jin, Houyu Zhang, Meng Xie, Carlos F. Ibáñez
Genome-wide studies have identified three missense variants in the human gene , encoding the TGF-β superfamily receptor ALK7, that correlate with altered waist-to-hip ratio adjusted for body mass index (WHR/BMI), a measure of body fat distribution. To move from correlation to causation and understand the effects of these variants on fat accumulation and adipose tissue function, we introduced each of
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Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity Mol. Metab. (IF 8.1) Pub Date : 2024-01-26 Maria F. Fernandes, Juan J. Aristizabal-Henao, Phillip M. Marvyn, Iman M'Hiri, Meghan A. Wiens, Monica Hoang, Manuel Sebastian, Renato Nachbar, Philippe St-Pierre, Kalsha Diaguarachchige De Silva, Geoffrey A. Wood, Jamie W. Joseph, Christine A. Doucette, André Marette, Ken D. Stark, Robin E. Duncan
Lipotoxic injury from renal lipid accumulation in obesity and type 2 diabetes (T2D) is implicated in associated kidney damage. However, models examining effects of renal ectopic lipid accumulation independent of obesity or T2D are lacking. We generated renal tubule-specific adipose triglyceride lipase knockout (RT-SAKO) mice to determine if this targeted triacylglycerol (TAG) over-storage affects glycemic
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Brown adipose Vanin-1 is required for the maintenance of mitochondrial homeostasis and prevents diet-induced metabolic dysfunction Mol. Metab. (IF 8.1) Pub Date : 2024-01-19 Chen Sun, Jiaqi Liang, Jia Zheng, Shuyu Mao, Siyu Chen, Ainiwaer Aikemu, Chang Liu
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Identification of AgRP cells in the murine hindbrain that drive feeding Mol. Metab. (IF 8.1) Pub Date : 2024-01-19 Tomas P. Bachor, Eunsang Hwang, Ernie Yulyaningsih, Kush Attal, Francois Mifsud, Viana Pham, Eirini Vagena, Renzo Huarcaya, Martin Valdearcos, Christian Vaisse, Kevin W. Williams, Paul J. Emmerson, Allison W. Xu
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All–potassium channel CRISPR screening reveals a lysine-specific pathway of insulin secretion Mol. Metab. (IF 8.1) Pub Date : 2024-01-19 Jing Lu, Ru-Xuan Zhao, Feng-Ran Xiong, Juan-Juan Zhu, Ting-Ting Shi, Ying-Chao Zhang, Gong-Xin Peng, Jin-Kui Yang
Objective Genome-scale CRISPR–Cas9 knockout coupled with single-cell RNA sequencing (scRNA-seq) has been used to identify function-related genes. However, this method may knock out too many genes, leading to low efficiency in finding genes of interest. Insulin secretion is controlled by several electrophysiological events, including fluxes of KATP depolarization and K+ repolarization. It is well known
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Hepatic regulator of G protein signaling 14 ameliorates NAFLD through activating cAMP-AMPK signaling by targeting Giα1/3 Mol. Metab. (IF 8.1) Pub Date : 2024-01-17 Junyong Wang, Yaping Guo, Yunduan He, Yifan Qin, Xiuling Li, Ling Yang, Kangdong Liu, Li Xiao
Objective Nonalcoholic fatty liver disease (NAFLD) is an emerging public health threat as the most common chronic liver disease worldwide. However, there remains no effective medication to improve NAFLD. G protein-coupled receptors (GPCRs) are the most frequently investigated drug targets family. The Regulator of G protein signaling proteins 14 (RGS14), as an essential negative modulator of GPCR signaling
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TAAR1 agonists improve glycemic control, reduce body weight and modulate neurocircuits governing energy balance and feeding Mol. Metab. (IF 8.1) Pub Date : 2024-01-16 Nina Dedic, Lien Wang, Eva Hajos-Korcsok, Jacob Hecksher-Sørensen, Urmas Roostalu, Steven P. Vickers, Serena Wu, Christoph Anacker, Colleen Synan, Philip G. Jones, Snezana Milanovic, Seth C. Hopkins, Linda J. Bristow, Kenneth S. Koblan
Objective Metabolic Syndrome, which can be induced or exacerbated by current antipsychotic drugs (APDs), is highly prevalent in schizophrenia patients. Recent preclinical and clinical evidence suggest that agonists at trace amine-associated receptor 1 (TAAR1) have potential as a new treatment option for schizophrenia. Intriguingly, preclinical tudies have also identified TAAR1 as a novel regulator
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Permanent neonatal diabetes-causing insulin mutations have dominant negative effects on beta cell identity Mol. Metab. (IF 8.1) Pub Date : 2024-01-16 Yuwei Zhang, Lina Sui, Qian Du, Leena Haataja, Yishu Yin, Ryan Viola, Shuangyi Xu, Christian Ulrik Nielsson, Rudolph L. Leibel, Fabrizio Barbetti, Peter Arvan, Dieter Egli
Objective Heterozygous coding sequence mutations of the INS gene are a cause of permanent neonatal diabetes (PNDM), requiring insulin therapy similar to T1D. While the negative effects on insulin processing and secretion are known, how dominant insulin mutations result in a continued decline of beta cell function after birth is not well understood. Methods We explored the causes of beta cell failure
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Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism Mol. Metab. (IF 8.1) Pub Date : 2024-01-11 Elizabeth Nunn, Natasha Jaiswal, Matthew Gavin, Kahealani Uehara, Megan Stefkovich, Karima Drareni, Ryan Calhoun, Michelle Lee, Corey D. Holman, Joseph A. Baur, Patrick Seale, Paul M. Titchenell
Objective Glucagon-like peptide 1 (GLP-1) receptor agonists reduce food intake, producing remarkable weight loss in overweight and obese individuals. While much of this weight loss is fat mass, there is also a loss of lean mass, similar to other approaches that induce calorie deficit. Targeting signaling pathways that regulate skeletal muscle hypertrophy is a promising avenue to preserve lean mass
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Long non-coding RNA LncCplx2 regulates glucose homeostasis and pancreatic β cell function Mol. Metab. (IF 8.1) Pub Date : 2024-01-11 Linlin Wang, Liqiao Hu, Xingyue Wang, Zhaoxu Geng, Meng Wan, Junfeng Hao, Huisheng Liu, Yuying Fan, Tao Xu, Zonghong Li
Objective Numerous studies have highlighted the role of clock genes in diabetes disease and pancreatic β cell functions. However, whether rhythmic long non-coding RNAs involve in this process is unknown. Methods RNA-seq and 3’ rapid amplification of cDNA ends (RACE)-PCR were used to identify the rat LncCplx2 in pancreatic β cells. The subcellular analysis with qRT-PCR and RNA-Scope were used to assess
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Programming of cardiac metabolism by miR-15b-5p, a miRNA released in cardiac extracellular vesicles following ischemia-reperfusion injury Mol. Metab. (IF 8.1) Pub Date : 2024-01-11 Lucas C. Pantaleão, Elena Loche, Denise S. Fernandez-Twinn, Laura Dearden, Adriana Córdova-Casanova, Clive Osmond, Minna K. Salonen, Eero Kajantie, Youguo Niu, Juliana de Almeida-Faria, Benjamin D. Thackray, Tuija M. Mikkola, Dino A. Giussani, Andrew J. Murray, Martin Bushell, Johan G. Eriksson, Susan E. Ozanne
Objective We investigated the potential involvement of miRNAs in the developmental programming of cardiovascular diseases (CVD) by maternal obesity. Methods Serum miRNAs were measured in individuals from the Helsinki Birth Cohort (with known maternal body mass index), and a mouse model was used to determine causative effects of maternal obesity during pregnancy and ischemia-reperfusion on offspring
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RIPK3 promotes islet amyloid-induced β-cell loss and glucose intolerance in a humanized mouse model of type 2 diabetes Mol. Metab. (IF 8.1) Pub Date : 2024-01-11 Noyonika Mukherjee, Christopher J. Contreras, Li Lin, Kaitlyn A. Colglazier, Egan G. Mather, Michael A. Kalwat, Nathalie Esser, Steven E. Kahn, Andrew T. Templin
Objective Aggregation of human islet amyloid polypeptide (hIAPP), a β-cell secretory product, leads to islet amyloid deposition, islet inflammation and β-cell loss in type 2 diabetes (T2D), but the mechanisms that underlie this process are incompletely understood. Receptor interacting protein kinase 3 (RIPK3) is a pro-death signaling molecule that has recently been implicated in amyloid-associated
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NF1 deficiency drives metabolic reprogramming in ER+ breast cancer Mol. Metab. (IF 8.1) Pub Date : 2024-01-10 Rachel (Rae) J. House, Elizabeth A. Tovar, Luke N. Redlon, Curt J. Essenburg, Patrick S. Dischinger, Abigail E. Ellis, Ian Beddows, Ryan D. Sheldon, Evan C. Lien, Carrie R. Graveel, Matthew R. Steensma
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Conditional hepatocyte ablation of PDIA1 uncovers indispensable roles in both APOB and MTTP folding to support VLDL secretion Mol. Metab. (IF 8.1) Pub Date : 2024-01-09 Zhouji Chen, Shiyu Wang, Anita Pottekat, Alec Duffey, Insook Jang, Benny H. Chang, Jaehyung Cho, Brian N. Finck, Nicholas O. Davidson, Randal J. Kaufman
Objectives The assembly and secretion of hepatic very low-density lipoprotein (VLDL) plays pivotal roles in hepatic and plasma lipid homeostasis. Protein disulfide isomerase A1 (PDIA1/P4HB) is a molecular chaperone whose functions are essential for protein folding in the endoplasmic reticulum. Here we investigated the physiological requirement in vivo for PDIA1 in maintaining VLDL assembly and secretion
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Deletion of the mitochondrial calcium uniporter in adipose tissue promotes energy expenditure and alleviates diet-induced obesity Mol. Metab. (IF 8.1) Pub Date : 2024-01-09 Mengting Jia, Siqi Liu, Yang Xiao, Zhiwang Zhang, Mingming Li, Xinyu Qi, Xinyi Qi, Lin Yu, Caiyong Zhang, Tianyu Jiang, Tingli Pan, Yu Sun, Jingsu Yu, Songtao Su, Yixing Li, Turtushikh Damba, Khongorzul Batchuluun, Yunxiao Liang, Lei Zhou
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ATP7A-dependent copper sequestration contributes to termination of β-CATENIN signaling during early adipogenesis Mol. Metab. (IF 8.1) Pub Date : 2024-01-06 H. Yang, E. Kabin, Y. Dong, X. Zhang, M. Ralle, S. Lutsenko
Objectives Adipocyte fate determination is tightly regulated by extrinsic signaling pathways and intrinsic metabolic and morphologic changes that maintain adipose tissue function. Copper (Cu) homeostasis is required for the normal metabolism of mature adipocytes, whereas the role of Cu in adipogenesis is unclear. Methods To determine the role of Cu is adipocytes differentiation, we used 3T3-L1 adipocytes
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Adipose knockout of H-ferritin improves energy metabolism in mice Mol. Metab. (IF 8.1) Pub Date : 2024-01-05 Binyu Lu, Shanshan Guo, Jialin Zhao, Xiaoting Wang, Bing Zhou
Objective Ferritin, the principal iron storage protein, is essential to iron homeostasis. How iron homeostasis affects the adipose tissue is not well understood. We investigated the role of ferritin heavy chain in adipocytes in energy metabolism. Methods We generated adipocyte-specific ferritin heavy chain (Fth, also known as Fth1) knockout mice, herein referred to as FthAKO. These mice were analyzed
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Two-step regulation by matrix Gla protein in brown adipose cell differentiation Mol. Metab. (IF 8.1) Pub Date : 2024-01-04 Li Zhang, Xinjiang Cai, Feiyang Ma, Xiaojing Qiao, Jaden Ji, Jocelyn A. Ma, Laurent Vergnes, Yan Zhao, Yucheng Yao, Xiuju Wu, Kristina I. Boström
Objective Bone morphogenetic protein (BMP) signaling is intricately involved in adipose tissue development. BMP7 together with BMP4 have been implicated in brown adipocyte differentiation but their roles during development remains poorly specified. Matrix Gla protein (MGP) inhibits BMP4 and BMP7 and is expressed in endothelial and progenitor cells. The objective was to determine the role of MGP in
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A viral insulin-like peptide inhibits IGF-1 receptor phosphorylation and regulates IGF1R gene expression Mol. Metab. (IF 8.1) Pub Date : 2024-01-03 Martina Chrudinová, Nicholas S. Kirk, Aurelien Chuard, Hari Venugopal, Fa Zhang, Marta Lubos, Vasily Gelfanov, Terezie Páníková, Lenka Žáková, Julianne Cutone, Matthew Mojares, Richard DiMarchi, Jiří Jiráček, Emrah Altindis
Objective The insulin/IGF superfamily is conserved across vertebrates and invertebrates. Our team has identified five viruses containing genes encoding viral insulin/IGF-1 like peptides (VILPs) closely resembling human insulin and IGF-1. This study aims to characterize the impact of Mandarin fish ranavirus (MFRV) and Lymphocystis disease virus-Sa (LCDV-Sa) VILPs on the insulin/IGF system for the first
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Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice Mol. Metab. (IF 8.1) Pub Date : 2023-12-30 Alena Akhmetshina, Valentina Bianco, Ivan Bradić, Melanie Korbelius, Anita Pirchheim, Katharina B. Kuentzel, Thomas O. Eichmann, Helga Hinteregger, Dagmar Kolb, Hansjoerg Habisch, Laura Liesinger, Tobias Madl, Wolfgang Sattler, Branislav Radović, Simon Sedej, Ruth Birner-Gruenberger, Nemanja Vujić, Dagmar Kratky
Objective Lysosomal acid lipase (LAL) is the only enzyme known to hydrolyze cholesteryl esters (CE) and triacylglycerols in lysosomes at an acidic pH. Despite the importance of lysosomal hydrolysis in skeletal muscle (SM), research in this area is limited. We hypothesized that LAL may play an important role in SM development, function, and metabolism as a result of lipid and/or carbohydrate metabolism
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Sestrin2 maintains hepatic immune homeostasis and redox balance partially via inhibiting RIPK3-mediated necroptosis in metabolic dysfunction-associated steatohepatitis Mol. Metab. (IF 8.1) Pub Date : 2023-12-30 Jian-Bin Zhang, Qian-Ren Zhang, Qian Jin, Jing Yang, Shuang-Zhe Lin, Jian-Gao Fan
Background & aims Necroptosis, a novel type of programmed cell death, is intricately associated with inflammatory response. Currently, most studies focus on the activation of necroptosis, while the mechanisms underlying the negative regulation of necroptosis remain poorly understood. Methods The effects of sestrin2 (SESN2) overexpression or knockdown on the regulation of necroptosis were assessed in
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Endothelin receptor B-deficient mice are protected from high-fat diet-induced metabolic syndrome Mol. Metab. (IF 8.1) Pub Date : 2023-12-28 Martina Feger, Leonie Meier, Jörg Strotmann, Miriam Hoene, Julia Vogt, Alexandra Wisser, Susanna Hirschle, Marie-Jo Kheim, Berthold Hocher, Cora Weigert, Michael Föller
Objective Endothelin receptor B (ETB) together with ETA mediates cellular effects of endothelin 1 (ET-1), an autocrine and endocrine peptide produced by the endothelium and other cells. It regulates vascular tone and controls kidney function. Metabolic syndrome is due to high caloric intake and is characterized by insulin resistance, dyslipidemia, and white adipose tissue (WAT) accumulation. ETA/ETB
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Exploring the role of purinergic receptor P2RY1 in type 2 diabetes risk and pathophysiology: Insights from human functional genomics Mol. Metab. (IF 8.1) Pub Date : 2023-12-28 Arnaud Dance, Justine Fernandes, Bénédicte Toussaint, Emmanuel Vaillant, Raphaël Boutry, Morgane Baron, Hélène Loiselle, Beverley Balkau, Guillaume Charpentier, Sylvia Franc, Mark Ibberson, Michel Marre, Marie Gernay, Marjorie Fadeur, Nicolas Paquot, Martine Vaxillaire, Mathilde Boissel, Souhila Amanzougarene, Mehdi Derhourhi, Amna Khamis, Amélie Bonnefond
Objective Human functional genomics has proven powerful in discovering drug targets for common metabolic disorders. Through this approach, we investigated the involvement of the purinergic receptor P2RY1 in type 2 diabetes (T2D). Methods P2RY1 was sequenced in 9,266 participants including 4,177 patients with T2D. In vitro analyses were then performed to assess the functional effect of each variant
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Hepatic GRK2 is dispensable for glucose homeostasis and other key metabolic parameters in mice Mol. Metab. (IF 8.1) Pub Date : 2023-12-28 Antwi-Boasiako Oteng, Srinivas Pittala, Andrea Kliewer, Yishu Qiu, Jürgen Wess
Objective G-protein-coupled receptor (GPCR) kinases (GRKs) abrogate GPCR signaling by promoting receptor desensitization and internalization. Accumulating evidence suggests that GRK2 represents an important regulator of GPCR-mediated effects on systemic glucose metabolism, obesity, and insulin resistance. Despite the key role of the liver in maintaining euglycemia, the potential metabolic relevance
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Maternal Western diet programs cardiometabolic dysfunction and hypothalamic inflammation via epigenetic mechanisms predominantly in the male offspring Mol. Metab. (IF 8.1) Pub Date : 2023-12-28 Mona Elgazzaz, Clara Berdasco, Jone Garai, Melody Baddoo, Shiping Lu, Hisham Daoud, Jovanny Zabaleta, Franck Mauvais-Jarvis, Eric Lazartigues
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Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes Mol. Metab. (IF 8.1) Pub Date : 2023-12-23 Anna Janz, Katharina Walz, Alexandra Cirnu, Jessica Surjanto, Daniela Urlaub, Miriam Leskien, Michael Kohlhaas, Alexander Nickel, Theresa Brand, Naoko Nose, Philipp Wörsdörfer, Nicole Wagner, Takahiro Higuchi, Christoph Maack, Jan Dudek, Kristina Lorenz, Eva Klopocki, Süleyman Ergün, Henry J. Duff, Brenda Gerull
Background Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19
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Activation of a non-neuronal cholinergic system in visceral white adipose tissue of obese mice and humans Mol. Metab. (IF 8.1) Pub Date : 2023-12-22 Ilenia Severi, Jessica Perugini, Chiara Ruocco, Lara Coppi, Silvia Pedretti, Eleonora Di Mercurio, Martina Senzacqua, Maurizio Ragni, Gabriele Imperato, Alessandra Valerio, Nico Mitro, Maurizio Crestani, Enzo Nisoli, Antonio Giordano
Background and objectives Since white adipose tissue (WAT) lacks parasympathetic cholinergic innervation, the source of the acetylcholine (ACh) acting on white adipocyte cholinergic receptors is unknown. This study was designed to identify ACh-producing cells in mouse and human visceral WAT and to determine whether a non-neuronal cholinergic system becomes activated in obese inflamed WAT. Methods Mouse
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Developmental metformin exposure does not rescue physiological impairments derived from early exposure to altered maternal metabolic state in offspring mice Mol. Metab. (IF 8.1) Pub Date : 2023-12-23 Lídia Cantacorps, Jiajie Zhu, Selma Yagoub, Bethany M. Coull, Joanne Falck, Robert A. Chesters, Katrin Ritter, Miguel Serrano-Lope, Katharina Tscherepentschuk, Lea-Sophie Kasch, Maya Paterson, Paula Täger, David Baidoe-Ansah, Shuchita Pandey, Carla Igual-Gil, Annett Braune, Rachel N. Lippert
Objective The incidence of gestational diabetes mellitus (GDM) and metabolic disorders during pregnancy are increasing globally. This has resulted in increased use of therapeutic interventions such as metformin to aid in glycemic control during pregnancy. Even though metformin can cross the placental barrier, its impact on offspring brain development remains poorly understood. As metformin promotes
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Hindbrain REV-ERB nuclear receptors regulate sensitivity to diet-induced obesity and brown adipose tissue pathophysiology Mol. Metab. (IF 8.1) Pub Date : 2023-12-23 Lauren N. Woodie, Lily C. Melink, Ahren J. Alberto, Michelle Burrows, Samantha M. Fortin, Calvin C. Chan, Matthew R. Hayes, Mitchell A. Lazar
Objective The dorsal vagal complex (DVC) of the hindbrain is a major point of integration for central and peripheral signals that regulate a wide variety of metabolic functions to maintain energy balance. The REV-ERB nuclear receptors are important modulators of molecular metabolism, but their role in the DVC has yet to be established. Methods Male REV-ERBα/β floxed mice received stereotaxic injections
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Lysine tRNA fragments and miR-194-5p co-regulate hepatic steatosis via β-Klotho and perilipin 2 Mol. Metab. (IF 8.1) Pub Date : 2023-12-22 Yonat Tzur, Katarzyna Winek, Nimrod Madrer, Serafima Dubnov, Estelle R. Bennett, David S. Greenberg, Geula Hanin, Asaad Gammal, Joseph Tam, Isaiah T. Arkin, Iddo Paldor, Hermona Soreq
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A forebrain-hypothalamic ER stress driven circuit mediates hepatic steatosis during obesity Mol. Metab. (IF 8.1) Pub Date : 2023-12-21 Katherine Blackmore, Claire J. Houchen, Hayk Simonyan, Hovhannes Arestakesyan, Alyssa K. Stark, Samantha A. Dow, Han Rae Kim, Jin Kwon Jeong, Anastas Popratiloff, Colin N. Young
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Molecular profiling of high-level athlete skeletal muscle after acute endurance or resistance exercise – A systems biology approach Mol. Metab. (IF 8.1) Pub Date : 2023-12-21 Stefan M. Reitzner, Eric B. Emanuelsson, Muhammad Arif, Bogumil Kaczkowski, Andrew TJ. Kwon, Adil Mardinoglu, Erik Arner, Mark A. Chapman, Carl Johan Sundberg
Objective Long-term high-level exercise training leads to improvements in physical performance and multi-tissue adaptation following changes in molecular pathways. While skeletal muscle baseline differences between exercise-trained and untrained individuals have been previously investigated, it remains unclear how training history influences human multi-omics responses to acute exercise. Methods We
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Adipose retinol saturase is regulated by β-adrenergic signaling and its deletion impairs lipolysis in adipocytes and acute cold tolerance in mice Mol. Metab. (IF 8.1) Pub Date : 2023-12-19 Chen Li, Marie F. Kiefer, Sarah Dittrich, Roberto E. Flores, Yueming Meng, Na Yang, Sascha Wulff, Sabrina Gohlke, Manuela Sommerfeld, Sylvia J. Wowro, Konstantin M. Petricek, Dominic Dürbeck, Leonard Spranger, Knut Mai, Holger Scholz, Tim J. Schulz, Michael Schupp
Objective Retinol saturase (RetSat) is an endoplasmic reticulum-localized oxidoreductase highly expressed in organs involved in lipid metabolism such as white (WAT) and brown adipose tissue (BAT). Cold exposure was shown to increase RETSAT protein in BAT but its relevance for non-shivering thermogenesis, a process with beneficial effects on metabolic health, is unknown. Methods We analyzed the regulation
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Need for speed: Human fast-twitch mitochondria favor power over efficiency Mol. Metab. (IF 8.1) Pub Date : 2023-12-15 Sebastian Edman, Mikael Flockhart, Filip J. Larsen, William Apró
Objective Human skeletal muscle consists of a mixture of slow- and fast-twitch fibers with distinct capacities for contraction mechanics, fermentation, and oxidative phosphorylation. While the divergence in mitochondrial volume favoring slow-twitch fibers is well established, data on the fiber type-specific intrinsic mitochondrial function and morphology are highly limited with existing data mainly
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Insulin regulates human pancreatic endocrine cell differentiation in vitro Mol. Metab. (IF 8.1) Pub Date : 2023-12-14 Perla Cota, Özüm Sehnaz Caliskan, Aimée Bastidas-Ponce, Changying Jing, Jessica Jaki, Lama Saber, Oliver Czarnecki, Damla Taskin, Anna Karolina Blöchinger, Thomas Kurth, Michael Sterr, Ingo Burtscher, Natalie Krahmer, Heiko Lickert, Mostafa Bakhti
Objective The consequences of mutations in genes associated with monogenic forms of diabetes on human pancreas development cannot be studied in a time-resolved fashion in vivo. More specifically, if recessive mutations in the insulin gene influence human pancreatic endocrine lineage formation is still an unresolved question. Methods To model the extremely reduced insulin levels in patients with recessive
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Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation Mol. Metab. (IF 8.1) Pub Date : 2023-12-12 Da Mi Kim, Jong Han Lee, Quan Pan, Hye Won Han, Zheng Shen, Sahar Eshghjoo, Chia-Shan Wu, Wanbao Yang, Ji Yeon Noh, David W. Threadgill, Shaodong Guo, Gus Wright, Robert Alaniz, Yuxiang Sun
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Overexpression of ORMDL3 confers sexual dimorphism in diet-induced non-alcoholic steatohepatitis Mol. Metab. (IF 8.1) Pub Date : 2023-12-09 Ryan D.R. Brown, Christopher D. Green, Cynthia Weigel, Bin Ni, Francesco S. Celi, Richard L. Proia, Sarah Spiegel
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Evaluation of long acting GLP1R/GCGR agonist in a DIO and biopsy-confirmed mouse model of NASH suggest a beneficial role of GLP-1/glucagon agonism in NASH patients Mol. Metab. (IF 8.1) Pub Date : 2023-12-07 Thomas Monfeuga, Jenny Norlin, Anne Bugge, Elisabeth D. Gaalsgaard, Cesar A. Prada-Medina, Markus Latta, Sanne S. Veidal, Pia S. Petersen, Michael Feigh, Dorte Holst
Objective The metabolic benefits of GLP-1 receptor (GLP-1R) agonists on glycemic and weight control are well established as therapy for type 2 diabetes and obesity. Glucagon's ability to increase energy expenditure is well described, and the combination of these mechanisms-of-actions has the potential to further lower hepatic steatosis in metabolic disorders and could therefore be attractive for the