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  • Melatonin Effects on Glucose Metabolism: Time To Unlock the Controversy
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2020-01-01
    Marta Garaulet; Jingyi Qian; Jose C. Florez; Josephine Arendt; Richa Saxena; Frank A.J.L. Scheer

    The past decade has witnessed a revival of interest in the hormone melatonin, partly attributable to the discovery that genetic variation in MTNR1B – the melatonin receptor gene – is a risk factor for impaired fasting glucose and type 2 diabetes (T2D). Despite intensive investigation, there is considerable confusion and seemingly conflicting data on the metabolic effects of melatonin and MTNR1B variation, and disagreement on whether melatonin is metabolically beneficial or deleterious, a crucial issue for melatonin agonist/antagonist drug development and dosing time. We provide a conceptual framework – anchored in the dimension of 'time' – to reconcile paradoxical findings in the literature. We propose that the relative timing between elevated melatonin concentrations and glycemic challenge should be considered to better understand the mechanisms and therapeutic opportunities of melatonin signaling in glycemic health and disease.

  • Uterine Luminal Epithelium as the Transient Gateway for Embryo Implantation
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-12-20
    Xiaoqin Ye

    The uterine luminal epithelium (LE) is the first maternal contact for an implanting embryo. Intrauterine fluid resorption, cessation of LE proliferation and apoptosis, and LE structural changes are prerequisites for establishing transient uterine receptivity for embryo implantation. Vesicle trafficking in the LE and receptor-mediated paracrine and autocrine mechanisms are crucial both for LE preparation and LE communications with the embryo and stroma during the initiation of embryo implantation. This review mainly covers recent in vivo studies in LE of mouse models from 0.5 days post-coitus (D0.5) to ∼D4 20 h when the trophoblasts pass through the LE layer for embryo implantation. The review is organized into three interconnected sections: preimplantation LE preparation for embryo attachment, embryo–LE communications, and LE–stroma communications.

  • Metabolism, Epigenetics, and Causal Inference in Heart Failure
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-12-19
    Todd H. Kimball; Thomas M. Vondriska

    Eukaryotes must balance the metabolic and cell death actions of mitochondria via control of gene expression and cell fate by chromatin, thereby functionally binding the metabolome and epigenome. This interaction has far-reaching implications for chronic diseases in humans, the most common of which are those of the cardiovascular system. The most devastating consequence of cardiovascular disease, heart failure, is not a single disease, diagnosis, or endpoint. Human and animal studies have revealed that, regardless of etiology and symptoms, heart failure is universally associated with abnormal metabolism and gene expression – to frame this as cause or consequence, however, may be to wrongfoot the question. This essay aims to challenge current thinking on metabolic–epigenetic crosstalk in heart failure, presenting hypotheses for how chronic diseases arise, take hold, and persist. We unpack assumptions about the order of operations for gene expression and metabolism, exploring recent findings in noncardiac systems that link metabolic intermediates directly to chromatin remodeling. Lastly, we discuss potential mechanisms by which chromatin may serve as a substrate for metabolic memory, and how changes in cellular transcriptomes (and hence in cellular behavior) in response to stress correspond to global changes in chromatin accessibility and structure.

  • Science and Health Policies to Tackle Chronic Diseases in Chile
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-12-16
    Claudia Bambs; Roberto Bravo-Sagua; Paula Margozzini; Sergio Lavandero

    Chile has experienced rapid epidemiological transitions characterized by decreasing infant mortality, population aging, and a shift towards obesity with an increase in noncommunicable diseases (NCDs). Today, tobacco, alcohol, and ultraprocessed foods are the main risk factors for these diseases. Based on Chile’s experience in tobacco control, we discuss paths to make progress in population evidence-based strategies to improve overall community health.

  • Mineralocorticoid Receptors in Metabolic Syndrome: From Physiology to Disease
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-12-14
    Alessandra Feraco; Vincenzo Marzolla; Angelo Scuteri; Andrea Armani; Massimiliano Caprio

    Over the past decade, several studies have shown that activity of extra-renal mineralocorticoid receptors (MR) regulates vascular tone, adipogenesis, adipose tissue function, and cardiomyocyte contraction. In mice, abnormal activation of MR in the vasculature and in adipose tissue favors the occurrence of several components of the metabolic syndrome (MetS), such as hypertension, obesity, and glucose intolerance. Accordingly, high levels of aldosterone are associated with obesity and MetS in humans, suggesting that altered activation of aldosterone-MR system in extra-renal tissues leads to profound metabolic dysfunctions. In this context, in addition to the classical indications for heart failure and hypertension, MR antagonists (MRAs) nowadays represent a promising approach to tackle cardiovascular and metabolic disorders occurring in the MetS.

  • Endocrinological Toxicity Secondary to Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs)
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-12-12
    Krystallenia I. Alexandraki; Kosmas Daskalakis; Marina Tsoli; Ashley B. Grossman; Gregory A. Kaltsas

    Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasingly recognized, characterized by prolonged survival even with metastatic disease. Their medical treatment is complex involving various specialties, necessitating awareness of treatment-related adverse effects (AEs). As GEP-NENs express somatostatin receptors (SSTRs), long-acting somatostatin analogs (SSAs) that are used for secretory syndrome and tumor control may lead to altered glucose metabolism. Everolimus and sunitinib are molecular targeted agents that affect glucose and lipid metabolism and may induce hypothyroidism or hypocalcemia, respectively. Chemotherapeutic drugs can affect the reproductive system and water homeostasis, whereas immunotherapeutic agents can cause hypophysitis and thyroiditis or other immune-mediated disorders. Treatment with radiopeptides may temporarily lead to radiation-induced hormone disturbances. As drugs targeting GEP-NENs are increasingly introduced, recognition and management of endocrine-related AEs may improve compliance and the quality of life of these patients.

  • Role of Lipoproteins in the Microenvironment of Hormone-Dependent Cancers
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-12-11
    Monica Gomaraschi

    The tumor microenvironment (TME) is an attractive target to develop novel strategies for hormone-dependent cancers. Several molecules in the TME can favor tumor development and progression, including lipoproteins. Lipoproteins are taken up by cancer cells, providing them with cholesterol and fatty acids. Cholesterol regulates cell signaling and it is converted into a series of bioactive metabolites, including hormones. The conflicting results of epidemiological and interventional studies suggest that the local availability of lipoproteins in the TME is more relevant for cancer biology than their circulating levels. Thus, reducing lipoprotein uptake and stimulating cell cholesterol efflux to high-density lipoproteins (HDLs) can represent a novel adjuvant strategy for cancer management. HDL-like particles can also act as drug delivery systems for tumor targeting.

  • Reducing Type 1 Diabetes Mortality: Role for Adjunctive Therapies?
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-12-07
    Jennifer R. Snaith, Deborah J. Holmes-Walker, Jerry R. Greenfield

    Individuals with type 1 diabetes (T1D) frequently fail to achieve glycemic goals and have excess cardiovascular risk and premature death. Adjunctive agents may play a role in reducing morbidity, mortality, and the adverse sequelae of insulin treatment. A surge in type 2 diabetes drug development has revealed agents with benefits beyond glucose lowering, including cardiovascular risk reduction. Could these benefits translate to T1D? Specific trials for T1D demonstrate substantial hemoglobin (Hb)A1c reductions with sodium glucose cotransporter inhibitors (SGLTis) and glucagon-like peptide (GLP)1 agonists, and modest improvements with metformin, dipeptidyl peptidase-4 inhibitor (DPP4i), and pramlintide. Studies exploring cardiovascular risk reduction are warranted. This review synthesizes the emerging literature for researchers and clinicians treating people with T1D. Challenges in T1D research are discussed.

  • Impacts of Caffeine during Pregnancy
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-12-06
    Jingjing Qian, Qi Chen, Sean M. Ward, Enkui Duan, Ying Zhang

    Epidemiological studies have revealed that caffeine consumption during pregnancy is associated with adverse gestational outcomes, yet the underlying mechanisms remain obscure. Recent animal studies with physiologically relevant dosages have begun to dissect adverse effects of caffeine during pregnancy with respect to oviduct contractility, embryo development, uterine receptivity, and placentation that jointly contribute to pregnancy complications. Interestingly, caffeine’s effects are highly variable between individual animals under well-controlled experimental settings, suggesting the possibility of epigenetic regulation of these phenotypes, in addition to genetic variants. Moreover, caffeine exposure during sensitive windows of pregnancy may induce epigenetic changes in the developing fetus or even the germ cells to cause adult-onset diseases in subsequent generations. We discuss these research frontiers in light of emerging data.

  • Coronary Microvascular Dysfunction and Estrogen Receptor Signaling
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-29
    Elif Tunc, Alicia Arredondo Eve, Zeynep Madak-Erdogan

    Chest pain with non-obstructive coronary artery disease (NOCAD) occurs more frequently in women than in men and is mainly related to coronary microvascular disease (CMD). The majority of CMD patients are postmenopausal women, suggesting a role for lack of estrogens in the development and progression of CMD. Patients are often discharged without a clear treatment plan due to the limited understanding of etiology and diagnostic parameters of CMD and have significantly higher rates of future cardiovascular events. Thus, there is a need for a better understanding of the underlying biology, and CMD-specific diagnostic tests and therapies. In this article, we reviewed recent studies on CMD, estrogen action in coronary microvasculature, and diagnosis and treatment options for CMD in postmenopausal women.

  • A Novel Mechanism for Th17 Inflammation in Human Type 2 Diabetes Mellitus
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-22
    Kaitlin Kiernan, Nancie J. MacIver

    In their recent study, Nicholas et al. challenge the current dogma that T cell inflammation must be fueled by glycolysis and demonstrate a novel metabolic mechanism for Th17 inflammation in human type 2 diabetes mellitus (T2DM): a combination of increased environmental long-chain fatty acid metabolites coupled with decreased fatty acid oxidation.

  • Methylglyoxal Metabolism and Aging-Related Disease: Moving from Correlation toward Causation
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-19
    Rasmus Kold-Christensen, Mogens Johannsen

    Methylglyoxal (MG) is a ubiquitous metabolite that spontaneously reacts with biopolymers forming advanced glycation end-products (AGEs). AGEs are strongly associated with aging-related diseases, including cancer, neurodegenerative diseases, and diabetes. As the formation of AGEs is nonenzymatic, the damage caused by MG and AGEs has been regarded as unspecific. This may have resulted in the field generally been regarded as unappealing by many researchers, as detailed mechanisms have been difficult to probe. However, accumulating evidence highlighting the importance of MG in human metabolism and disease, as well as data revealing how MG can elicit its signaling function via specific protein AGEs, could change the current mindset, accelerating the field to the forefront of future research.

  • Diet-Induced Modification of the Sperm Epigenome Programs Metabolism and Behavior
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-16
    Carina Bodden, Anthony J. Hannan, Amy C. Reichelt

    Globally, obesity has reached epidemic proportions. The rapidly increasing numbers of overweight people can be traced back to overconsumption of energy-dense, poor-quality foods as well as physical inactivity. This development has far-reaching and costly implications. Not only is obesity associated with serious physiological and psychological complications, but mounting evidence also indicates a ripple effect through generations via epigenetic changes. Parental obesity could induce intergenerational and transgenerational changes in metabolic and brain function of the offspring. Most research has focused on maternal epigenetic and gestational effects; however, paternal contributions are likely to be substantial. We focus on the latest advances in understanding the mechanisms of epigenetic inheritance of obesity-evoked metabolic and neurobiological changes through the paternal germline that predict wide-ranging consequences for the following generation(s).

  • Immunoregulatory Functions of Nuclear Receptors: Mechanisms and Therapeutic Implications
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-06
    Linjie Zhao, Ryan C. Gimple, Zhengnan Yang, Yuquan Wei, Jan-Åke Gustafsson, Shengtao Zhou

    Members of the nuclear receptor superfamily serve as master regulators in signaling by either positively or negatively regulating gene expression. Accumulating evidence has suggested that nuclear receptors are actively involved in immune responses, with specific roles in different immune cell compartments that contribute to both normal function and to disease development. The druggable properties of nuclear receptors have made them ideal modulatory therapeutic targets. Here, we revisit nuclear receptor biology, summarize recent advances in our understanding of the immunological functions of nuclear receptors, describe cell-type-specific roles and specific nuclear receptors in disease pathogenesis, and explore their potential as novel therapeutic targets. These nuclear receptor-dependent alterations in the immune system are amenable to pharmacological manipulation and suggest novel therapeutic strategies.

  • Temporally Tuned Corticosteroid Feedback Regulation of the Stress Axis
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-05
    Joon S. Kim, Karl J. Iremonger

    Activity of the hypothalamic–pituitary–adrenal (HPA) axis is tuned by corticosteroid feedback. Corticosteroids regulate cellular function via genomic and nongenomic mechanisms, which operate over diverse time scales. This review summarizes recent advances in our understanding of how corticosteroid feedback regulates hypothalamic stress neuron function and output through synaptic plasticity, changes in intrinsic excitability, and modulation of neuropeptide production. The temporal kinetics of corticosteroid actions in the brain versus the pituitary have important implications for how organisms respond to stress. Furthermore, we will discuss, some of the technical limitations and missing links in the field, and the potential implications these may have on our interpretations of corticosteroid negative feedback experiments.

  • Epigenetic Mechanisms of the Glucocorticoid Receptor
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-05
    Andrew A. Bartlett, Hannah E. Lapp, Richard G. Hunter

    The glucocorticoid receptor (GR) has been shown to be important for mediating cellular responses to stress and circulating glucocorticoids. Ligand-dependent transcriptional changes induced by GR are observed across numerous tissues. However, the mechanisms by which GR achieves cell and tissue-specific effects are less clear. Epigenetic mechanisms have been proposed to explain some of these differences as well as some of the lasting, even transgenerational, effects of stress and glucocorticoid action. GR functions in tandem with epigenetic cellular machinery to coordinate transcription and shape chromatin structure. Here, we describe GR interactions with these effectors and how GR acts to reshape the epigenetic landscape in response to the environment.

  • Avian Leptin: Bird’s-Eye View of the Evolution of Vertebrate Energy-Balance Control
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-05
    Miriam Friedman-Einat, Eyal Seroussi

    Discovery of the satiety hormone leptin in 1994 and its characterization in mammals provided a key tool to deciphering the complex mechanism governing adipose tissue regulation of appetite and energy expenditure. Surprisingly, despite the perfectly logical notion of an energy-storing tissue announcing the amount of fat stores using leptin signaling, alternate mechanisms were chosen in bird evolution. This conclusion emerged based on the recent discovery and characterization of genuine avian leptin – after it had been assumed missing by some, and erroneously identified by others. Critical evaluation of the past and present indications of the role of leptin in Aves provides a new perspective on the evolution of energy-balance control in vertebrates; proposing a regulation strategy alternative to the adipostat mechanism.

  • Diabetes Type 2 and Kisspeptin: Central and Peripheral Sex-Specific Actions
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-05
    Monika Dudek, Kamil Ziarniak, Marie-Line Cateau, Laurence Dufourny, Joanna Helena Sliwowska

    Kisspeptin (KP) plays a major role in the regulation of reproduction governed by the hypothalamic–pituitary–gonadal (HPG) axis. However, recent findings suggest that the KP system is present not only centrally (at the level of the hypothalamus), but also in the peripheral organs crucial for the control of metabolism. The KP system is sexually differentiated in the hypothalamus, and it is of particular interest to study whether sex-specific responses to type 2 diabetes (DM2) exist centrally and peripherally. As collection of data is limited in humans, animal models of DM2 are useful to understand crosstalk between metabolism and reproduction. Sex-specific variations in the KP system reported in animals suggest a need for the development of gender specific therapeutic strategies to treat DM2.

  • PTH/PTHrP Receptor Signaling, Allostery, and Structures
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-05
    Ieva Sutkeviciute, Lisa J. Clark, Alex D. White, Thomas J. Gardella, Jean-Pierre Vilardaga

    The parathyroid hormone (PTH) type 1 receptor (PTHR) is the canonical G protein-coupled receptor (GPCR) for PTH and PTH-related protein (PTHrP) and the key regulator of calcium homeostasis and bone turnover. PTHR function is critical for human health to maintain homeostatic control of ionized serum Ca2+ levels and has several unusual signaling features, such as endosomal cAMP signaling, that are well-studied but not structurally understood. In this review, we discuss how recently solved high resolution near-atomic structures of hormone-bound PTHR in its inactive and active signaling states and discovery of extracellular Ca2+ allosterism shed light on the structural basis for PTHR signaling and function.

  • Pros and Cons of Chaperone-Mediated Autophagy in Cancer Biology
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-04
    Esperanza Arias, Ana Maria Cuervo

    Autophagy contributes to cellular quality control and energetics through lysosomal breakdown and recycling of essential cellular components. Chaperone-mediated autophagy (CMA) adds to these autophagic functions the ability to timely and selectively degrade single tagged proteins to terminate their cellular function and, in this way, participate in the regulation of multiple cellular processes. Many cancer cells upregulate CMA for protumorigenic and prosurvival purposes. However, growing evidence supports a physiological role for CMA in limiting malignant transformation. Understanding the mechanisms behind this functional switch of CMA from antioncogenic to pro-oncogenic is fundamental for targeting CMA in cancer treatment. We summarize current understanding of CMA functions in cancer biology and discuss the basis for its context-dependent dual role in oncogenesis.

  • Growth Factor-Dependent and -Independent Activation of mTORC2
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-04
    Jonas R. Knudsen, Andreas M. Fritzen, David E. James, Thomas E. Jensen, Maximilian Kleinert, Erik A. Richter

    The target of rapamycin complex 2 (TORC2) was discovered in 2002 in budding yeast. Its mammalian counterpart, mTORC2, was first described in 2004. Soon thereafter it was demonstrated that mTORC2 directly phosphorylates Akt on Ser473, ending a long search for the elusive ‘second’ insulin-responsive Akt kinase. In this review we discuss key evidence pertaining to the subcellular localization of mTORC2, highlighting a spatial heterogeneity that relates to mTORC2 activation. We summarize current models for how growth factors (GFs), such as insulin, trigger mTORC2 activation, and we provide a comprehensive discussion focusing on a new exciting frontier, the molecular mechanisms underpinning GF-independent activation of mTORC2.

  • Role of Nitric Oxide in Insulin Secretion and Glucose Metabolism
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-11-02
    Zahra Bahadoran, Parvin Mirmiran, Asghar Ghasemi

    Nitric oxide (NO) contributes to carbohydrate metabolism and decreased NO bioavailability is involved in the development of type 2 diabetes mellitus (T2DM). NO donors may improve insulin signaling and glucose homeostasis in T2DM and insulin resistance (IR), suggesting the potential clinical importance of NO-based interventions. In this review, site-specific roles of the NO synthase (NOS)–NO pathway in carbohydrate metabolism are discussed. In addition, the metabolic effects of physiological low levels of NO produced by constitutive NOS (cNOS) versus pathological high levels of NO produced by inducible NOS (iNOS) in pancreatic β-cells, adipocytes, hepatocytes, and skeletal muscle cells are summarized. A better understanding of the NOS–NO system in the regulation of glucose homeostasis can hopefully facilitate the development of new treatments for T2DM.

  • Intersection of the Gut Microbiome and Circadian Rhythms in Metabolism
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-31
    Katya Frazier, Eugene B. Chang

    The gut microbiome and circadian rhythms (CRs) both exhibit unique influence on mammalian hosts and have been implicated in the context of many diseases, particularly metabolic disorders. It has become increasingly apparent that these systems also interact closely to alter host physiology and metabolism. However, the mechanisms that underlie these observations remain largely unknown. Recent findings have implicated microbially derived mediators as potential signals between the gut microbiome and host circadian clocks; two specific mediators are discussed in this review: short-chain fatty acids (SCFAs) and bile acids (BAs). Key gaps in knowledge and major challenges that remain in the circadian and microbiome fields are also discussed, including animal versus human models and the need for precise timed sample collection.

  • Energy Trade-offs in Host Defense: Immunology Meets Physiology
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-25
    Alexandre A. Steiner, Andrej A. Romanovsky

    Host defense relies not only on microbicidal mechanisms (resistance), but also on management of collateral damage (tolerance). Here, we discuss how this immunology concept converges with a physiology-born theory on the dichotomy of thermometabolic responses in infection (fever versus hypothermia), yielding a model of immunity that transcends discipline barriers.

  • Polymeric Carriers for Controlled Drug Delivery in Obesity Treatment
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-25
    Di Huang, Meng Deng, Shihuan Kuang

    The global rise in the prevalence of obesity and affiliated metabolic syndrome poses a significant threat to human health. Various approaches, including bariatric surgery and pharmacotherapy, have been used in the clinical setting for obesity treatment; however, these conventional options remain ineffective and carry risks of adverse effects. Therefore, treatments with higher efficacy and specificity are urgently required. Emerging drug delivery systems use polymeric materials and chemical strategies to improve therapeutic efficacy and specificity through stabilization and spatiotemporally controlled release of antiobesity agents. In this review, we provide insights into current treatments for obesity with a focus on recent developments of polymeric carriers for enhanced antiobesity drug delivery.

  • Endocrine Regulations in Human–Dog Coexistence through Domestication
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-23
    Takefumi Kikusui, Miho Nagasawa, Kensaku Nomoto, Sayaka Kuse-Arata, Kazutaka Mogi

    Endocrine system regulation is important for the maintenance of homeostasis; it controls hormonal functions in complex physiology and behavior and adaptations to social environments. Evidence indicates that for more than 35 000 years, dogs (Canis familiaris) have been domesticated through living with humans. For example, they have acquired human-like social skills, such as eye gazing and pointing gestures. These unique behaviors are, at least partially, regulated by hormones and are thought to have been genetically altered throughout domestication. Glucocorticoids affect social tolerance, while oxytocin facilitates social coordination and familiarity between individuals. We review historical and recent literature to facilitate an understanding of the roles of glucocorticoid and oxytocin functions in the human–canine coexistence dynamic established during domestication.

  • A Tale of Two Proteins: Betaglycan, IGSF1, and the Continuing Search for the Inhibin B Receptor
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-22
    Daniel J. Bernard, Courtney L. Smith, Emilie Brûlé

    Inhibins are gonadal hormones that suppress follicle-stimulating hormone (FSH) synthesis by pituitary gonadotrope cells. The structurally related activins stimulate FSH by signaling through complexes of type I and type II receptors. Two models of inhibin action were proposed in 2000. First, inhibins function as competitive receptor antagonists, binding activin type II receptors with high affinity in the presence of the TGF-β type III coreceptor, betaglycan. Second, immunoglobulin superfamily, member 1 (IGSF1, then called p120) was proposed to mediate inhibin B antagonism of activin signaling via its type I receptor. These ideas have been challenged over the past few years. Rather than playing a role in inhibin action, IGSF1 is involved in the central control of the thyroid gland. Betaglycan binds inhibin A and inhibin B with high affinity, but only functions as an obligate inhibin A coreceptor in murine gonadotropes. There is likely to be a distinct, but currently unidentified coreceptor for inhibin B.

  • A Metabolic Perspective on Reward Abnormalities in Anorexia Nervosa
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-21
    Philibert Duriez, Nicolas Ramoz, Philip Gorwood, Odile Viltart, Virginie Tolle

    Anorexia nervosa (AN) is the psychiatric disorder with the highest mortality rate; however, the mechanisms responsible for its pathogenesis remain largely unknown. Large-scale genome-wide association studies (GWAS) have identified genetic loci associated with metabolic features in AN. Metabolic alterations that occur in AN have been mostly considered as consequences of the chronic undernutrition state but until recently have not been linked to the etiology of the disorder. We review the molecular basis of AN based on human genetics, with an emphasis on the molecular components controlling energy homeostasis, highlight the main metabolic and endocrine alterations occurring in AN, and decipher the possible connection between metabolic factors and abnormalities of reward processes that are central in AN.

  • Ghrelin Signaling: GOAT and GHS-R1a Take a LEAP in Complexity
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-19
    Alfonso Abizaid, James L. Hougland

    Ghrelin and the growth hormone secretagogue receptor 1a (GHS-R1a) are important targets for disorders related to energy balance and metabolic regulation. Pharmacological control of ghrelin signaling is a promising avenue to address health issues involving appetite, weight gain, obesity, and related metabolic disorders, and may be an option for patients suffering from wasting conditions like cachexia. In this review, we summarize recent developments in the biochemistry of ghrelin and GHS-R1a signaling. These include unravelling the enzymatic transformations that generate active ghrelin and the discovery of multiple proteins that interact with ghrelin and GHS-R1a to regulate signaling. Furthermore, we propose that harnessing these processes will lead to highly selective treatments to address obesity, diabetes, and other metabolism-linked disorders.

  • What Is GLP-1 Really Doing in Obesity?
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-18
    Tohru Hira, Jukkrapong Pinyo, Hiroshi Hara

    Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released in response to meal ingestion and enhances insulin secretion from pancreatic β cells. In several human studies, GLP-1 secretory responses to oral glucose load or a meal were decreased in subjects with obesity, glucose intolerance, or diabetes compared with those in healthy subjects. However, the results of meta-analysis and cohort studies do not necessarily support this concept. Results from animal studies are also inconsistent; in multiple studies, GLP-1 secretory responses to a meal were repeatedly higher in diet-induced obese rats than in control rats. Thus, the postprandial GLP-1 response is not necessarily decreased but rather enhanced during obesity development, which is likely to play a protective role against glucose intolerance.

  • NAFLD and Atherosclerosis: Two Sides of the Same Dysmetabolic Coin?
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-17
    Daniela Stols-Gonçalves, G. Kees Hovingh, Max Nieuwdorp, Adriaan G. Holleboom

    The prevalence of non-alcoholic fatty liver disease (NAFLD) is strongly increasing and may put patients at increased risk for atherosclerotic cardiovascular disease (asCVD). Both disease phenotypes often co-occur, in the case of obesity, insulin resistance, diabetes mellitus type 2, and the metabolic syndrome. We explore the pathogenesis of NAFLD, the epidemiology of asCVD in NAFLD patients, shared drivers of both phenotypes, and factors caused by NAFLD that contribute to asCVD. Genetic studies support that NAFLD may drive asCVD through mixed hyperlipidemia. Next, we discuss the prospects of lifestyle improvement and pharmacological treatment of NAFLD for asCVD risk reduction. Finally, we point out that earlier identification of patients with NAFLD should be pursued by increasing awareness of the association of these two phenotypes and collaboration between the involved physicians.

  • Neuronal Cell Cycle Events Link Caloric Intake to Obesity
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-16
    Niloy Iqbal, LIang Zhu, Streamson C. Chua

    Obesity is a neurological disorder that operates by favoring energy storage within adipose depots and increased caloric intake. Most cases of human obesity are acquired without any underlying genetic basis. Here, we suggest that obesity can impair the function of some hypothalamic neurons critical to body weight regulation. Genetic ablation of the retinoblastoma (Rb) gene within pro-opiomelanocortin (POMC) neurons leads to death of the neurons and subsequent obesity. The Rb protein (pRb), a key inhibitor of the cell cycle, can also be inactivated by cyclin dependent kinase (CDK)-mediated phosphorylation. Extensive development led to the production of FDA-approved CDK4/6 inhibitors. Based on our own results, we propose that maintaining or re-instating pRb function using CDK4/6 inhibitors are potentially effective treatments of diet-induced obesity (DIO).

  • The Complexity of Making Ubiquinone
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-07
    Ying Wang, Siegfried Hekimi

    Ubiquinone (UQ, coenzyme Q) is an essential electron transfer lipid in the mitochondrial respiratory chain. It is a main source of mitochondrial reactive oxygen species (ROS) but also has antioxidant properties. This mix of characteristics is why ubiquinone supplementation is considered a potential therapy for many diseases involving mitochondrial dysfunction. Mutations in the ubiquinone biosynthetic pathway are increasingly being identified in patients. Furthermore, secondary ubiquinone deficiency is a common finding associated with mitochondrial disorders and might exacerbate these conditions. Recent developments have suggested that ubiquinone biosynthesis occurs in discrete domains of the mitochondrial inner membrane close to ER–mitochondria contact sites. This spatial requirement for ubiquinone biosynthesis could be the link between secondary ubiquinone deficiency and mitochondrial dysfunction, which commonly results in loss of mitochondrial structural integrity.

  • Clinical/Translational Aspects of Advanced Glycation End-Products
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-06
    Chang Zeng, Yuanyuan Li, Jingzhi Ma, Lina Niu, Franklin R. Tay

    Advanced glycation end-products (AGEs) have been implicated in chronic hyperglycemia and age-related diseases. Endogenous AGEs produced by humans generate oxidative stress and activation of inflammatory signaling pathways via AGE-specific receptors. The present review summarizes current knowledge on the pathogenic role of AGEs in chronic noncommunicable diseases. Although correlations exist between glycation and the pathogenesis of these diseases, uncertainties remain in light of recurrent intervention failures of apparently promising animal models to be translated into clinically useful anti-AGE strategies. Future intervention of AGEs or their receptors should embrace more carefully executed clinical trials. Nevertheless, suppressing symptoms via lifetime drug application is unlikely to eliminate the burden of chronic diseases unless deep-rooted lifestyle issues that cause these diseases are simultaneously addressed.

  • Natural Killer Cells as Sensors of Adipose Tissue Stress
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-06
    Johan Fernø, Kristina Strand, Gunnar Mellgren, Natalie Stiglund, Niklas K. Björkström

    Adipose tissue macrophages (ATMs) orchestrate low-grade chronic adipose tissue inflammation, linking obesity and insulin resistance. Whereas factors contributing to macrophage accumulation in adipose tissue are established, little is known regarding signals that link adipocyte stress to proinflammatory activation of macrophages. Natural killer (NK) cells are specialized innate lymphocytes that identify and respond to stressed cells. In this Opinion, we discuss the possibility of NK cells to function as sensors recognizing adipose tissue stress. We further summarize recent literature suggesting NK cells to play an important role in development of insulin resistance via secretion of cytokines that stimulate proinflammatory polarization of ATMs. This suggests adipose tissue-resident NK cells as a pharmacological target for the treatment of obesity-induced insulin resistance.

  • Emerging Molecular Targets for Treatment of Nonalcoholic Fatty Liver Disease
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-10-06
    Ze Chen, Yao Yu, Jingjing Cai, Hongliang Li

    In parallel with the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide. Disequilibrium of lipid metabolism and the subsequent metabolic-stress-induced inflammation are believed to be central in the pathogenesis of NAFLD. Of note, metabolic inflammation is primarily mediated by innate immune signaling, which is increasingly recognized as a driving force in NAFLD progression. Currently, a series of agents targeting one or more of these pathomechanisms have shown encouraging results in preclinical models and clinical trials. This review summarizes the emerging molecular targets involved in signaling in the lipid metabolism and innate immunity aspects of NAFLD, focusing on their mechanistic roles and translational potentials.

  • Reconstitution of Organismal Liver Clock Function Requires Light
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-07-31
    Takahito Miyake, Masao Doi
  • Antagonism between Antiviral Signaling and Glycolysis
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-07-23
    Anoop Singh Chauhan, Li Zhuang, Boyi Gan
  • Neuron–Astrocyte Liaison to Maintain Lipid Metabolism of Brain
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-08
    Soham Mukherjee, S.N. Suresh
  • 更新日期:2019-09-30
  • Heterogeneity and Similarities in GLP-1 Receptor Agonist Cardiovascular Outcomes Trials
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-07
    Irene Caruso, Angelo Cignarelli, Francesco Giorgino
  • The Changing Clinical Spectrum of Hypophysitis
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-07-22
    Sabrina Chiloiro, Ettore Domenico Capoluongo, Tommaso Tartaglione, Antonella Giampietro, Antonio Bianchi, Andrea Giustina, Alfredo Pontecorvi, Laura De Marinis
  • Role of Diacylglycerol Kinases in Glucose and Energy Homeostasis
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-07-19
    Julie Massart, Juleen R. Zierath
  • Reassessing the Role of Diacylglycerols in Insulin Resistance
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-07-30
    Sisitha U. Jayasinghe, Aurel T. Tankeu, Francesca Amati
  • Epigenetics and Exercise
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-07-03
    Sean L. McGee, Mark Hargreaves
  • 更新日期:2019-09-30
  • The FoxO–Autophagy Axis in Health and Disease
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-20
    Zhiyong Cheng

    Autophagy controls cellular remodeling and quality control. Dysregulated autophagy has been implicated in several human diseases including obesity, diabetes, cardiovascular disease, neurodegenerative diseases, and cancer. Current evidence has revealed that FoxO (forkhead box class O) transcription factors have a multifaceted role in autophagy regulation and dysregulation. Nuclear FoxOs transactivate genes that control the formation of autophagosomes and their fusion with lysosomes. Independently of transactivation, cytosolic FoxO proteins induce autophagy by directly interacting with autophagy proteins. Autophagy is also controlled by FoxOs through epigenetic mechanisms. Moreover, FoxO proteins can be degraded directly or indirectly by autophagy. Cutting-edge evidence is reviewed that the FoxO–autophagy axis plays a crucial role in health and disease.

  • Efferocytosis and Atherosclerosis: Regulation of Phagocyte Function by MicroRNAs
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-02
    Amir Tajbakhsh, Vanessa Bianconi, Matteo Pirro, Seyed Mohammad Gheibi Hayat, Thomas P. Johnston, Amirhossein Sahebkar
  • Hormesis in Health and Chronic Diseases
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-09-11
    Xin Li, Tingting Yang, Zheng Sun
  • Maternal Microbiome and Metabolic Health Program Microbiome Development and Health of the Offspring
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-09-05
    Marta Calatayud, Omry Koren, Maria Carmen Collado
  • Hypothalamic Heuristics for Survival
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-09-03
    Denis Burdakov, Daria Peleg-Raibstein
  • Lots of Movement in Gut and Parkinson’s Research
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-28
    Gabriela Mercado, Patrik Brundin
  • Hypogonadism in Pediatric Health: Adult Medicine Concepts Fail
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-27
    Romina P. Grinspon, Analía V. Freire, Rodolfo A. Rey
  • ER Stress Priming of Mitochondrial Respiratory suPERKomplex Assembly
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-24
    Ruben Quintana-Cabrera, Maria Eugenia Soriano
  • Ghrelin-Mediated Hippocampal Neurogenesis: Implications for Health and Disease
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-21
    Luke Buntwal, Martina Sassi, Alwena H. Morgan, Zane B. Andrews, Jeffrey S. Davies
  • Impact of Circadian Disruption on Cardiovascular Function and Disease
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-16
    Sarah L. Chellappa, Nina Vujovic, Jonathan S. Williams, Frank A.J.L. Scheer
  • Lipid Regulators of Thermogenic Fat Activation
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-16
    Hongsuk Park, Anyuan He, Irfan J. Lodhi
  • Are Lifestyle Therapies Effective for NAFLD Treatment?
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-15
    Nermeen N. El-Agroudy, Anica Kurzbach, Roman N. Rodionov, John O’Sullivan, Michael Roden, Andreas L. Birkenfeld, Dominik H. Pesta
  • Handling Parathormone Receptor Type 1 in Skeletal Diseases: Realities and Expectations of Abaloparatide
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-11
    Juan A. Ardura, Sergio Portal-Núñez, Verónica Alonso, Beatriz Bravo, Arancha R. Gortazar
  • Metformin as Anti-Aging Therapy: Is It for Everyone?
    Trends Endocrin. Met. (IF 9.777) Pub Date : 2019-08-09
    Alexander A. Soukas, Haibin Hao, Lianfeng Wu
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上海纽约大学William Glover