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Renata Risi Department of Experimental Medicine, Sapienza University of Rome, Sapienza University of Rome, Rome, Italy
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK

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Antonio Vidal-Puig University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, P. R. China
Centro de Investigacion Principe Felipe, Valencia, Spain

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Guillaume Bidault University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK

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Obesity and diabetes represent two increasing and invalidating public health issues that often coexist. It is acknowledged that fat mass excess predisposes to insulin resistance and type 2 diabetes mellitus (T2D), with the increasing incidence of the two diseases significantly associated. Moreover, emerging evidence suggests that obesity might also accelerate the appearance of type 1 diabetes (T1D), which is now a relatively frequent comorbidity in patients with obesity. It is a common clinical finding that not all patients with obesity will develop diabetes at the same level of adiposity, with gender, genetic, and ethnic factors playing an important role in defining the timing of diabetes appearance. The adipose tissue (AT) expandability hypothesis explains this paradigm, indicating that the individual capacity to appropriately store energy surplus in the form of fat within the AT determines and prevents the toxic deposition of lipids in other organs, such as the pancreas. Thus, we posit that when the maximal storing capacity of AT is exceeded, individuals will develop T2D. In this review, we provide insight into mechanisms by which the AT controls pancreas lipid content and homeostasis in case of obesity to offer an adipocentric perspective of pancreatic lipotoxicity in the pathogenesis of diabetes. Moreover, we suggest that improving AT function is a valid therapeutic approach to fighting obesity-associated complications including diabetes.

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Xiong Weng Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK

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Hao Jiang Gene Expression and Regulation, School of Life Sciences, University of Dundee, Dundee, Scotland, UK

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David J Walker Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK

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Houjiang Zhou MRC Protein Phosphorylation Unit, School of Life Sciences, Dundee, Scotland, UK

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De Lin Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee, Scotland, UK

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Jing Wang Science for Life Laboratory, Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden

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Li Kang Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK

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CD44, a cell surface adhesion receptor and stem cell biomarker, is recently implicated in chronic metabolic diseases. Ablation of CD44 ameliorates adipose tissue inflammation and insulin resistance in obesity. Here, we investigated cell type-specific CD44 expression in human and mouse adipose tissue and further studied how CD44 in preadipocytes regulates adipocyte function. Using Crispr Cas9-mdediated gene deletion and lentivirus-mediated gene re-expression, we discovered that deletion of CD44 promotes adipocyte differentiation and adipogenesis, whereas re-expression of CD44 abolishes this effect and decreases insulin responsiveness and adiponectin secretion in 3T3-L1 cells. Mechanistically, CD44 does so via suppressing Pparg expression. Using quantitative proteomics analysis, we further discovered that cell cycle-regulated pathways were mostly decreased by deletion of CD44. Indeed, re-expression of CD44 moderately restored expression of proteins involved in all phases of the cell cycle. These data were further supported by increased preadipocyte proliferation rates in CD44-deficient cells and re-expression of CD44 diminished this effect. Our data suggest that CD44 plays a crucial role in regulating adipogenesis and adipocyte function possibly through regulating PPARγ and cell cycle-related pathways. This study provides evidence for the first time that CD44 expressed in preadipocytes plays key roles in regulating adipocyte function outside immune cells where CD44 is primarily expressed. Therefore, targeting CD44 in (pre)adipocytes may provide therapeutic potential to treat obesity-associated metabolic complications.

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Katherine N Balantekin Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, USA
Center for Ingestive Behavior Research, University at Buffalo, Buffalo, New York, USA

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Martin J Kretz Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, USA

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Elizabeth G Mietlicki-Baase Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, USA
Center for Ingestive Behavior Research, University at Buffalo, Buffalo, New York, USA

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Binge eating is a central component of two clinical eating disorders: binge eating disorder and bulimia nervosa. However, the large treatment gap highlights the need to identify other strategies to decrease binge eating. Novel pharmacotherapies may be one such approach. Glucagon-like peptide-1 (GLP-1) is an intestinal and brain-derived neuroendocrine signal with a critical role in promoting glycemic control through its incretin effect. Additionally, the energy balance effects of GLP-1 are well-established; activation of the GLP-1 receptor (GLP-1R) reduces food intake and body weight. Aligned with these beneficial metabolic effects, there are GLP-1R agonists that are currently used for the treatment of diabetes and obesity. A growing body of literature suggests that GLP-1 may also play an important role in binge eating. Dysregulation of the endogenous GLP-1 system is associated with binge eating in non-human animal models, and GLP-1R agonists may be a promising approach to suppress the overconsumption that occurs during binge eating. Here, we briefly discuss the role of GLP-1 in normal energy intake and reward and then review the emerging evidence suggesting that disruptions to GLP-1 signaling are associated with binge eating. We also consider the potential utility of GLP-1-based pharmacotherapies for reducing binge eating behavior.

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Graham W Aberdeen Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA

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Jeffery S Babischkin Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA

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Gerald J Pepe Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia, USA

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Eugene D Albrecht Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA

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We recently showed that the ratio of capillaries to myofibers in skeletal muscle, which accounts for 80% of insulin-directed glucose uptake and metabolism, was reduced in baboon fetuses in which estrogen was suppressed by maternal letrozole administration. Since vascular endothelial growth factor (VEGF) promotes angiogenesis, the present study determined the impact of estrogen deprivation on fetal skeletal muscle VEGF expression, capillary development, and long-term vascular and metabolic function in 4- to 8-year-old adult offspring. Maternal baboons were untreated or treated with letrozole or letrozole plus estradiol on days 100–164 of gestation (term = 184 days). Skeletal muscle VEGF protein expression was suppressed by 45% (P < 0.05) and correlated (P = 0.01) with a 47% reduction (P < 0.05) in the number of capillaries per myofiber area in fetuses of baboons in which serum estradiol levels were suppressed 95% (P < 0.01) by letrozole administration. The reduction in fetal skeletal muscle microvascularization was associated with a 52% decline (P = 0.02) in acetylcholine-induced brachial artery dilation and a 23% increase (P = 0.01) in mean arterial blood pressure in adult progeny of letrozole-treated baboons, which was restored to normal by letrozole plus estradiol. The present study indicates that estrogen upregulates skeletal muscle VEGF expression and systemic microvessel development within the fetus as an essential programming event critical for ontogenesis of systemic vascular function and insulin sensitivity/glucose homeostasis after birth in primate offspring.

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Se-Min Kim The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Farhath Sultana The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Steven Sims The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Judit Gimenez-Roig The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Victoria Laurencin The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Anusha Pallapati The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Satish Rojekar The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Tal Frolinger The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Weibin Zhou The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Anisa Gumerova The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Anne Macdonald The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Vitaly Ryu The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Daria Lizneva The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Funda Korkmaz The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Tony Yuen The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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Mone Zaidi The Mount Sinai Bone Program, Departments of Pharmacological Sciences and Medicine, and Center for Translational Medicine and Pharmacology, Icahn School of Medicine, Mount Sinai, New York, USA

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The pituitary gland orchestrates multiple endocrine organs by secreting tropic hormones, and therefore plays a significant role in a myriad of physiological processes, including skeletal modeling and remodeling, fat and glucose metabolism, and cognition. Expression of receptors for each pituitary hormone and the hormone itself in the skeleton, fat, immune cells, and the brain suggest that their role is much broader than the traditionally attributed functions. FSH, believed solely to regulate gonadal function is also involved in fat and bone metabolism, as well as in cognition. Our emerging understanding of nonreproductive functions of FSH, thus, opens potential therapeutic opportunities to address detrimental health consequences during and after menopause, namely, osteoporosis, obesity, and dementia. In this review, we outline current understanding of the cross-talk between the pituitary, bone, adipose tissue, and brain through FSH. Preclinical evidence from genetic and pharmacologic interventions in rodent models, and human data from population-based observations, genetic studies, and a small number of interventional studies provide compelling evidence for independent functions of FSH in bone loss, fat gain, and congnitive impairment.

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Jane Stremming Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Eileen I Chang Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Alicia White Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Paul J Rozance Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Laura D Brown Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Insulin-like growth factor 1 (IGF-1) is a critical fetal anabolic hormone. IGF-1 infusion to the normally growing sheep fetus increases the weight of some organs but does not consistently increase body weight. However, IGF-1 infusion profoundly decreases fetal plasma insulin concentrations, which may limit fetal growth potential. In this study, normally growing late-gestation fetal sheep received an intravenous infusion of either: IGF-1 (IGF), IGF-1 with insulin and dextrose to maintain fetal euinsulinemia and euglycemia (IGF+INS), or vehicle control (CON) for 1 week. The fetus underwent a metabolic study immediately prior to infusion start and after 1 week of the infusion to measure uterine and umbilical uptake rates of nutrients and oxygen. IGF+INS fetuses were 23% heavier than CON (P = 0.0081) and had heavier heart, liver, and adrenal glands than IGF and CON (P < 0.01). By design, final fetal insulin concentrations in IGF were 62% and 65% lower than IGF+INS and CON, respectively. Final glucose concentrations were similar in all groups. IGF+INS had lower final oxygen content than IGF and CON (P < 0.0001) and lower final amino acid concentrations than CON (P = 0.0002). Final umbilical oxygen uptake was higher in IGF+INS compared to IGF and CON (P < 0.05). Final umbilical uptake of several essential amino acids was higher in IGF+INS compared to CON (P < 0.05). In summary, maintaining euinsulinemia and euglycemia during fetal IGF-1 infusion is necessary to maximally support body growth. We speculate that IGF-1 and insulin stimulate placental nutrient transport to support fetal growth.

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Galit Levi Dunietz Department of Neurology, Division of Sleep Medicine, University of Michigan, Ann Arbor, Michigan, USA

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Lucas J Tittle Department of Psychology, University of Michigan, Ann Arbor, Michigan, USA

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Sunni L Mumford Department of Biostatistics, Epidemiology and Informatics and Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Louise M O’Brien Department of Neurology, Division of Sleep Medicine, University of Michigan, Ann Arbor, Michigan, USA
Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA

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Ana Baylin Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA

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Enrique F Schisterman Department of Biostatistics, Epidemiology and Informatics and Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Ronald D Chervin Department of Neurology, Division of Sleep Medicine, University of Michigan, Ann Arbor, Michigan, USA

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Larry J Young Center for Translational Social Neuroscience, Emory National Primate Research Center, Emory University, Atlanta, Georgia, USA
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA

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Menopause marks the cessation of fertility and the transition to post-reproductive years. Nearly 1 million US women experience menopause annually, but despite the significant impact it has on their physical and mental health, menopause has been insufficiently studied. Oxytocin is a neurohormone that regulates emotionality, social behaviors, and fundamental physiological systems. Localization of oxytocin receptors in the brain, reproductive tissues, bone, and heart support their role in mental health and potentially sleep, along with reproductive and cardiovascular functions. While experimental data linking oxytocin to behavior and physiology in animals are largely consistent, human data are correlative and inconclusive. As women transition into menopause, oxytocin levels decrease while their susceptibility to mood disorders, poor sleep, osteoporosis, and cardiovascular diseases increases. These concurrent changes highlight oxytocin as a potential influence on the health and mood of women along their reproductive life span. Here, we summarize experimental rodent and non-human primate studies that link oxytocin to reproductive aging and metabolic health and highlight the inconclusive findings in studies of women. Most human studies relied on a single oxytocin assessment in plasma or on intranasal oxytocin administration. The pulsatile release and short half-life of plasma oxytocin limit the validity of these methods. We discuss the need for oxytocin assessments in stable bio-samples, such as urine, and to use valid assays for assessment of associations between changing oxytocin levels and well-being across the reproductive life span. This work has the potential to guide therapeutic strategies that will one day alleviate adverse health outcomes for many women.

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Stephen P Fitzgerald Departments of General Medicine and Endocrinology, The Royal Adelaide Hospital, Adelaide, Australia
The University of Adelaide, Discipline of Medicine, Adelaide Medical School, Adelaide, Australia

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Nigel G Bean School of Mathematical Sciences, University of Adelaide, Adelaide, Australia

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Henrik Falhammar Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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Rudolf Hoermann Klinikum Lüdenscheid, Paulmannshöherstr, Lüdenscheid, Germany

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Yael Korem Kohanim Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA

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Hermann Pohlabeln Department Biometry and Data Management, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany

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Niels Grote Beverborg Department of Cardiology University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Sarah Tomassetti Hematology-Oncology Division, Harbor-UCLA Medical Center, Torrance, California, USA
Health Sciences, UCLA, Los Angeles, California, USA
The Lundquist Institute, Harbor-UCLA Medical Center, Torrance, California, USA

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The fundamental models underlying hormonal physiological regulation and homeostasis remain poorly understood. We aimed to derive quantitative evidence regarding these models from the study of population data of balance points of different parameters and their respective controlling hormones. We studied the slopes of correlations between concentrations of circulating free thyroxine and thyrotropin, calcium and parathyroid hormone, hemoglobin and erythropoietin, and glucose and insulin in such population data, as well as the slopes of the limbs of various feedback loops estimated empirically and by reverse engineering of the population data. We used computer simulations to model the factors that influence the slopes derived from the population data, and then matched these simulations with the empirically derived slopes. Our simulations showed that changes to the population distribution of feedback loop limbs may alter the slopes of correlations within population data in specific ways. Non-random (interdependent) associations of the limbs of feedback loops may also have this effect, as well as producing discrepancies between the slopes of feedback limb loops determined experimentally and the same slopes determined by derivation from population data. Our corresponding empirical findings were consistent with the presence of such interdependence in the free thyroxine/thyrotropin, hemoglobin/erythropoietin, and glucose/insulin systems. The glucose/insulin data provided evidence consistent with increasing interdependence with age in childhood. Our findings therefore provide strong evidence that the interdependence of the limbs of feedback loops is a general feature of endocrine homeostatic regulation. This interdependence potentially bestows evolutionary homeostatic and regulatory advantages.

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Elisa Villalobos E Villalobos, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Allende Miguelez-Crespo A Miguelez-Crespo, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Ruth A Morgan R Morgan, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Lisa Ivatt L Ivatt, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Mhairi Paul M Paul, The Queen's Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Joanna P Simpson J Simpson, The Queen's Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Natalie ZM Z.m. Homer N Homer, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Dominic Kurian D Kurian, The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, The University of Edinburgh The Roslin Institute, Roslin, United Kingdom of Great Britain and Northern Ireland

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Judit Aguilar J Aguilar, The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, The University of Edinburgh The Roslin Institute, Roslin, United Kingdom of Great Britain and Northern Ireland

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Rachel Kline R Kline, The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Easter Bush, The University of Edinburgh The Roslin Institute, Roslin, United Kingdom of Great Britain and Northern Ireland

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T Wishart T Wishart, The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Easter Bush, The University of Edinburgh The Roslin Institute, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Nicholas Morton N Morton, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Roland H Stimson R Stimson, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Ruth Andrew R Andrew, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Brian R Walker B Walker, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Mark Nixon M Nixon, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Glucocorticoids modulate glucose homeostasis, acting on metabolically active tissues such as liver, skeletal muscle, and adipose tissue. Intracellular regulation of glucocorticoid action in adipose tissue impacts metabolic responses to obesity. ATP-binding cassette family C member 1 (ABCC1) is a transmembrane glucocorticoid transporter known to limit the accumulation of exogenously administered corticosterone in adipose tissue. However, the role of ABCC1 in the regulation of endogenous glucocorticoid action and its impact on fuel metabolism has not been studied. Here, we investigate the impact of Abcc1 deficiency on glucocorticoid action and high fat-diet (HFD)-induced obesity. In lean mice, deficiency of Abcc1 increased endogenous corticosterone levels in skeletal muscle and adipose tissue but did not impact insulin sensitivity. In contrast, Abcc1-deficient mice on HFD displayed impaired glucose and insulin tolerance, and fasting hyperinsulinemia, without alterations in tissue corticosterone levels. Proteomics and bulk RNA sequencing revealed that Abcc1 deficiency amplified the transcriptional response to an obesogenic diet in adipose tissue but not in skeletal muscle. Moreover, Abcc1 deficiency impairs key signalling pathways related to glucose metabolism in both skeletal muscle and adipose tissue, in particular those related to OXPHOS machinery and Glut4. Together, our results highlight a role for ABCC1 in regulating glucose homeostasis, demonstrating diet-dependent effects that are not associated with altered tissue glucocorticoid concentrations.

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Huanan Zhang H Zhang, School of Pharmacy, Yantai University, Yantai, China

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John Speakman J Speakman, Center for Energy metabolism and reproduction., Shenzhen Institutes of Advanced Technology Chinese Academy of Sciences, Stonehaven, China

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Coffee is one of the three most consumed beverages in the world. It is made by first roasting coffee beans and then grinding and boiling or steeping the roasted beans in water (brewing). The process of roasting and brewing produces a complex mix of bioactive compounds which include methylxanthines (caffeine, theobromine, theophylline), diterpenes, chlorogenic acid, trigonelline, flavonoids and hydroxycinnamic acid. In the body these compounds may be metabolized to produce other bioactive compounds. For example, caffeine is primarily (80%) broken down by demethylation to produce paraxanthine. In the post ingestion period levels of paraxanthine may be higher than caffeine due to its slower elimination. Hence, while paraxanthine is not found in coffee itself, it has many of the same properties of caffeine and may be a major contributor to its metabolic effects. The impacts of caffeine and paraxanthine on metabolism relate to their impact on adenosine receptors (notably the A2A receptor). It has been known for almost 100 years that intake of coffee stimulates metabolism by between 5 and 20% for at least 3 hours. About half of the increase in metabolic rate after drinking coffee is due to caffeine and derivatives, but the source of the other half is unclear. There are large differences in the response to the same amount of coffee in different individuals, which may be related to caffeine clearance rates, effects of other unknown pathways, genetic polymorphism, age, sex and body composition.

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