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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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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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L Strauss Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Turku, Finland

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A Junnila Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Turku, Finland

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A Wärri Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Turku, Finland

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M Manti Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

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Y Jiang Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden

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E Löyttyniemi Department of Biostatistics, University of Turku, Turku, Finland

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E Stener-Victorin Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

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M K Lagerquist Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden

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K Kukoricza Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Turku, Finland

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T Heinosalo Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Turku, Finland

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S Blom Aiforia Technologies Oyj, Pursimiehenkatu, Helsinki, Finland

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M Poutanen Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Turku, Finland
Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden

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The mouse estrous cycle is divided into four stages: proestrus (P), estrus (E), metestrus (M), and diestrus (D). The estrous cycle affects reproductive hormone levels in a wide variety of tissues. Therefore, to obtain reliable results from female mice, it is important to know the estrous cycle stage during sampling. The stage can be analyzed from a vaginal smear under a microscope. However, it is time-consuming, and the results vary between evaluators. Here, we present an accurate and reproducible method for staging the mouse estrous cycle in digital whole-slide images (WSIs) of vaginal smears. We developed a model using a deep convolutional neural network (CNN) in a cloud-based platform, Aiforia Create. The CNN was trained by supervised pixel-level multiclass semantic segmentation of image features from 171 hematoxylin-stained samples. The model was validated by comparing the results obtained by CNN with those of four independent researchers. The validation data included three separate studies comprising altogether 148 slides. The total agreement attested by the Fleiss kappa value between the validators and the CNN was excellent (0.75), and when D, E, and P were analyzed separately, the kappa values were 0.89, 0.79, and 0.74, respectively. The M stage is short and not well defined by the researchers. Thus, identification of the M stage by the CNN was challenging due to the lack of proper ground truth, and the kappa value was 0.26. We conclude that our model is reliable and effective for classifying the estrous cycle stages in female mice.

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Emma Rose McGlone Department of Surgery and Cancer, Imperial College London, London, UK

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Stephen R Bloom Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Tricia M-M Tan Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Metabolic-associated steatotic liver disease (MASLD) is closely associated with obesity. MASLD affects over 1 billion adults globally but there are few treatment options available. Glucagon is a key metabolic regulator, and its actions include the reduction of liver fat through direct and indirect means. Chronic glucagon signalling deficiency is associated with hyperaminoacidaemia, hyperglucagonaemia and increased circulating levels of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF-21). Reduction in glucagon activity decreases hepatic amino acid and triglyceride catabolism; metabolic effects include improved glucose tolerance, increased plasma cholesterol and increased liver fat. Conversely, glucagon infusion in healthy volunteers leads to increased hepatic glucose output, decreased levels of plasma amino acids and increased urea production, decreased plasma cholesterol and increased energy expenditure. Patients with MASLD share many hormonal and metabolic characteristics with models of glucagon signalling deficiency, suggesting that they could be resistant to glucagon. Although there are few studies of the effects of glucagon infusion in patients with obesity and/or MASLD, there is some evidence that the expected effect of glucagon on amino acid catabolism may be attenuated. Taken together, this evidence supports the notion that glucagon resistance exists in patients with MASLD and may contribute to the pathogenesis of MASLD. Further studies are warranted to investigate the direct effects of glucagon on metabolism in patients with MASLD.

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María Victoria Zanardi Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina
Faculty of Biology, Institute of Zoology, Technische Universität Dresden, Dresden, Germany

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María Paula Gastiazoro Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina

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María Florencia Rossetti Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
Departamento de Bioquímica Clínica y Cuantitativa, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina

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Florencia Doná Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina

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Gisela Paola Lazzarino Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
Departamento de Bioquímica Clínica y Cuantitativa, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina

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Oliver Zierau Faculty of Biology, Institute of Zoology, Technische Universität Dresden, Dresden, Germany

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Jorgelina Varayoud Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina

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Milena Durando Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina

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Exposure to glyphosate-based herbicides (GBH) and consumption of cafeteria (CAF) diet, which are widespread in Western society, seem to be associated with endometrial hyperplasia (EH). Here, we aimed to evaluate the effects of a subchronic low dose of GBH added to the CAF diet on the rat uterus. Female Wistar rats were fed from postnatal day (PND)21 until PND240 with chow (control) or CAF diet. Since PND140, rats also received GBH (2 mg of glyphosate/kg/day) or water through food, yielding four experimental groups: control, CAF, GBH, and CAF+GBH. On PND240, CAF and CAF+GBH animals showed an increased adiposity index. With respect to the control group, no changes in the serum levels of 17β-estradiol and progesterone were found. However, progesterone levels were higher in the CAF+GBH group than in the CAF and GBH groups. In the uterus, both studied factors alone and in combination induced morphological and molecular changes associated with EH. Furthermore, the addition of GBH provoked an increased thickness of subepithelial stroma in rats fed with the CAF diet. As a consequence of GBH exposure, CAF+GBH rats exhibited an increased density of abnormal gland area, considered preneoplastic lesions, as well as a reduced PTEN and p27 expression, both tumor suppressor molecules that inhibit cell proliferation, with respect to control rats. These results indicate that the addition of GBH exacerbates the CAF effects on uterine lesions and that the PTEN/p27 signaling pathway seems to be involved. Further studies focusing on the interaction between unhealthy diets and environmental chemicals should be encouraged to better understand uterine pathologies.

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Irena Audzeyenka Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Gdansk, Poland
Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Gdansk, Poland

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Patrycja Rachubik Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Gdansk, Poland

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Dorota Rogacka Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Gdansk, Poland
Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Gdansk, Poland

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Moin A Saleem Bristol Renal, University of Bristol, Dorothy Hodgkin Building, Bristol, United Kingdom

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Agnieszka Piwkowska Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Gdansk, Poland
Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Gdansk, Poland

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Diabetic nephropathy (DN) is one of the most frequent complications of diabetes. Early stages of DN are associated with hyperinsulinemia and progressive insulin resistance in insulin-sensitive cells, including podocytes. The diabetic environment induces pathological changes, especially in podocyte bioenergetics, which is tightly linked with mitochondrial dynamics. The regulatory role of insulin in mitochondrial morphology in podocytes has not been fully elucidated. Therefore, the main goal of the present study was to investigate effects of insulin on the regulation of mitochondrial dynamics and bioenergetics in human podocytes. Biochemical analyses were performed to assess oxidative phosphorylation efficiency by measuring the oxygen consumption rate (OCR) and glycolysis by measuring the extracellular acidification rate (ECAR). mRNA and protein expression were determined by real-time polymerase chain reaction and Western blot. The intracellular mitochondrial network was visualized by MitoTracker staining. All calculations were conducted using CellProfiler software. Short-term insulin exposure exerted inhibitory effects on various parameters of oxidative respiration and adenosine triphosphate production, and glycolysis flux was elevated. After a longer time of treating cells with insulin, an increase in mitochondrial size was observed, accompanied by a reduction of expression of the mitochondrial fission markers DRP1 and FIS1 and an increase in mitophagy. Overall, we identified a previously unknown role for insulin in the regulation of oxidative respiration and glycolysis and elucidated mitochondrial dynamics in human podocytes. The present results emphasize the importance of the duration of insulin stimulation for its metabolic and molecular effects, which should be considered in clinical and experimental studies of DN.

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Samrin Kagdi Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

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Sulayman A Lyons Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

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Jacqueline L Beaudry Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

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Adipose tissue was once known as a reservoir for energy storage but is now considered a crucial organ for hormone and energy flux with important effects on health and disease. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted from the small intestinal K cells, responsible for augmenting insulin release, and has gained attention for its independent and amicable effects with glucagon-like peptide 1 (GLP-1), another incretin hormone secreted from the small intestinal L cells. The GIP receptor (GIPR) is found in whole adipose tissue, whereas the GLP-1 receptor (GLP-1R) is not, and some studies suggest that GIPR action lowers body weight and plays a role in lipolysis, glucose/lipid uptake/disposal, adipose tissue blood flow, lipid oxidation, and free-fatty acid (FFA) re-esterification, which may or may not be influenced by other hormones such as insulin. This review summarizes the research on the effects of GIP in adipose tissue (distinct depots of white and brown) using cellular, rodent, and human models. In doing so, we explore the mechanisms of GIPR-based medications for treating metabolic disorders, such as type 2 diabetes and obesity, and how GIPR agonism and antagonism contribute to improvements in metabolic health outcomes, potentially through actions in adipose tissues.

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Affiong Ika Oqua Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Yusman Manchanda Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Emma Rose McGlone Department of Surgery and Cancer, Imperial College London, London, UK

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Ben Jones Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Sarah Rouse Department of Life Sciences, Imperial College, London, UK

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Alejandra Tomas Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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The glucagon receptor family are typical class B1 G protein-coupled receptors (GPCRs) with important roles in metabolism, including the control of pancreas, brain, and liver function. As proteins with seven transmembrane domains, GPCRs are intimately in contact with lipid bilayers and therefore can be putatively regulated by interactions with their lipidic components, including cholesterol, sphingolipids, and other lipid species. Additionally, these receptors, as well as the agonists they bind to, can undergo lipid modifications, which can influence their binding capacity and/or elicit modified or biased signalling profiles. While the effect of lipids, and in particular cholesterol, has been widely studied for other GPCR classes, information about their role in regulating the glucagon receptor family is only beginning to emerge. Here we summarise our current knowledge on the effects of cholesterol modulation of glucagon receptor family signalling and trafficking profiles, as well as existing evidence for specific lipid–receptor binding and indirect effects of lipids via lipid modification of cognate agonists. Finally, we discuss the different methodologies that can be employed to study lipid–receptor interactions and summarise the importance of this area of investigation to increase our understanding of the biology of this family of metabolically relevant receptors.

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