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Xi Tao Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, China

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Yaxin Xu Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, China

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Joseph Adu-Amankwaah Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, China

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Zheng Gong The School of Public Affairs & Governance, Silliman University, Dumaguete, Negros, Philippines

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Yuxuan Wang The Second Clinical School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu, China

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Fei Huang Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, China

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Hong Sun Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, China

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Cardiac lipid accumulation and inflammation have been linked to stress. There is mounting evidence that estrogen reduces lipid deposition and has anti-inflammatory properties; however, the exact mechanism is unknown. Recent studies showed that NLRP3 inflammasome is a key trigger of cardiac inflammation, and it is also involved in the progression of metabolic diseases. This study investigated the crucial role of the NLRP3 inflammasome in lipid accumulation during stress and the regulatory mechanism of estrogen in this process. Stress models were established by isoproterenol treatments in mice and H9c2 cells. With 5 mM isoproterenol, NLRP3 inflammasome activation was observed earlier at 0.5 h than that of lipid accumulation at 1 h in H9c2 cells. At 1 h after stress, the isoproterenol concentration required for NLRP3 inflammasome activation was lower compared to the concentration required for lipid deposition in mice myocardia and H9c2 cells; the former required 210 mg/kg or 10 μM for activation while the latter required 280 mg/kg or 5 mM. Knocking out or inhibiting NLRP3 inflammasome reduced myocardial lipid accumulation caused by stress in the mice myocardia and H9c2 cells. Estrogen downregulated NLRP3 inflammasome and reduced lipid accumulation in cardiomyocytes during stress. Finally, the anti-inflammatory and lipid-lowering effect of estrogen disappeared in β2ARKO mice and H9c2 cells pre-treated with ICI118,551. In conclusion, the upregulation of NLRP3 inflammasome induced by stress led to myocardial lipid accumulation, and β2AR downregulated NLRP3 inflammasome thereby reducing lipid accumulation which was dependent on the estrogenic environment.

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Brittany M Duggan Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada

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Daniel M Marko Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada

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Raveen Muzaffar Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada

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Darryl Y Chan Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada

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Jonathan D Schertzer Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada

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Small molecule kinase inhibitors (SMKIs) are a class of therapeutic drugs that target protein kinases in diseases such as cancer. SMKIs are often designed to inhibit kinases involved in cell proliferation, but these drugs alter cell metabolism and the endocrine control of organismal metabolism. SMKI treatment in diabetic cancer patients reveals that certain SMKIs improve blood glucose levels and can mitigate insulin dependence or diabetic medication requirements in both type 1 diabetes (T1D) and type 2 diabetes (T2D). Certain SMKIs can preserve functional β-cell mass and increase insulin secretion or insulin sensitivity. It is not yet clear why different SMKIs can have opposing effects on insulin and blood glucose. Understanding the therapeutic effects of these drugs in T1D and T2D is complicated by overlapping off-target effects of SMKIs. The potency of inhibition of the intended protein kinase and inhibition of multiple off-target kinases may underpin conflicting reports of how certain SMKIs alter blood glucose and insulin. We summarize the effects of SMKIs on the intended and off-target kinases that can alter blood glucose and insulin, including c-Abl, c-Kit, EGFR, and VEGF. Inhibition of PDGFRβ consistently lowers blood glucose in T1D and T2D. The effects of SMKIs on the kinases that regulate immune pathways, such as BTK and RIPKs, mediate many of the diverse effects of these drugs on metabolism. We highlight that inhibition of RIPK2 by SMKIs is a central node in metabolism that influences key metabolic pathways including lipolysis, blood glucose control, insulin secretion, and insulin resistance.

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Eva M G Viho Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Jan Kroon Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
Corcept Therapeutics, Menlo Park, CA, USA

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Richard A Feelders Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands

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René Houtman Precision Medicine Lab, Oss, the Netherlands

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Elisabeth S R van den Dungen Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands

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Alberto M Pereira Department of Endocrinology and Metabolism, Amsterdam University Medical Center, Amsterdam, the Netherlands

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Hazel J Hunt Corcept Therapeutics, Menlo Park, CA, USA

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Leo J Hofland Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands

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Onno C Meijer Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
Corcept Therapeutics, Menlo Park, CA, USA

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Glucocorticoid stress hormones are produced in response to hypothalamic–pituitary–adrenal (HPA) axis activation. Glucocorticoids are essential for physiology and exert numerous actions via binding to the glucocorticoid receptor (GR). Relacorilant is a highly selective GR antagonist currently undergoing a phase 3 clinical evaluation for the treatment of endogenous Cushing’s syndrome. It was found that increases in serum adrenocorticotropic hormone (ACTH) and cortisol concentrations after relacorilant treatment were substantially less than the increases typically observed with mifepristone, but it is unclear what underlies these differences. In this study, we set out to further preclinically characterize relacorilant in comparison to the classical but non-selective GR antagonist mifepristone. In human HEK-293 cells, relacorilant potently antagonized dexamethasone- and cortisol-induced GR signaling, and in human peripheral blood mononuclear cells, relacorilant largely prevented the anti-inflammatory effects of dexamethasone. In mice, relacorilant treatment prevented hyperinsulinemia and immunosuppression caused by increased corticosterone exposure. Relacorilant treatment reduced the expression of classical GR target genes in peripheral tissues but not in the brain. In mice, relacorilant induced a modest disinhibition of the HPA axis as compared to mifepristone. In line with this, in mouse pituitary cells, relacorilant was generally less potent than mifepristone in regulating Pomc mRNA and ACTH release. This contrast between relacorilant and mifepristone is possibly due to the distinct transcriptional coregulator recruitment by the GR. In conclusion, relacorilant is thus an efficacious peripheral GR antagonist in mice with only modest disinhibition of the HPA axis, and the distinct properties of relacorilant endorse the potential of selective GR antagonist treatment for endogenous Cushing’s syndrome.

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Lauren Brady Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Center, Seattle, Washington, USA

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Peter S Nelson Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Center, Seattle, Washington, USA
Division of Medical Oncology, University of Washington, Seattle, Washington, USA

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Neuroendocrine prostate cancer, generally arising late in the disease trajectory, is a heterogeneous subtype that infers a worse prognosis and limited treatment options for patients. Characterization of the complex landscape of this disease subtype and scrutiny of the relationship between tumor cells and cells of the surrounding tumor microenvironment have aided in elucidating some of the mechanisms of neuroendocrine disease biology and have uncovered a multitude of signaling pathways involved in disease transdifferentiation under therapeutic selection. In this review, we discuss current efforts to better understand the heterogeneous landscape of neuroendocrine prostate cancer and summarize research efforts to define the interplay between tumor cells and the microenvironment, with an emphasis on the immune component. Research efforts have uncovered several potential therapeutic approaches that may improve disease outcomes for patients diagnosed with neuroendocrine prostate cancer, including the potential for combination immunotherapies. However, additional research is required to fully address and exploit the contribution of tumor cell and microenvironment heterogeneity in developing effective treatment strategies.

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Elliott S Neal School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia

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Vinod Kumar School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia

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Karin Borges School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia

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James S M Cuffe School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia

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Vitamin B12 (B12) deficiency is common among individuals with diabetes mellitus, but it is unknown if B12 deficiency contributes to impaired glucose homeostasis in this disorder. Female Sprague–Dawley rats were assigned to a control or B12-deficient diet for 4 weeks. Intraperitoneal glucose tolerance tests were performed after 25 days, and blood and liver samples were collected for metabolic profiling. B12 deficiency resulted in a prediabetic-like phenotype characterised by glucose intolerance, a delayed peak in plasma insulin levels following a glucose challenge and increased ketogenesis. We attributed increased ketogenesis to reduced liver anaplerosis, which limited the availability of the TCA cycle intermediates citrate, succinate and succinyl-CoA. This was associated with increased Mut mRNA levels and citrate synthase activity in the liver. One-carbon metabolite levels were altered in plasma and the liver, which was linked to reduced methylation capacity, altered amino acid levels and elevated Slc7a5 mRNA expression. Plasma folate and biotin levels were reduced, as were the majority of B vitamins in the liver. Changes in these B12-dependent processes and reduced B vitamin amounts likely contributed to deficits in glucose handling. Our findings highlight that B12 deficiency may promote the development of metabolic disorders like diabetes mellitus and emphasise the importance of adequate B12 intake for metabolic health.

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Sofie Dinesen Department of Science and Environment, Roskilde University, Universitetsvej 1, Roskilde, Denmark

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Alisar El-Faitarouni Department of Science and Environment, Roskilde University, Universitetsvej 1, Roskilde, Denmark

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Louise T Dalgaard Department of Science and Environment, Roskilde University, Universitetsvej 1, Roskilde, Denmark

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Different types of small non-coding RNAs, especially miRNAs, may be found in the circulation, either protein-bound or enclosed in extracellular vesicles. During gestation, and particularly during gestational diabetes mellitus (GDM), the levels of several miRNAs are altered. Worldwide the incidence of GDM is increasing, in part driven by the current obesity epidemic. This is a point of public health concern because offspring of women with GDM frequently suffer from short- and long-term complications of maternal GDM. This has prompted the investigation of whether levels of specific miRNA species, detected early in gestation, may be used as diagnostic or prognostic markers for the development of GDM. Here, we summarize the mechanisms of RNA secretion and review circulating miRNAs associated with GDM. Several miRNAs are associated with GDM: miR-29a-3p and miR-29b-3p are generally upregulated in GDM pregnancies, also when measured prior to the development of GDM, while miR-16-5p is consistently upregulated in GDM pregnancies, especially in late gestation. miR-330-3p in circulation is increased in late gestation GDM women, especially in those with poor insulin secretion. miR-17-5p, miR-19a/b-3p, miR-223-3p, miR-155-5p, miR-125-a/b-5p, miR-210-3p and miR-132 are also associated with GDM, but less so and with more contradictory results reported. There could be a publication bias as miRNAs identified early are investigated the most, suggesting that it is likely that additional, more recently detected miRNAs could also be associated with GDM. Thus, circulating miRNAs show potential as biomarkers of GDM diagnosis or prognosis, especially multiple miRNAs containing prediction algorithms show promise, but further studies are needed.

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Yi Jun Desmond Tan Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Faculty of Medicine & Health Sciences, UCSI University, Cheras, Kuala Lumpur, Malaysia

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Danielle L Brooks Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

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Kelly Yin Han Wong Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Faculty of Medicine & Health Sciences, UCSI University, Cheras, Kuala Lumpur, Malaysia

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Yuefei Huang Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

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Jose R Romero Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

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Jonathan S Williams Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

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Luminita H Pojoga Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

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Biologic sex influences the development of cardiovascular disease and modifies aldosterone (ALDO) and blood pressure (BP) phenotypes: females secrete more ALDO, and their adrenal glomerulosa cell is more sensitive to stimulation. Lysine-specific demethylase 1 (LSD1) variants in Africans and LSD1 deficiency in mice are associated with BP and/or ALDO phenotypes. This study, in 18- and 40-week-old wild type (WT) and LSD1+/− mice, was designed to determine whether (1) sex modifies ALDO biosynthetic enzymes; (2) LSD1 deficiency disrupts the effect of sex on these enzymes; (3) within each genotype, there is a positive relationship between ALDO biosynthesis (proximate phenotype), plasma ALDO (intermediate phenotype) and BP levels (distant phenotype); and (4) sex and LSD1 genotype interact on these phenotypes. In WT mice, female sex increases the expression of early enzymes in ALDO biosynthesis but not ALDO levels or systolic blood pressure (SBP). However, enzyme expressions are shifted downward in LSD1+/− females vs males, so that early enzyme levels are similar but the late enzymes are substantially lower. In both age groups, LSD1 deficiency modifies the adrenal enzyme expressions, circulating ALDO levels, and SBP in a sex-specific manner. Finally, significant sex/LSD1 genotype interactions modulate the three phenotypes in mice. In conclusion, biologic sex in mice interacts with LSD1 deficiency to modify several phenotypes: (1) proximal (ALDO biosynthetic enzymes); (2) intermediate (circulating ALDO); and (3) distant (SBP). These results provide entry to better understand the roles of biological sex and LSD1 in (1) hypertension heterogeneity and (2) providing more personalized treatment.

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Leke Wiering Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany

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Frank Tacke Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany

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Non-alcoholic fatty liver disease (NAFLD) with its more progressive form non-alcoholic steatohepatitis (NASH) has become the most common chronic liver disease, thereby representing a great burden for patients and healthcare systems. Specific pharmacological therapies for NAFLD are still missing. Inflammation is an important driver in the pathogenesis of NASH, and the mechanisms underlying inflammation in NAFLD represent possible therapeutic targets. In NASH, various intra- and extrahepatic triggers involved in the metabolic injury typically lead to the activation of different immune cells. This includes hepatic Kupffer cells, i.e. liver-resident macrophages, which can adopt an inflammatory phenotype and activate other immune cells by releasing inflammatory cytokines. As inflammation progresses, Kupffer cells are increasingly replaced by monocyte-derived macrophages with a distinct lipid-associated and scar-associated phenotype. Many other immune cells, including neutrophils, T lymphocytes – such as auto-aggressive cytotoxic as well as regulatory T cells – and innate lymphoid cells balance the progression and regression of inflammation and subsequent fibrosis. The detailed understanding of inflammatory cell subsets and their activation pathways prompted preclinical and clinical exploration of potential targets in NAFLD/NASH. These approaches to target inflammation in NASH include inhibition of immune cell recruitment via chemokine receptors (e.g. cenicriviroc), neutralization of CD44 or galectin-3 as well as agonism to nuclear factors like peroxisome proliferator-activated receptors and farnesoid X receptor that interfere with the activation of immune cells. As some of these approaches did not demonstrate convincing efficacy as monotherapies, a rational and personalized combination of therapeutic interventions may be needed for the near future.

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Mariana Rosolen Tavares Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brazil

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Renata Frazao Department of Anatomy, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brazil

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Jose Donato Jr Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brazil

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Growth hormone (GH) is secreted by the anterior pituitary gland and plays a key role in controlling tissue and body growth. While basal GH secretion is considerably reduced along adulthood and aging, several situations of metabolic stress can lead to robust increases in circulating GH levels. The objective of the present review is to summarize and discuss the importance of GH regulating different physiological functions in situations of metabolic stress, including prolonged food restriction, hypoglycemia, exercise, pregnancy, and obesity. The presented data indicate that GH increases hunger perception/food intake, fat mobilization, blood glucose levels, and insulin resistance and produces changes in energy expenditure and neuroendocrine responses during metabolic challenges. When all these effects are considered in the context of situations of metabolic stress, they contribute to restore homeostasis by (1) helping the organism to use appropriate energy substrates, (2) preventing hypoglycemia or increasing the availability of glucose, (3) stimulating feeding to provide nutrients in response to energy-demanding activities or to accelerate the recovery of energy stores, and (4) affecting the activity of neuronal populations involved in the control of metabolism and stress response. Thus, the central and peripheral effects of GH coordinate multiple adaptations during situations of metabolic stress that ultimately help the organism restore homeostasis, increasing the chances of survival.

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