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N Zlocowski Centro de Microscopía Electrónica, Facultad de Ciencias Médicas (CME-FCM) - Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas Técnicas (INICSA-CONICET), Universidad Nacional de Córdoba, Córdoba, ArgentinaFacultad de Ciencias Médicas (CME-FCM) - Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas Técnicas (INICSA-CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina

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L d V Sosa Centro de Microscopía Electrónica, Facultad de Ciencias Médicas (CME-FCM) - Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas Técnicas (INICSA-CONICET), Universidad Nacional de Córdoba, Córdoba, ArgentinaFacultad de Ciencias Médicas (CME-FCM) - Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas Técnicas (INICSA-CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina

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B De la Cruz-Thea Cellular and Molecular Neurobiology Department, CONICET - Universidad Nacional de Córdoba - Instituto de Investigación Médica Mercedes y Martín Ferreyra, Córdoba, Argentina

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C B Guido Centro de Microscopía Electrónica, Facultad de Ciencias Médicas (CME-FCM) - Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas Técnicas (INICSA-CONICET), Universidad Nacional de Córdoba, Córdoba, ArgentinaFacultad de Ciencias Médicas (CME-FCM) - Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas Técnicas (INICSA-CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina

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M G Martín Cellular and Molecular Neurobiology Department, CONICET - Universidad Nacional de Córdoba - Instituto de Investigación Médica Mercedes y Martín Ferreyra, Córdoba, Argentina

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J H Mukdsi Centro de Microscopía Electrónica, Facultad de Ciencias Médicas (CME-FCM) - Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas Técnicas (INICSA-CONICET), Universidad Nacional de Córdoba, Córdoba, ArgentinaFacultad de Ciencias Médicas (CME-FCM) - Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas Técnicas (INICSA-CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina

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A I Torres Centro de Microscopía Electrónica, Facultad de Ciencias Médicas (CME-FCM) - Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas Técnicas (INICSA-CONICET), Universidad Nacional de Córdoba, Córdoba, ArgentinaFacultad de Ciencias Médicas (CME-FCM) - Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas Técnicas (INICSA-CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina

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J P Petiti Centro de Microscopía Electrónica, Facultad de Ciencias Médicas (CME-FCM) - Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas Técnicas (INICSA-CONICET), Universidad Nacional de Córdoba, Córdoba, ArgentinaFacultad de Ciencias Médicas (CME-FCM) - Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas Técnicas (INICSA-CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina

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Interest in epigenetics has gained substantial momentum as a result of their identified role in the regulation of tumor progression as well as their ability to pharmacologically target genes. Pituitary neuroendocrine tumors (PitNETs) tend to be inactivated via epigenetic modification, and although emerging evidence has suggested a role for epigenetic factors in PitNET tumorigenesis, the degree to which these factors may be targeted by new therapeutic strategies still remains poorly understood. The objective of the present study was to examine the participation of the EZH2/H3K27me3 axis in the proliferation of lactotroph tumor cells. We demonstrated that the levels of EZH2 and H3K27me3 were increased in murine experimental prolactin (PRL) tumors with respect to a control pituitary, in contrast with the low p21 mRNA levels encountered, with an H3K27me3 enrichment being observed in its promoter region in a GH3 tumor cell. Furthermore, specific EZH2/H3K27me3 axis inhibition blocked the proliferation of primary tumor cell culture and GH3 cells, thereby making it an attractive therapeutic target for PRL PitNETs.

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Bettina Geidl-Flueck Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Switzerland

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Philipp A Gerber Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Switzerland

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Despite the existence of numerous studies supporting a pathological link between fructose consumption and the development of the metabolic syndrome and its sequelae, such as non-alcoholic fatty liver disease (NAFLD), this link remains a contentious issue. With this article, we shed a light on the impact of sugar/fructose intake on hepatic de novo lipogenesis (DNL), an outcome parameter known to be dysregulated in subjects with type 2 diabetes and/or NAFLD. In this review, we present findings from human intervention studies using physiological doses of sugar as well as mechanistic animal studies. There is evidence from both human and animal studies that fructose is a more potent inducer of hepatic lipogenesis than glucose. This is most likely due to the liver’s prominent physiological role in fructose metabolism, which may be disrupted under pathological conditions by increased hepatic expression of fructolytic and lipogenic enzymes. Increased DNL may not only contribute to ectopic fat deposition (i.e. in the liver), but it may also impair several metabolic processes through DNL-related fatty acids (e.g. beta-cell function, insulin secretion, or insulin sensitivity).

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Vicki Chen Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada

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Gia V Shelp Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada

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Jacob L Schwartz Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada

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Niklas D J Aardema Department of Nutrition, Dietetics and Food Sciences, Utah State University, Logan, Utah, United States

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Madison L Bunnell Department of Nutrition, Dietetics and Food Sciences, Utah State University, Logan, Utah, United States

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Clara E Cho Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada

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Micronutrients consumed in excess or imbalanced amounts during pregnancy may increase the risk of metabolic diseases in offspring, but the mechanisms underlying these effects are unknown. Serotonin (5-hydroxytryptamine, 5-HT), a multifunctional indoleamine in the brain and the gut, may have key roles in regulating metabolism. We investigated the effects of gestational micronutrient intakes on the central and peripheral serotonergic systems as modulators of the offspring's metabolic phenotypes. Pregnant Wistar rats were fed an AIN-93G diet with 1-fold recommended vitamins (RV), high 10-fold multivitamins (HV), high 10-fold folic acid with recommended choline (HFolRC), or high 10-fold folic acid with no choline (HFolNC). Male and female offspring were weaned to a high-fat RV diet for 12 weeks. We assessed the central function using the 5-HT2C receptor agonist, 1-(3-chlorophenyl)piperazine (mCPP), and found that male offspring from the HV- or HFolRC-fed dams were less responsive (P < 0.05) whereas female HFolRC offspring were more responsive to mCPP (P < 0.01) at 6 weeks post-weaning. Male and female offspring from the HV and HFolNC groups, and male HFolRC offspring had greater food intake (males P < 0.001; females P < 0.001) and weight gain (males P < 0.0001; females P < 0.0001), elevated colon 5-HT (males P < 0.01; females P < 0.001) and fasting glucose concentrations (males P < 0.01; females P < 0.01), as well as body composition toward obesity (males P < 0.01; females P < 0.01) at 12 weeks post-weaning. Colon 5-HT was correlated with fasting glucose concentrations (males R2=0.78, P < 0.0001; females R2=0.71, P < 0.0001). Overall, the serotonergic systems are sensitive to the composition of gestational micronutrients, with alterations consistent with metabolic disturbances in offspring.

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Sy-Ying Leu Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, ROC

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Yi-Ling Tsang Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
Institute of Physiological Chemistry and Pathobiochemistry and Cells in Motion Interfaculty Centre, University of Münster, Münster, Germany

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Li-Chun Ho School of Medicine, I-Shou University, Kaohsiung, Taiwan, ROC
Division of General Medicine, Department of Internal Medicine, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan, ROC

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Ching-Chun Yang Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC

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Ai-Ning Shao Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC

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Chia-Yu Chang Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC

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Hui-Kuan Lin Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA

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Pei-Jane Tsai Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC

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Junne-Ming Sung Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, ROC

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Yau-Sheng Tsai Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA
Clinical Medicine Research Center, National Cheng Kung University Hospital, Tainan, Taiwan, ROC

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The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an oligomeric complex that assembles in response to exogenous signals of pathogen infection and endogenous danger signals of non-microbial origin. When NLRP3 inflammasome assembly activates caspase-1, it promotes the maturation and release of the inflammatory cytokines interleukin-1B and IL-18. Aberrant activation of the NLRP3 inflammasome has been implicated in various diseases, including chronic inflammatory, metabolic, and cardiovascular diseases. The NLRP3 inflammasome can be activated through several principal mechanisms, including K+ efflux, lysosomal damage, and the production of mitochondrial reactive oxygen species. Interestingly, metabolic danger signals activate the NLRP3 inflammasome to induce metabolic diseases. NLRP3 contains three crucial domains: an N-terminal pyrin domain, a central nucleotide-binding domain, and a C-terminal leucine-rich repeat domain. Protein–protein interactions act as a ‘pedal or brake’ to control the activation of the NLRP3 inflammasome. In this review, we present the mechanisms underlying NLRP3 inflammasome activation after induction by metabolic danger signals or via protein–protein interactions with NLRP3 that likely occur in metabolic diseases. Understanding these mechanisms will enable the development of specific inhibitors to treat NLRP3-related metabolic diseases.

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Timothy J Dreyer Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, UK

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Jacob AC Keen Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, UK

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Leah M Wells Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, UK

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Scott J Roberts Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, UK

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As a key regulator of bone homeostasis, sclerostin has garnered a lot of interest over the last two decades. Although sclerostin is primarily expressed by osteocytes and is well known for its role in bone formation and remodelling, it is also expressed by a number of other cells and potentially plays a role in other organs. Herein, we aim to bring together recent sclerostin research and discuss the effect of sclerostin on bone, cartilage, muscle, liver, kidney and the cardiovascular and immune systems. Particular focus is placed on its role in diseases, such as osteoporosis and myeloma bone disease, and the novel development of sclerostin as a therapeutic target. Anti-sclerostin antibodies have recently been approved for the treatment of osteoporosis. However, a cardiovascular signal was observed, prompting extensive research into the role of sclerostin in vascular and bone tissue crosstalk. The study of sclerostin expression in chronic kidney disease was followed by the investigation of its role in liver–lipid–bone interactions, and the recent discovery of sclerostin as a myokine prompted new research into sclerostin within the bone–muscle relationship. Potentially, the effects of sclerostin reach beyond that of bone alone. We further summarise recent developments in the use of sclerostin as a potential therapeutic for osteoarthritis, osteosarcoma and sclerosteosis. Overall, these new treatments and discoveries illustrate progress within the field, however, also highlight remaining gaps in our knowledge.

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Ken KY Ho Garvan Institute of Medical Research, St. Vincent’s Hospital and the UNSW Sydney, Sydney, New South Wales, Australia

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Anthony J O’Sullivan St. George Hospital and the Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia

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Morton G Burt Southern Adelaide Diabetes and Endocrine, Flinders Medical Centre and College of Medicine and Public Health, and Flinders University, Adelaide, South Australia, Australia

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The fact that growth hormone (GH) plays an important role in health after the cessation of growth requiring replacement therapy in adult life has only been recognised in the last three decades. This has only been made possible by recombinant technology providing GH supplies required to undertake investigations in the physiology of GH action and the benefits of replacement therapy in patients identified by rigorously validated diagnostic tests for GH deficiency (GHD). Human studies have revealed important regulatory roles in substrate metabolism, sodium homeostasis, body composition, and physical function. GH-induced anabolism is achieved by stimulating amino acid incorporation into protein while reducing oxidative loss simultaneously enhancing lipid utilisation by stimulating fatty acid oxidation and reducing lipid storage. Sodium and fluid retention are enhanced by activating the renin–angiotensin system and distal renal tubular reabsorption. GH stimulates the aerobic and anaerobic energy systems that underpin muscle and cardiovascular function. These pleiotropic actions explain the clinical picture of increased adiposity, reduced lean mass, and impaired physical and psychological function in the GHD adult, all of which are reversed when GH is replaced. Women require a greater replacement dose of GH than men. This is because androgens enhance while oestrogens attenuate GH action. The oestrogen effect is route-dependent, occurring with oral delivery blunting the liver-mediated actions of GH by directly inhibiting GH receptor signalling, global experience spanning over 30 years has attested to the safety, efficacy, and benefits of replacement therapy for adults with GHD.

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Yuta Kasahara Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan

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Hiroshi Kishi Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan

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Ryo Yokomizo Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan

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Aikou Okamoto Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan

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There are many previous reports on the effects of ethanol on physiological function, including reports of elevated blood estrogen levels in women who drank alcohol. However, the mechanism of ethanol's effects on ovarian functions, such as follicle development and hormone secretion, has not been fully clarified. Therefore, in this study, we investigated the impacts of ethanol on these phenomena and their mechanisms using a primary culture system of rat ovarian granulosa cells (GCs). In the present experiment, groups were created in which follicle-stimulating hormone (FSH) or ethanol was added alone or FSH and ethanol were co-added, and mRNA and protein expression in each group was measured for luteinizing hormone receptor (LHR) and sex steroid hormone synthase, as well as for estradiol (E2) production, cAMP production, and FSH receptor (FSHR) internalization rate. The addition of FSH induced mRNA expression of LHR and aromatase, which led to membrane LHR expression and E2 production. The coexistence of ethanol enhanced all these responses. The action of FSH is exerted via cAMP, and the co-addition of ethanol enhanced this cAMP production. Ethanol alone did not induce cAMP production. The enhancing effect of ethanol was also observed for cAMP induced by cholera toxin. Ethanol had no significant effect on the internalization rate of FSHR. In conclusion, ethanol increased FSH-stimulated cAMP production by increasing the activity of adenylyl cyclase, which enhanced FSH actions in rat GCs. Alcohol is an exacerbating factor in several female hormone-related diseases, and the mechanism of ethanol-induced increase in estrogen secretion revealed in this study may be involved in the pathogenesis of these diseases.

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Jitendra Vishwakarma Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

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Keerti Gupta Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

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Juhi Mishra Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India

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Asmita Garg Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

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Rafat Malik Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India

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Amit Kashyap Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India

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Manoj Shukla Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226014, Uttar Pradesh, India

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Dhirendra Singh Central Pathology Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR–IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India

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Sanghamitra Bandyopadhyay Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

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Thyroid hormones (TH) are vital for brain functions, while TH deficiency, i.e. hypothyroidism, induces neurological impairment in children and adults. Cerebellar neuronal apoptosis and motor deficits are crucial events in hypothyroidism; however, the underlying mechanism is less-known. Using a methimazole-treated hypothyroidism rat model, we investigated cerebellar autophagy, growth factor, and apoptotic mechanisms that participate in motor functions. We first identified that methimazole up-regulated cerebellar autophagy, marked by enhanced LC3B-II, Beclin-1, ATG7, ATG5-12, p-AMPKα/AMPKα, and p62 degradation as well as reduced p-AKT/AKT, p-mTOR/mTOR, and p-ULK1/ULK1 in developing and young adult rats. We probed upstream effectors of this abnormal autophagy and detected a methimazole-induced reduction in cerebellar phospho-epidermal growth factor receptor (p-EGFR)/EGFR and heparin-binding EGF-like growth factor (HB-EGF). Here, while a thyroxine-induced TH replenishment alleviated autophagy process and restored HB-EGF/EGFR, HB-EGF treatment regulated AKT-mTOR and autophagy signaling in the cerebellum. Moreover, neurons of the rat cerebellum demonstrated this reduced HB-EGF-dependent increased autophagy in hypothyroidism. We further checked whether the above events were related to cerebellar neuronal apoptosis and motor functions. We detected that comparable to thyroxine, treatment with HB-EGF or autophagy inhibitor, 3-MA, reduced methimazole-induced decrease in Nissl staining and increase in c-Caspase-3 and TUNEL-+ve apoptotic count of cerebellar neurons. Additionally, 3-MA, HB-EGF, and thyroxine attenuated the methimazole-induced diminution in riding time on rota-rod and grip strength for the motor performance of rats. Overall, our study enlightens HB-EGF/EGFR-dependent autophagy mechanism as a key to cerebellar neuronal loss and functional impairments in developmental hypothyroidism, which may be inhibited by HB-EGF and 3-MA treatments, like thyroxine.

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Mari van de Vyver Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

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Inflammation is part of the body’s innate immune response and is an essential process that not only defends against harmful bacteria and pathogens but also plays a key role in the maintenance and repair of tissues. Under pathological conditions, there is bilateral crosstalk between immune regulation and aberrant metabolism resulting in persistent inflammation in the absence of infection. This phenomenon is referred to as sterile metabolic inflammation (metainflammation) and occurs if the initiating stimulus is not removed or if the resolution process is disrupted. Disruption of this tightly regulated immune response and its failure to resolve as is evident in metabolic disorders is not only associated with disease progression but also leads to immune senescence and should not be neglected in the clinical management of patients. This review gives an overview of the mechanisms underlying chronic metabolic inflammation, the aberrant metabolic activation of innate immune cells (neutrophils, macrophages, mast cells, dendritic cells), and its role in disease progression using obesity–diabetes as a prime example. Addressing the underlying subclinical metabolic inflammation in addition to achieving glucose control may contribute significantly towards therapeutic interventions aimed at preventing the onset of co-morbidities in diabetic patients.

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Samuel M Lee Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois, USA

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Jose Muratalla Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois, USA

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Marta Sierra-Cruz Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois, USA

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Jose Cordoba-Chacon Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois, USA

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Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target of a group of insulin sensitizers called thiazolidinediones (TZDs) which regulate the expression of genes involved in glucose and lipid metabolism as well as adipokines that regulate metabolic function in other tissues. Non-alcoholic fatty liver disease (NAFLD) has a high prevalence worldwide and is even higher in patients with obesity and insulin resistance. TZD-mediated activation of PPARγ could serve as a good treatment for NAFLD because TZDs have shown anti-fibrogenic and anti-inflammatory effectsin vitro and increase insulin sensitivity in peripheral tissues which improves liver pathology. However, mechanistic studies in mouse models suggest that the activation of PPARγ in hepatocytes might reduce or limit the therapeutic potential of TZD against NAFLD. In this review, we briefly describe the short history of PPAR isoforms, the relevance of their expression in different tissues, as well as the pathogenesis and potential therapeutics for NAFLD. We also discuss some evidence derived from mouse models that could be useful for endocrinologists to assess tissue-specific roles of PPARs, complement reverse endocrinology approaches, and understand the direct role that PPARγ has in hepatocytes and non-parenchymal cells.

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