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Sunita M C De Sousa Endocrine & Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
South Australian Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, Australia
Adelaide Medical School, University of Adelaide, Adelaide, Australia

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Nèle F Lenders Department of Endocrinology, St Vincent’s Hospital, Sydney, NSW, Australia
Garvan Institute of Medical Research, Sydney, NSW, Australia
St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia

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Lydia S Lamb Garvan Institute of Medical Research, Sydney, NSW, Australia
St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia

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Warrick J Inder Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, Australia
Academy for Medical Education, Faculty of Medicine, the University of Queensland, Brisbane, Australia

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Ann McCormack Department of Endocrinology, St Vincent’s Hospital, Sydney, NSW, Australia
Garvan Institute of Medical Research, Sydney, NSW, Australia
St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia

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‘Pituitary tumours’ is an umbrella term for various tumours originating from different regions of the hypothalamic–pituitary system. The vast majority of pituitary tumours are pituitary adenomas, also recently referred to as pituitary neuroendocrine tumours. The prevalence of clinically relevant pituitary adenomas is approximately 1 in 1000; other pituitary tumours such as craniopharyngioma and pituicytoma are comparatively very rare. This review addresses the molecular and genetic aspects of pituitary adenomas. We first discuss the germline genetic variants underlying familial pituitary tumours, which account for approximately 5% of all pituitary adenoma cases. This includes variants in established pituitary adenoma/hyperplasia predisposition genes (MEN1, PRKAR1A, AIP, CDKN1B, GPR101, SDHA, SDHB, SDHC, SDHD, SDHAF2) as well as emerging genetic associations. In addition, we discuss McCune–Albright syndrome which lies between the germline and somatic pituitary tumour genes as the causative GNAS mutations are postzygotic rather than being inherited, and the condition is associated with multiglandular features due to the involvement of different cell lines rather than being limited to the pituitary. By contrast, somatic GNAS mutations contribute to sporadic acromegaly. USP8 is the only other gene where somatic driver mutations have been established in sporadic pituitary tumorigenesis. However, there are now known to be a variety of other somatic genetic and molecular changes underpinning sporadic pituitary adenomas which we review here, namely: copy number variation, molecular changes in signalling and hypoxia pathways, epithelial–mesenchymal transition, DNA repair, senescence, the immune microenvironment and epigenetics.

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Chau Thien Tay Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Victoria, Australia
Department of Endocrinology and Diabetes, Monash Health, Victoria, Australia

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Rhonda Garrad Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Victoria, Australia

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Aya Mousa Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Victoria, Australia

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Mahnaz Bahri Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Victoria, Australia

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Anju Joham Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Victoria, Australia
Department of Endocrinology and Diabetes, Monash Health, Victoria, Australia

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Helena Teede Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Victoria, Australia
Department of Endocrinology and Diabetes, Monash Health, Victoria, Australia

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Polycystic ovary syndrome (PCOS) affects 8–13% of reproductive-aged women, impacts biopsychosocial factors and creates a significant health-related economic burden across the reproductive, metabolic and psychological spectrum of complications. Despite being a heterogenous condition, recent genomic studies indicate that PCOS, regardless of diagnostic criteria and clinical features, shares similar underlying biologic mechanisms. However, recent advances have shown that clinical reproductive and diagnostic features are poorly correlated to genotypes and do not represent true phenotypes. Until we have a better understanding of genetic and epigenetic influences on PCOS and long-term outcomes, targeted treatment is limited.

In the interim, a unified approach to integrate evidence, optimise management and guide future research in PCOS is necessary. This has motivated an international collaboration to develop an International Evidence-Based PCOS Guideline to improve health outcomes in women with PCOS. Dissemination and translation of the guideline into health policy and clinical practice are crucial steps to close the knowledge–-practice gap, guide future research and enhance positive impact on the health of women with PCOS.

Here, we review the (i) understanding of aetiology and genetics of PCOS; (ii) development and translation efforts of the 2018 International Evidence-based PCOS Guideline; (iii) current progress and plans for the guideline update, including the involvement of an early career researcher network to assist with evidence synthesis and (iv) the opportunity to target and guide future research for PCOS.

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Virginia L Pszczolkowski Department of Animal and Dairy Sciences, University of Wisconsin, Madison, Wisconsin, USA
Endocrinologh and Reproductive Physiology Graduate Training Program, University of Wisconsin, Madison, Wisconsin, USA

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Meghan K Connelly Department of Animal and Dairy Sciences, University of Wisconsin, Madison, Wisconsin, USA
Vita Plus Corporation, Madison, Wisconsin, USA

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Adam D Beard Department of Animal and Dairy Sciences, University of Wisconsin, Madison, Wisconsin, USA
Endocrinologh and Reproductive Physiology Graduate Training Program, University of Wisconsin, Madison, Wisconsin, USA

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Amara D Benn Department of Animal and Dairy Sciences, University of Wisconsin, Madison, Wisconsin, USA

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Jimena Laporta Department of Animal and Dairy Sciences, University of Wisconsin, Madison, Wisconsin, USA
Endocrinologh and Reproductive Physiology Graduate Training Program, University of Wisconsin, Madison, Wisconsin, USA

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Laura L Hernandez Department of Animal and Dairy Sciences, University of Wisconsin, Madison, Wisconsin, USA
Endocrinologh and Reproductive Physiology Graduate Training Program, University of Wisconsin, Madison, Wisconsin, USA

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Sebastian I Arriola Apelo Department of Animal and Dairy Sciences, University of Wisconsin, Madison, Wisconsin, USA
Endocrinologh and Reproductive Physiology Graduate Training Program, University of Wisconsin, Madison, Wisconsin, USA

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Energy partitioning in lactating cows affects milk production, feed efficiency, and body reserves, with the latter having health implications for the transition into the following lactation. One molecule likely involved in the regulation of energy partitioning is serotonin. The objective of this experiment was to explore how increasing circulating serotonin, by intravenous infusion of the serotonin precursor 5-hydroxytryptophan (5-HTP), affects metabolic responses to a glucose challenge in midlactation cows as a means to manipulate energy partitioning. We intravenously infused Holstein cows with 5-HTP (1 mg/kg bodyweight dissolved in saline, n = 11) or saline alone as control (n = 9) over 1 h/day for 3 days. Cows were fasted overnight on day 2. On day 3, fasted cows were given an intravenous bolus of glucose (0.092 g/kg bodyweight). Blood samples were collected for the following 120 min for metabolic and hormonal analysis. Infusion of 5-HTP elevated circulating concentrations of serotonin and free fatty acids, reduced the concentration of insulin and amino acids, and did not affect the concentration of glucose and glucagon before the glucose challenge. Surrogate insulin sensitivity indices indicated improved insulin sensitivity in 5-HTP cows, but due to the unique metabolism of lactating ruminants, these index changes may instead reflect effects in insulin-independent glucose disposal, like milk synthesis. Challenging 5-HTP-treated cows with a glucose bolus reduced the insulin spike and blunted the decrease in free fatty acids, compared to saline cows, without changing glucose dynamics. Overall, these results suggest that serotonin stimulates insulin-independent glucose disposal, requiring less insulin to maintain normoglycemia.

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Hikari Hirakida Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan

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Taiga Okumura Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan

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Ryosuke Fujita Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan

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Yoshiki Kuse Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan

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Takahiro Mizoguchi Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan

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Satoshi Inagaki Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan

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Shinsuke Nakamura Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan

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Masamitsu Shimazawa Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
Lab. of Collaborative Research for Innovative Drug Discovery, Gifu Pharmaceutical University, Gifu, Japan

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Hideaki Hara Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
Lab. of Collaborative Research for Innovative Drug Discovery, Gifu Pharmaceutical University, Gifu, Japan

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VGF nerve growth factor inducible (VGF) is a secreted polypeptide involved in metabolic regulation. VGF-derived peptides have been reported to regulate insulin secretion in the plasma of patients with type 2 diabetes and model mice. However, the protective effects of VGF on pancreatic β-cells in diabetic model are not well understood. In this study, we aimed to elucidate the β-cell protective effect of VGF on a streptozotocin (STZ)-induced diabetic model using VGF-overexpressing (OE) mice and also examined the therapeutic effect by a small molecule, SUN N8075 which is an inducer of VGF. VGF-OE mice improved blood glucose levels and maintained β-cell mass compared to wild-type (WT) mice on STZ-induced diabetic model. In addition, VGF-OE mice showed better glucose tolerance than WT mice. In culture, AQEE-30, a VGF-derived peptide, suppressed STZ-induced β-cell death in vitro and attenuated the decrease in the phosphorylation of Akt and GSK3β. Furthermore, SUN N8075 suppressed the blood glucose levels and increased VGF expression in the pancreatic islet. SUN N8075 also protected STZ-induced β-cell death in vitro. These findings indicate that VGF plays a hypoglycemic role in response to blood glucose levels in diabetes and protects β-cells from STZ-induced cell death. Therefore, VGF and its inducer have the therapeutic potential by preserving β-cells in diabetes.

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Renea A Taylor Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia
Department of Physiology, Biomedicine Discovery Institute, Cancer Program, Monash University, Melbourne, Victoria, Australia
Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Cabrini Institute, Cabrini Health, Malvern, Victoria, Australia

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Mitchell G Lawrence Department of Physiology, Biomedicine Discovery Institute, Cancer Program, Monash University, Melbourne, Victoria, Australia
Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Cabrini Institute, Cabrini Health, Malvern, Victoria, Australia
Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Cancer Program, Monash University, Melbourne, Victoria, Australia

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Gail P Risbridger Department of Physiology, Biomedicine Discovery Institute, Cancer Program, Monash University, Melbourne, Victoria, Australia
Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Cabrini Institute, Cabrini Health, Malvern, Victoria, Australia
Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Cancer Program, Monash University, Melbourne, Victoria, Australia

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There is longstanding interest in the role of androgens in the aetiology of prostate cancer, one of the most common malignancies worldwide. In this review, we reflect on the ways that knowledge of prostate development and hormone action have catalysed advances in the management of patients with prostate cancer. The use of hormone therapies to treat prostate cancer has changed significantly over time, including the emergence of androgen receptor signalling inhibitors (ARSI). These compounds have improved outcomes for patients with castration-resistant prostate cancer, which was once considered ‘androgen-independent’ but is clearly still driven by androgen receptor signalling in many cases. There is also a need for new therapies to manage neuroendocrine prostate cancer, which is not responsive to hormonal agents. One of the major gaps is understanding how treatment-induced neuroendocrine prostate cancer emerges and whether it can be re-sensitised to treatment. Patient-derived models, including patient-derived xenografts (PDXs), will be instrumental in facilitating future discoveries in these areas. Developments in the use of PDXs have been fostered by lessons from the field of endocrinology, such as the role of stroma and hormones in normal and developmental tissues. Thus, there is ongoing reciprocity between the discoveries in endocrinology and advances in prostate cancer research and treatment.

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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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