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Gang Wei Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China
Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, China
Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province, Hangzhou, China
Department of Endocrinology and Metabolism, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China

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Juan-Juan Zhu Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China

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Feng-Jie Shen Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China

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Rong-Rong Xie Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China

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Chen-Yang Zhang Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China

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Yuan Wang Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China

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Ting-Ting Shi Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China

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Xi Cao Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China

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Xin Ding Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China

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Jin-Kui Yang Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China

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Pregnancy requires metabolic adaptations in order to meet support fetal growth with nutrient availability. In this study, the influence of pregnancy on metabolically active organs (adipose tissues in particular) was investigated. Our results showed that maternal weight and adipose mass presented dynamic remodeling in the periparturient mice. Meanwhile, pregnancy mice displayed obvious glucose intolerance and insulin resistance in late pregnancy as compared to non-pregnancy, which were partially reversed at parturition. Further analyses revealed that different fat depots exhibited site-specific adaptions of morphology and functionality as pregnancy advanced. Brown and inguinal white adipose tissue (BAT and IngWAT) exhibited obviously decreased thermogenic activity; by contrast, gonadal white adipose tissue (GonWAT) displayed remarkably increased lipid mobilization. Notably, we found that mammary gland differentiation was enhanced in IngWAT, followed by BAT but not in GonWAT. These result indicated that brown and white adipose tissues might synergistically play a crucial role in maintaining the maximum of energy supply for mother and fetus, which facilitates the mammary duct luminal epithelium development as well as the growth and development of fetus. Accompanied with adipose adaptation, however, our results revealed that the liver and pancreas also displayed significant metabolic adaptability, which together tended to trigger the risk of maternal metabolic diseases. Importantly, pregnancy-dependent obesity in our mice model resembled the disturbed metabolic phenotypes of pregnant women such as hyperglyceridemia and hypercholesterolemia. Our findings in this study could provide valuable clues for better understanding the underlying mechanisms of metabolic maladaptation and facilitate the development of the prevention and treatment of metabolic diseases.

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Yan Jin Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada

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Jessica S Jarmasz Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada

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Shakila Sultana Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada

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Luis Cordero-Monroy Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Albrechtsen Research Centre, Winnipeg, Manitoba, Canada

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Carla G Taylor Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada
Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Albrechtsen Research Centre, Winnipeg, Manitoba, Canada
Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

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Peter Zahradka Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada
Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Albrechtsen Research Centre, Winnipeg, Manitoba, Canada

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Elissavet Kardami Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada

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Peter A Cattini Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada

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The objective was to assess the potential differential effects of human versus mouse growth hormone in vivo, given that human unlike mouse growth hormone can bind prolactin as well as the growth hormone receptor. To this end, a transgenic CD-1 mouse expressing human but not mouse growth hormone was generated, and the phenotypes of male mice fed with a regular chow or high-fat diet were assessed. Pancreas and epididymal white adipose tissue gene expression and/or related function were targeted as the pancreas responds to both prolactin and growth hormone receptor signaling, and catabolic effects like lipolytic activity are more directly attributable to growth hormone and growth hormone receptor signaling. The resulting human growth hormone-expressing mice are smaller than wild-type CD-1 mice, despite higher body fat and larger adipocytes, but both mouse types grow at the same rate with similar bone densities. Unlike wild-type mice, there was no significant delay in glucose clearance in human growth hormone-expressing mice when assessed at 8 versus 24 weeks on a high-fat diet. However, both mouse types showed signs of hepatic steatosis that correlated with elevated prolactin but not growth hormone RNA levels. The larger adipocytes in human growth hormone-expressing mice were associated with modified leptin (higher) and adiponectin (lower) RNA levels. Thus, while limited to observations in the male, the human growth hormone-expressing mice exhibit signs of growth hormone insufficiency and adipocyte dysfunction as well as an initial resistance to the negative effects of high-fat diet on glucose clearance.

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Hsien-Ming Wu Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University School of Medicine, Taoyuan, Taiwan

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Liang-Hsuan Chen Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University School of Medicine, Taoyuan, Taiwan

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Wei-Jung Chiu Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University School of Medicine, Taoyuan, Taiwan

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Chia-Lung Tsai Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University School of Medicine, Taoyuan, Taiwan

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In this study, we investigate the effects of miRNA-138-5p and probable G-protein coupled receptor 124 (GPR124)-regulated inflammasome and downstream leukemia inhibitory factor (LIF)–STAT and adhesion molecule signaling in human decidual stromal cells. After informed consent was obtained from women aged 25–38 years undergoing surgical termination of the normal pregnancy and spontaneous miscarriage after 6–9 weeks of gestation, human decidual stromal cells were extracted from the decidual tissue. Extracellular vesicles (EVs) with microRNA (miRNA) between cells have been regarded as critical factors for embryo–maternal interactions on embryo implantation and programming of human pregnancy. MicroRNA-138-5p acts as the transcriptional regulator of GPR124 and the mediator of downstream inflammasome. LIF-regulated STAT activation and expression of integrins might influence embryo implantation. Hence, a better understanding of LIF–STAT and adhesion molecule signaling would elucidate the mechanism of microRNA-138-5p- and GPR124-regulated inflammasome activation on embryo implantation and pregnancy. Our results show that microRNA-138-5p, purified from the EVs of decidual stromal cells, inhibits the expression of GPR124 and the inflammasome, and activates the expression of LIF–STAT and adhesion molecules in human decidual stromal cells. Additionally, the knockdown of GPR124 and NLRP3 through siRNA increases the expression of LIF–STAT and adhesion molecules. The findings of this study help us gain a better understanding the role of EVs, microRNA-138-5p, GPR124, inflammasomes, LIF–STAT, and adhesion molecules in embryo implantation and programming of human pregnancy.

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Junling Wang Gynecologic Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China

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Hongyan Zhang Gynecologic Department, Hainan Traditional Chinese Medicine Hospital, Haikou, China

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Yue Cao Science and technology department, Guangzhou University of Chinese Medicine, Guangzhou, China

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Irene Ma Gynecologic Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China

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Xuefang Liang Gynecologic Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China

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Dongfang Xiang Gynecologic Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China

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Postmenopausal osteoporosis (OP) is a prevalent skeletal disease with not fully understood molecular mechanisms. This study aims to investigate the role of circular RNA (circRNA) in postmenopausal OP and to elucidate the potential mechanisms of the circRNA–miRNA–mRNA regulatory network. We obtained circRNA and miRNA expression profiles from postmenopausal OP patients from the Gene Expression Omnibus database. By identifying differentially expressed circRNAs and miRNAs, we constructed a circRNA–miRNA–mRNA network and identified key genes associated with OP. Further, through a range of experimental approaches, including dual-luciferase reporter assays, RNA pull-down experiments, and qRT-PCR, we examined the roles of circ_0134120, miR-590-5p, and STAT3 in the progression of OP. Our findings reveal that the interaction between circ_0134120 and miR-590-5p in regulating STAT3 gene expression is a key mechanism in OP, suggesting the circRNA–miRNA–mRNA network is a potential therapeutic target for this condition.

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Abigail R Walker Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Holly A Parkin Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Sung Hye Kim Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Vasso Terzidou Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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David F Woodward Department of Bioengineering, Imperial College London, London, UK

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Phillip R Bennett Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Aylin C Hanyaloglu Institute of Reproductive and Developmental Biology, Department Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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The prostanoid G protein-coupled receptor (GPCR) EP2 is widely expressed and implicated in endometriosis, osteoporosis, obesity, pre-term labour and cancer. Internalisation and intracellular trafficking are critical for shaping GPCR activity, yet little is known regarding the spatial programming of EP2 signalling and whether this can be exploited pharmacologically. Using three EP2-selective ligands that favour activation of different EP2 pathways, we show that EP2 undergoes limited agonist-driven internalisation but is constitutively internalised via dynamin-dependent, β-arrestin-independent pathways. EP2 was constitutively trafficked to early and very early endosomes (VEE), which was not altered by ligand activation. APPL1, a key adaptor and regulatory protein of the VEE, did not impact EP2 agonist-mediated cAMP. Internalisation was required for ~70% of the acute butaprost- and AH13205-mediated cAMP signalling, yet PGN9856i, a Gαs-biased agonist, was less dependent on receptor internalisation for its cAMP signalling, particularly in human term pregnant myometrial cells that endogenously express EP2. Inhibition of EP2 internalisation partially reduced calcium signalling activated by butaprost or AH13205 and had no effect on PGE2 secretion. This indicates an agonist-dependent differential spatial requirement for Gαs and Gαq/11 signalling and a role for plasma membrane-initiated Gαq/11-Ca2+-mediated PGE2 secretion. These findings reveal a key role for EP2 constitutive internalisation in its signalling and potential spatial bias in mediating its downstream functions. This, in turn, could highlight important considerations for future selective targeting of EP2 signalling pathways.

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Yalan Hu Endocrine Laboratory, Department of Laboratory Medicine, University of Amsterdam, Amsterdam, The Netherlands
Amsterdam Gastroenterology, Endocrinology & Metabolism Research Institute, Amsterdam, The Netherlands

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Gemma F Codner The Mary Lyon Centre at MRC Harwell, Harwell Campus, Oxfordshire, UK

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Michelle Stewart The Mary Lyon Centre at MRC Harwell, Harwell Campus, Oxfordshire, UK

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Susanne E La Fleur Endocrine Laboratory, Department of Laboratory Medicine, University of Amsterdam, Amsterdam, The Netherlands
Amsterdam Gastroenterology, Endocrinology & Metabolism Research Institute, Amsterdam, The Netherlands
Amsterdam Neuroscience, Cellular and Molecular Mechanisms, Amsterdam, The Netherlands

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Paul A S van Trotsenburg Amsterdam Gastroenterology, Endocrinology & Metabolism Research Institute, Amsterdam, The Netherlands
Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam, The Netherlands

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Eric Fliers Amsterdam Gastroenterology, Endocrinology & Metabolism Research Institute, Amsterdam, The Netherlands
Department of Endocrinology, University of Amsterdam, Amsterdam, The Netherlands

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Raoul C Hennekam Department of Pediatrics, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Anita Boelen Endocrine Laboratory, Department of Laboratory Medicine, University of Amsterdam, Amsterdam, The Netherlands
Amsterdam Gastroenterology, Endocrinology & Metabolism Research Institute, Amsterdam, The Netherlands
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands

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Humans with the mutation Y509C in transducin beta like 1 X-linked (TBL1X HGNC ID HGNC:11585) have been reported to present with the combination of central congenital hypothyroidism and impaired hearing. TBL1X belongs to the WD40 repeat-containing protein family, is part of NCoR and SMRT corepressor complexes, and thereby involved in thyroid hormone signaling. In order to investigate the effects of the Y509C mutation in TBL1X on cellular thyroid hormone action, we aimed to generate a hemizygous male mouse cohort carrying the Tbl1x Y459C mutation which is equivalent to the human TBL1X Y509C mutation using CRISPR/Cas9 technology. Hemizygous male mice were small at birth and inactive. Their life span (median life span 93 days) was very short compared with heterozygous female mice (survived to >200 days with no welfare issues). About 52% of mice did not survive to weaning (133 mice). Of the remaining 118 mice, only 8 were hemizygous males who were unable to mate whereby it was impossible to generate homozygous female mice. In conclusion, the Tbl1x Y459C mutation in male mice has a marked negative effect on birth weight, survival, and fertility of male mice. The present findings are unexpected as they are in contrast to the mild phenotype in human males carrying the equivalent TBL1X Y509C mutation.

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Weiye Zhao Department of Biology, University of York, York, UK

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Susanna F Rose Department of Biology, University of York, York, UK

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Ryan Blake CRUK Cambridge Institute, University of Cambridge, Cambridge, UK

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Aňze Godicelj Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Smith Building, Boston, Massachusetts, USA

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Amy E Cullen CRUK Cambridge Institute, University of Cambridge, Cambridge, UK

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Jack Stenning Department of Biology, University of York, York, UK

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Lucy Beevors The Institute of Metabolism and Systems Research (IMSR), University of Birmingham, College of Medical and Dental Sciences, Birmingham, UK

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Marcel Gehrung CRUK Cambridge Institute, University of Cambridge, Cambridge, UK

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Sanjeev Kumar Chris O’Brien Lifehouse, Sydney, New South Wales, Australia

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Kamal Kishore CRUK Cambridge Institute, University of Cambridge, Cambridge, UK

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Ashley Sawle CRUK Cambridge Institute, University of Cambridge, Cambridge, UK

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Matthew Eldridge CRUK Cambridge Institute, University of Cambridge, Cambridge, UK

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Federico M Giorgi Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy

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Katherine S Bridge Department of Biology, University of York, York, UK
York Biomedical Research Institute, University of York, York, UK

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Florian Markowetz CRUK Cambridge Institute, University of Cambridge, Cambridge, UK

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Andrew N Holding Department of Biology, University of York, York, UK
York Biomedical Research Institute, University of York, York, UK
The Alan Turing Institute, Kings Cross, London, UK

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The estrogen receptor-α (ER) drives 75% of breast cancers. On activation, the ER recruits and assembles a 1–2 MDa transcriptionally active complex. These complexes can modulate tumour growth, and understanding the roles of individual proteins within these complexes can help identify new therapeutic targets. Here, we present the discovery of ER and ZMIZ1 within the same multi-protein assembly by quantitative proteomics, and validated by proximity ligation assay. We characterise ZMIZ1 function by demonstrating a significant decrease in the proliferation of ER-positive cancer cell lines. To establish a role for the ER-ZMIZ1 interaction, we measured the transcriptional changes in the estrogen response post-ZMIZ1 knockdown using an RNA-seq time-course over 24 h. Gene set enrichment analysis of the ZMIZ1-knockdown data identified a specific delay in the response of estradiol-induced cell cycle genes. Integration of ENCODE data with our RNA-seq results identified that ER and ZMIZ1 both bind the promoter of E2F2. We therefore propose that ER and ZMIZ1 interact to enable the efficient estrogenic response at subset of cell cycle genes via a novel ZMIZ1–ER–E2F2 signalling axis. Finally, we show that high ZMIZ1 expression is predictive of worse patient outcome, ER and ZMIZ1 are co-expressed in breast cancer patients in TCGA and METABRIC, and the proteins are co-localised within the nuclei of tumour cell in patient biopsies. In conclusion, we establish that ZMIZ1 is a regulator of the estrogenic cell cycle response and provide evidence of the biological importance of the ER–ZMIZ1 interaction in ER-positive patient tumours, supporting potential clinical relevance.

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Marta Santos-Hernández Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

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Frank Reimann Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

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Fiona M Gribble Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

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Enteroendocrine cells located along the gastrointestinal epithelium sense different nutrients/luminal contents that trigger the secretion of a variety of gut hormones with different roles in glucose homeostasis and appetite regulation. The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are involved in the regulation of insulin secretion, appetite, food intake and body weight after their nutrient-induced secretion from the gut. GLP-1 mimetics have been developed and used in the treatment of type 2 diabetes mellitus and obesity. Modulating the release of endogenous intestinal hormones may be a promising approach for the treatment of obesity and type 2 diabetes without surgery. For that reason, current understanding of the cellular mechanisms underlying intestinal hormone secretion will be the focus of this review. The mechanisms controlling hormone secretion depend on the nature of the stimulus, involving a variety of signalling pathways including ion channels, nutrient transporters and G-protein-coupled receptors.

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Nirvay Sah Department of Pathology, University of California San Diego, La Jolla, California, USA
Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, USA

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Francesca Soncin Department of Pathology, University of California San Diego, La Jolla, California, USA
Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, USA

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Trophoblast stem cells (TSCs) are a proliferative multipotent population derived from the trophectoderm of the blastocyst, which will give rise to all the functional cell types of the trophoblast compartment of the placenta. The isolation and culture of TSCs in vitro represent a robust model to study mechanisms of trophoblast differentiation into mature cells both in successful and diseased pregnancy. Despite the highly conserved functions of the placenta, there is extreme variability in placental morphology, fetal–maternal interface, and development among eutherian mammals. This review aims to summarize the establishment and maintenance of TSCs in mammals such as primates, including human, rodents, and nontraditional animal models with a primary emphasis on epigenetic regulation of their origin while defining gaps in the current literature and areas of further development. FGF signaling is critical for mouse TSCs but dispensable for derivation of TSCs in other species. Human, simian, and bovine TSCs have much more complicated requirements of signaling pathways including activation of WNT and inhibition of TGFβ cascades. Epigenetic features such as DNA and histone methylation as well as histone acetylation are dynamic during development and are expressed in cell- and gestational age-specific pattern in placental trophoblasts. While TSCs from different species seem to recapitulate some select epigenomic features, there is a limitation in the comprehensive understanding of TSCs and how well TSCs retain placental epigenetic marks. Therefore, future studies should be directed at investigating epigenomic features of global and placental-specific gene expression in primary trophoblasts and TSCs.

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Yan Meng School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, UK

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Maria Toledo-Rodriguez School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, UK

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Olena Fedorenko School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, UK

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Paul A Smith School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, UK

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White adipose tissue (WAT) requires extracellular Ca2+ influx for lipolysis, differentiation, and expansion. This partly occurs via plasma membrane Ca2+ voltage-dependent channels (CaVs). However, WFA exists in different depots whose function varies with age, sex, and location. To explore whether their CaV expression profiles also differ we used RNAseq and qPCR on gonadal, mesenteric, retroperitoneal, and inguinal subcutaneous fat depots from rats of different ages and sex. CaV expression was found dependent on age, sex, and WFA location. In the gonadal depots of both sexes a significantly lower expression of CaV1.2 and CaV1.3 was seen for adults compared to pre-pubescent juveniles. A lower level of expression was also seen for CaV3.1 in adult male but not female gonadal WFA, the latter of whose expression remained unchanged with age. Relatively little expression of CaV3.2 and 3.2 was observed. In post-pubescent inguinal subcutaneous fat, where the third and fourth mammary glands are located, CaV3.1 was decreased in males but increased in females – thus suggesting that this channel is associated with mammogenesis; however, no difference in intracellular Ca2+ levels or adipocyte size were noted. For all adult depots, CaV3.1 expression was larger in females than males – a difference not seen in pre-pubescent rats. These observations are consistent with the changes of CaV3.1 expression seen in 3T3-L1 cell differentiation and the ability of selective CaV3.1 antagonists to inhibit adipogensis. Our results show that changes in CaV expression patterns occur in fat depots related to sexual dimorphism: reproductive tracts and mammogenesis.

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