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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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Jenica H Kakadia Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
Children's Health Research Institute, London, Ontario, Canada

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Muhammad U Khalid Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada

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Ilka U Heinemann Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada

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Victor K Han Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
Children's Health Research Institute, London, Ontario, Canada
Department of Pediatrics, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada

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Mechanisms underlying limitations in glucose supply that restrict fetal growth are not well established. IGF-1 is an important regulator of fetal growth and IGF-1 bioavailability is markedly inhibited by IGFBP-1 especially when the binding protein is hyperphosphorylated. We hypothesized that the AMPK–mTORC1 pathway increases IGFBP-1 phosphorylation in response to glucose deprivation. Glucose deprivation in HepG2 cells activated AMPK and TSC2, inhibited mTORC1 and increased IGFBP-1 secretion and site-specific phosphorylation. Glucose deprivation also decreased IGF-1 bioavailability and IGF-dependent activation of IGF-1R. AICAR (an AMPK activator) activated TSC2, inhibited mTORC1, and increased IGFBP-1 secretion/phosphorylation. Further, siRNA silencing of either AMPK or TSC2 prevented mTORC1 inhibition and IGFBP-1 secretion and phosphorylation in glucose deprivation. Our data suggest that the increase in IGFBP-1 phosphorylation in response to glucose deprivation is mediated by the activation of AMPK/TSC2 and inhibition of mTORC1, providing a possible mechanistic link between glucose deprivation and restricted fetal growth.

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Xiaosa Li Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

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Chao Fan Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

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Jiale Wang Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

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Ping Li Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

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Xingyan Xu Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

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Ruixin Guo Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

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Jinzhi Wei Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

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Yang Cheng Guangzhou First People’s Hospital, South China University of Technology, Guangzhou, Guangdong, China

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Huiping Lin Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

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Xiaodong Fu Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China

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Follicle-stimulating hormone (FSH) accelerates osteoporosis in postmenopausal women, while the underlying mechanism remains uncharacterized. N6-methyladenosine (m6A) is one of the most important regulations in the development of osteoporosis. In this study, we aimed to investigate the role of FSH in m6A modification and osteoclast function. Here, we showed that FSH upregulated m6A levels in osteoclasts via stimulating methyltransferase-like 3 (METTL3) protein expression. FSH enhanced osteoclast migration, while the knockdown of METTL3 eliminated this enhancement. Both MeRIP-seq and RNA sequencing identified that cathepsin K (CTSK) is the potential downstream target of METTL3. Knockdown of CTSK reduced FSH-upregulated osteoclast migration. Furthermore, silencing METTL3 decreased CTSK mRNA stability. Finally, FSH induced phosphorylation of cyclic-AMP response element-binding protein (CREB), while silencing of CREB attenuated the effects of FSH on the promoter transcriptional activity of Mettl3 and CTSK/METTL3 protein. Taken together, these findings indicate that FSH promotes osteoclast migration via the CREB/METTL3/CTSK signaling pathway, which may provide a potential target for suppressing osteoclast mobility and postmenopausal osteoporosis therapy.

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Isabelle Durrer Department of Nephrology and Hypertension University of Bern, Berne, Switzerland

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Daniel Ackermann Department of Nephrology and Hypertension University of Bern, Berne, Switzerland

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Rahel Klossner Department of Nephrology and Hypertension University of Bern, Berne, Switzerland
Department of Internal Medicine, Sonnenhof, Lindenhofgruppe, Berne, Switzerland

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Michael Grössl Department of Nephrology and Hypertension University of Bern, Berne, Switzerland

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Clarissa Vögel Department of Nephrology and Hypertension University of Bern, Berne, Switzerland

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Therina Du Toit Department for BioMedical Research University of Bern, Berne, Switzerland

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Bruno Vogt Department of Nephrology and Hypertension University of Bern, Berne, Switzerland

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Heidi Jamin Department of Nephrology and Hypertension University of Bern, Berne, Switzerland
Department for BioMedical Research University of Bern, Berne, Switzerland

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Markus G Mohaupt Department of Internal Medicine, Sonnenhof, Lindenhofgruppe, Berne, Switzerland
Department for BioMedical Research University of Bern, Berne, Switzerland

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Carine Gennari-Moser Department of Nephrology and Hypertension University of Bern, Berne, Switzerland
Department for BioMedical Research University of Bern, Berne, Switzerland

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Extra-adrenal de novo aldosterone (Aldo) production has been described inconsistently. Systematic data based upon state-of-the-art technology including validated controls are sparse. We hypothesized that aldosterone synthase (CYP11B2) expression and de novo Aldo production are absent in nonadrenal human cell lines, either immortalized cell lines or commercially available primary cell lines, including peripheral blood mononuclear cells (PBMCs) of individuals without and with primary hyperaldosteronism (PA). CYP11B2-transfected COS-7 and endogenous CYP11B2 expressing adrenal H295R cells served as positive controls. Various well-characterized, purchased, immortalized (BeWo, HEK293, HTR-8/SVneo, JEG-3) and primary (HAEC, HLEC, HRGEC, HRMC, HUAEC, HUVEC, PBMC) cell lines as well as self-isolated PBMCs from PA patients (n = 5) were incubated with the steroid hormone substrates progesterone, deoxycorticosterone, corticosterone or 18-OH-corticosterone with and without Ang II for 24 h to assess CYP11B2 enzymatic activity. CYP11B2 expression was analyzed by real-time PCR and liquid chromatography–mass spectrometry was used to quantify Aldo production. Pronounced CYP11B2 mRNA expression and Aldo production were observed in both positive controls, which followed an incremental time course. Neither substrates alone nor coincubation with Ang II significantly stimulated CYP11B2 expression or Aldo production in various immortalized and primary cell lines and PBMCs of PA patients. These results strongly support the absence of relevant de novo extra-adrenal Aldo production in nonadrenal cells, including blood mononuclear cells, irrespective of the absence or presence of autonomous adrenal Aldo production.

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Yalan Hu Y Hu, Laboratory Medicine, University of Amsterdam, Amsterdam, Netherlands

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Gemma F Codner G Codner, The Mary Lyon Centre at MRC Harwell, Harwell Science and Innovation Campus, Harwell, United Kingdom of Great Britain and Northern Ireland

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Michelle Stewart M Stewart, The Mary Lyon Centre at MRC Harwell, Harwell Science and Innovation Campus, Harwell, United Kingdom of Great Britain and Northern Ireland

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Susanne E La Fleur S La Fleur, Laboratory Medicine, University of Amsterdam, Amsterdam, Netherlands

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Paul As van Trotsenburg P van Trotsenburg, Dept of Pediatric Endocrinology, Amsterdam UMC Locatie AMC, Amsterdam, Netherlands

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Eric Fliers E Fliers, Dept of Endocrinology, Amsterdam UMC Locatie AMC, Amsterdam, Netherlands

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Raoul C Hennekam R Hennekam, Department of Pediatrics, Emma Children’s Hospital, Amsterdam UMC Locatie AMC, Amsterdam, Netherlands

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Anita Boelen A Boelen, Endocrine Laboratory, Department of Laboratory Medicine, University of Amsterdam, Amsterdam, 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 lifespan 93 days) was very short compared with heterozygote female mice (survived to >200 days with no welfare issues). 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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Xiaojing Wei Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Yutian Tan Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Jiaqi Huang Institute of Basic Medicine, School of Medicine, Tsinghua University, Beijing, China

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Ximing Dong Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Weijie Feng Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Tanglin Liu Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Zhao Yang Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China

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Guiying Yang Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China

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Xiao Luo Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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N1-methylnicotinamide (MNAM), a product of methylation of nicotinamide through nicotinamide N-methyltransferase, displays antidiabetic effects in male rodents. This study aimed to evaluate the ameliorative potential of MNAM on glucose metabolism in a gestational diabetes mellitus (GDM) model. C57BL/6N mice were fed with a high-fat diet (HFD) for 6 weeks before pregnancy and throughout gestation to establish the GDM model. Pregnant mice were treated with 0.3% or 1% MNAM during gestation. MNAM supplementation in CHOW diet and HFD both impaired glucose tolerance at gestational day 14.5 without changes in insulin tolerance. However, MNAM supplementation reduced hepatic lipid accumulation as well as mass and inflammation in visceral adipose tissue. MNAM treatment decreased GLUT4 mRNA and protein expression in skeletal muscle, where NAD+ salvage synthesis and antioxidant defenses were dampened. The NAD+/sirtuin system was enhanced in liver, which subsequently boosted hepatic gluconeogenesis. GLUT1 protein was diminished in placenta by MNAM. In addition, weight of placenta, fetus weight, and litter size were not affected by MNAM treatment. The decreased GLUT4 in skeletal muscle, boosted hepatic gluconeogenesis and dampened GLUT1 in placenta jointly contribute to the impairment of glucose tolerance tests by MNAM. Our data provide evidence for the careful usage of MNAM in treatment of GDM.

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Deyana Ivanova Department of Women and Children’s Health, Faculty of Life Science and Medicine, King’s College London, UK
Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

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Kevin T O’Byrne Department of Women and Children’s Health, Faculty of Life Science and Medicine, King’s College London, UK

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The exact neural construct underlying the dynamic secretion of gonadotrophin-releasing hormone (GnRH) has only recently been identified despite the detection of multiunit electrical activity volleys associated with pulsatile luteinising hormone (LH) secretion four decades ago. Since the discovery of kisspeptin/neurokinin B/dynorphin neurons in the mammalian hypothalamus, there has been much research into the role of this neuronal network in controlling the oscillatory secretion of gonadotrophin hormones. In this review, we provide an update of the progressive application of cutting-edge techniques combined with mathematical modelling by the neuroendocrine community, which are transforming the functional investigation of the GnRH pulse generator. Understanding the nature and function of the GnRH pulse generator can greatly inform a wide range of clinical studies investigating infertility treatments.

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Brenda Vidrio-Huerta Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

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Thomas Plötz Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

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Stephan Lortz Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

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The early phase of type 2 diabetes mellitus (T2DM) is characterised by insulin resistance, which can initially be compensated by elevated insulin secretion. However, as postulated by the workload hypothesis, over time harming insulin requirements contribute to β-cell dysfunction and death. The mechanisms behind this transition are complex and not fully understood but involve factors such as endoplasmic reticulum (ER) stress raised by gluco/lipotoxicity. To investigate the effect of excessive insulin folding on ER luminal H2O2 generation, ER stress and viability, insulin was expressed glucose-independently by a doxycycline-regulated Tet-On system in insulin-producing RINm5F cells. Additionally, the effect of palmitic acid (PA) as a subsidiary T2DM-associated factor was examined in this model system. Elevated insulin expression increased ER luminal H2O2 concentration quantified by the fluorescent sensor protein TriPer and reduced viability, but did not activate apoptosis. However, when combined with PA, insulin expression resulted in a significant increase in ER stress and apoptosis. Expression of ER-localised catalase verified the specificity of the applied H2O2 detection method without attenuating ER stress, caspase activation or viability loss. These findings suggest that hyperinsulinism alone can cause increased ER luminal H2O2 generation, mild ER stress and reduced viability, while hyperinsulinism in combination with PA accelerates these processes and triggers apoptosis. The inability of ER catalase to counteract these effects suggests that further damaging factors besides H2O2 are involved in cell dysfunction. Finally, reducing the high insulin demand in the initial phase of T2DM may be crucial in preventing further β-cell damage caused by gluco/lipotoxicity.

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Yan Meng Y Meng, School of LIfe Sciences, University of Nottingham Faculty of Medicine and Health Sciences, Nottingham, United Kingdom of Great Britain and Northern Ireland

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Maria Toledo-Rodriguez M Toledo-Rodriguez, School of Lfe Sciences, University of Nottingham Faculty of Medicine and Health Sciences, Nottingham, United Kingdom of Great Britain and Northern Ireland

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Olena Fedorenko O Fedorenko, Great Chesterford Research Park, Charles River Laboratories, Cambridge, United Kingdom of Great Britain and Northern Ireland

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Paul A. Smith P Smith, Life Sciences, University of Nottingham Faculty of Medicine and Health Sciences, Nottingham, United Kingdom of Great Britain and Northern Ireland

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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 mammary glands are sited, CaV3.1 was decreased in males but increased in females; data which suggests this channel is associated with mammogenesis, however no effect on 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 CaVs expression patterns occur in fat depots related to sexual dimorphism: reproductive tracts and mammogenesis.

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