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Serum prolactin increases from birth to adulthood in rats, being higher in females from birth. The maturation of hypothalamic/gonadal prolactin-releasing and -inhibiting factors does not explain some sex differences observed. During the first weeks of life, prolactin secretion increases, even when lactotrophs are isolated in vitro, in the absence of those controls, suggesting the participation of intra-pituitary factors in this control. The present work aimed to study the involvement of pituitary activins in the regulation of prolactin secretion during post-natal development. Sex differences were also highlighted. Female and male Sprague–Dawley rats at 11, 23 and 45postnatal days were used. Pituitary expression of activin subunits and activin receptors was maximum in p11 female pituitaries, being even higher than that observed in males. Those expressions decrease with age in females, and then the gender differences disappear at p23. Inhbb expression strongly increases at p45 in males, being the predominant subunit in this sex in adulthood. Activin inhibition of prolactin is mediated by the inhibition of Pit-1 expression. This action involves not only the canonical pSMAD pathway but also the phosphorylation of p38MAPK. At p11, almost all lactotrophs express p-p38MAPK in females, and its expression decreases with age with a concomitant increase in Pit-1. Our findings suggest that the inhibitory regulation of pituitary activins on prolactin secretion is sex specific; this regulation is more relevant in females during the first week of life and decreases with age; this intra-pituitary regulation is involved in the sex differences observed in serum prolactin levels during postnatal development.
Department of Pharmacology, School of Biomedical Sciences, UNSW Sydney, New South Wales, Australia
Department of Cellular and Molecular Medicine, Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Charles Perkins Centre, University of Sydney, New South Wales, Australia
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Department of Anatomy & Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia
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Charles Perkins Centre, University of Sydney, New South Wales, Australia
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Department of Pharmacology, School of Biomedical Sciences, UNSW Sydney, New South Wales, Australia
Cellular Bioenergetics Laboratory, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia
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Reduced expression of the NAD+-dependent deacetylase, SIRT3, has been associated with insulin resistance and metabolic dysfunction in humans and rodents. In this study, we investigated whether specific overexpression of SIRT3 in vivo in skeletal muscle could prevent high-fat diet (HFD)-induced muscle insulin resistance. To address this, we used a muscle-specific adeno-associated virus (AAV) to overexpress SIRT3 in rat tibialis and extensor digitorum longus (EDL) muscles. Mitochondrial substrate oxidation, substrate switching and oxidative enzyme activity were assessed in skeletal muscles with and without SIRT3 overexpression. Muscle-specific insulin action was also assessed by hyperinsulinaemic–euglycaemic clamps in rats that underwent a 4-week HFD-feeding protocol. Ex vivo functional assays revealed elevated activity of selected SIRT3-target enzymes including hexokinase, isocitrate dehydrogenase and pyruvate dehydrogenase that was associated with an increase in the ability to switch between fatty acid- and glucose-derived substrates in muscles with SIRT3 overexpression. However, during the clamp, muscles from rats fed an HFD with increased SIRT3 expression displayed equally impaired glucose uptake and insulin-stimulated glycogen synthesis as the contralateral control muscle. Intramuscular triglyceride content was similarly increased in the muscle of high-fat-fed rats, regardless of SIRT3 status. Thus, despite SIRT3 knockout (KO) mouse models indicating many beneficial metabolic roles for SIRT3, our findings show that muscle-specific overexpression of SIRT3 has only minor effects on the acute development of skeletal muscle insulin resistance in high-fat-fed rats.
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Testosterone acting via the androgen receptor, and via aromatisation to oestradiol, an activator of the oestrogen receptor, plays key roles in adipose tissue, bone and skeletal muscle biology. This is reflected in epidemiological studies associating obesity and disordered glucose metabolism with lower serum testosterone concentrations and an increased risk of type 2 diabetes (T2D) in men. Testosterone also modulates erythrocytosis and vascular endothelial and smooth muscle cell function, with potential impacts on haematocrit and the cardiovascular system. The Testosterone for the Prevention of Type 2 Diabetes (T4DM) study enrolled men aged 50 years and over with a waist circumference of 95 cm or over, impaired glucose tolerance or newly diagnosed T2D, and a serum testosterone concentration (as measured by chemiluminescence immunoassay) <14.0 nmol/L. The study reported that a 2-year treatment with testosterone undecanoate 1000 mg, administered 3-monthly intramuscularly, on the background of a lifestyle program, reduced the likelihood of T2D diagnosis by 40% compared to placebo. This effect was accompanied by a decrease in fasting serum glucose and associated with favourable changes in body composition, hand grip strength, bone mineral density and skeletal microarchitecture but not in HbA1c, a red blood cell-dependent measure of glycaemic control. There was no signal for cardiovascular adverse events. With the objective of informing translational science and future directions, this article discusses mechanistic studies underpinning the rationale for T4DM and translational implications of the key outcomes relating to glycaemia, and body composition, together with effects on erythrocytosis, cardiovascular risk and slow recovery of the hypothalamo–pituitary–testicular axis.
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School of Veterinary and Life Sciences, Murdoch University, Perth, Western Australia, Australia
Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Being born before 37 weeks’ gestation, or preterm birth, is a leading cause of early childhood death and life-long disability. Antenatal steroids (ANS) are recommended for women judged at risk of imminent preterm delivery. The primary intent of ANS treatment is to rapidly mature the fetal lungs to reduce the risk of mortality and lasting morbidity. Despite being used clinically for some 50 years, a large number of uncertainties remain surrounding the use of ANS. In particular, the choice of agent, dose/regimen, and appropriate gestational age range for ANS therapy all remain unclear. Unresolved concerns regarding the potential risk of harms from ANS treatment, especially in light of the modest benefits seen with expanding latepreterm administration, make it increasingly important to optimize the dosing and application of this important and widely used treatment. This review will serve to summarize past data, provide an update on recent developments, and chart a way forward to maximize the overall benefit of this important therapy.
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Glucagon is a peptide hormone that is produced primarily by the alpha cells in the islet of Langerhans in the pancreas, but also in intestinal enteroendocrine cells and in some neurons. Approximately 100 years ago, several research groups discovered that pancreatic extracts would cause a brief rise in blood glucose before they observed the decrease in glucose attributed to insulin. An overall description of the regulation of glucagon secretion requires the inclusion of its sibling insulin because they both are made primarily by the islet and they both regulate each other in different ways. For example, glucagon stimulates insulin secretion, whereas insulin suppresses glucagon secretion. The mechanism of action of glucagon on insulin secretion has been identified as a trimeric guanine nucleotide-binding protein (G-protein)-mediated event. The manner in which insulin suppresses glucagon release from the alpha cell is thought to be highly dependent on the peri-portal circulation of the islet through which blood flows downstream from beta cells to alpha cells. In this scenario, it is via the circulation that insulin is thought to suppress the release of glucagon. However, high levels of glucose also have been shown to suppress glucagon secretion. Consequently, the glucose-lowering effect of insulin may be additive to the direct effects of insulin to suppress alpha cell function, so that in vivo both the discontinuation of the insulin signal and the condition of low glucose jointly are responsible for induction of glucagon secretion.
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Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zürich, Switzerland
School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences & Medicine, King’s College London, London, UK
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Obesity is associated with a higher risk of severe coronavirus disease 2019 (COVID-19) and increased mortality. In the current study, we have investigated the expression of ACE2, NRP1, and HMGB1, known to facilitate severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cell entry, in adipose tissue from non-COVID-19 control patients with normal weight, overweight, and obesity. All factors were expressed, but no significant differences between the groups were observed. Furthermore, diabetes status and medications did not affect the expression of ACE2. Only in obese men, the expression of ACE2 in adipose tissue was higher than in obese women. In the adipose tissue from patients who died from COVID-19, SARS-CoV-2 was detected in the adipocytes even though the patients died more than 3 weeks after the acute infection. This suggests that adipocytes may act as reservoirs for the virus. In COVID-19 patients, the expression of NRP1 was increased in COVID-19 patients with overweight and obesity. Furthermore, we observed an increased infiltration with macrophages in the COVID-19 adipose tissues compared to control adipose tissue. In addition, crown-like structures of dying adipocytes surrounded by macrophages were observed in the adipose tissue from COVID-19 patients. These data suggest that in obese individuals, in addition to an increased mass of adipose tissue that could potentially be infected, increased macrophage infiltration due to direct infection with SARS-CoV-2 and sustained viral shedding, rather than preinfection ACE2 receptor expression, may be responsible for the increased severity and mortality of COVID-19 in patients with obesity.
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In birds, exposure to maternal (yolk) testosterone affects a diversity of offspring post-hatching traits, which eventually affect offspring competitiveness. However, maternal testosterone is heavily metabolized at very early embryonic developmental stages to hydrophilic metabolites that are often assumed to be much less biologically potent. Either the rapid metabolism could either keep the maternal testosterone from reaching the embryos, opening the possibility for a mother–offspring conflict or the metabolites may facilitate the uptake of the lipophilic testosterone from the yolk into the embryonic circulation after which they are either converted back to the testosterone or functioning directly as metabolites. To test these possibilities, we injected isotope-labeled testosterone (T-[D5]) into the yolk of freshly laid Rock pigeon (Columba livia) eggs and determined the concentration and distribution of T-[D5] and its labeled metabolites within different egg fractions by liquid chromatography combined with tandem mass spectrometry at day 2, 5 and 10 of incubation. Although under a supraphysiological dosage injection, yolk testosterone decreased within 2 days and was metabolized into androstenedione, conjugated testosterone, etiocholanolone and other components that were unidentifiable due to methodological limitation. We show for the first time that testosterone, androstenedione and conjugated testosterone, but not etiocholanolone, reached the embryo including its brain. Their high concentrations in the yolk and extraembryonic membranes suggest that conversion takes place here. We also found no sex-specific metabolism, explaining why maternal testosterone does not affect sexual differentiation. Our findings showed that maternal testosterone is quickly converted by the embryo, with several but not all metabolites reaching the embryo providing evidence for both hypotheses.
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The mineralocorticoid receptor (MR) plays a critical role in the mammalian brain as a mediator of appropriate cellular and behavioural responses under both baseline and stressful conditions. In the hippocampus, the MR has been implicated in several processes, such as neuronal maintenance, adult neurogenesis, inhibitory control of the hypothalamic–pituitary–adrenal axis, and learning and memory. Because of its high affinity for endogenous glucocorticoid hormones, the MR has long been postulated to mediate tonic actions in the brain, but more recent data have expanded on this view, indicating that the MR elicits dynamic responses as well. The complexity of the diverse molecular, cellular, and physiological functions fulfilled by the human, rat and mouse MR could at least partially be explained by the existence of different isoforms of the receptor. The structural and functional characteristics of these isoforms, however, have remained largely unexplored. The present article will review the current knowledge concerning human, rat, and mouse MR isoforms and evaluate seminal studies concerning the roles of the brain MR, with the intent to shed light on the function of its specific isoforms.
Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Cell protein biosynthesis is regulated by different factors, but implication of intercellular contacts on alpha and beta cell protein biosyntheses activity has not been yet investigated. Islet cell biosynthetic activity is essential in regulating not only the hormonal reserve within cells but also in renewing all the proteins involved in the control of secretion. Here we aimed to assess whether intercellular interactions affected similarly secretion and protein biosynthesis of rat alpha and beta cells. Insulin and glucagon secretion were analyzed by ELISA or reverse hemolytic plaque assay, and protein biosynthesis evaluated at single cell level using bioorthogonal noncanonical amino acid tagging. Regarding beta cells, we showed a positive correlation between insulin secretion and protein biosynthesis. We also observed that homologous contacts increased both activities at low or moderate glucose concentrations. By contrast, at high glucose concentration, homologous contacts increased insulin secretion and not protein biosynthesis. In addition, heterogeneous contacts between beta and alpha cells had no impact on insulin secretion and protein biosynthesis. Regarding alpha cells, we showed that when they were in contact with beta cells, they increased their glucagon secretion in response to a drop of glucose concentration, but, on the other hand, they decreased their protein biosynthesis under any glucose concentrations. Altogether, these results emphasize the role of intercellular contacts on the function of islet cells, showing that intercellular contacts increased protein biosynthesis in beta cells, except at high glucose, and decreased protein biosynthesis in alpha cells even when glucagon secretion is stimulated.
Paris Brain Institue-Institut du Cerveau, CNRS UMR7225, INSERM U1127, Hôpital de la Pitié Salpêtrière, Paris, France
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INSERM UMR 1195 (DHNS), Faculty of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France
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Myelination allows fast and synchronized nerve influxes and is provided by Schwann cells (SCs) in the peripheral nervous system. Glucocorticoid hormones are major regulators of stress, metabolism and immunity affecting all tissues. They act by binding to two receptors, the low-affinity glucocorticoid receptor (GR) and the high-affinity mineralocorticoid receptor (MR). Little is known about the effect of glucocorticoid hormones on the PNS, and this study focuses on deciphering the role of MR in peripheral myelination. In this work, the presence of a functional MR in SCs is demonstrated and the expression of MR protein in mouse sciatic nerve SC is evidenced. Besides, knockout of MR in SC (SCMRKO using Cre-lox system with DesertHedgeHog (Dhh) Cre promoter) was undertaken in mice. SCMRKO was not associated with alterations of performance in motor behavioral tests on 2- to 6-month-old male mice compared to their controls. No obvious modifications of myelin gene expression or MR signaling gene expression were observed in the SCMRKO sciatic nerves. Nevertheless, Gr transcript and GR protein amounts were significantly increased in SCMRKO nerves compared to controls, suggesting a possible compensatory effect. Besides, an increase in myelin sheath thickness was noted for axons with perimeters larger than 15 µm in SCMRKO illustrated by a significant 4.5% reduction in g-ratio (axon perimeter/myelin sheath perimeter). Thus, we defined MR as a new player in peripheral system myelination and in SC homeostasis.