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We have used a direct, non-immunochemical and highly accurate method to quantify the effects of testosterone and oestrogen on mitotic and apoptotic activity in the young, male rat anterior pituitary in vivo. Surgical gonadectomy resulted in a 3-fold increase in mitotic activity by the fourth post-operative day, which returned gradually to levels seen in intact animals over the subsequent 3–4 weeks. Both a single dose of Sustanon, a mixture of long-acting testosterone esters in arachis oil, and the same dose divided over 7 days (starting 6 days after gonadectomy), initially suppressed mitotic activity to levels seen in intact animals, but was associated after 48–96 h with a wave of increased mitotic activity. The latter was blocked by co-administration of Sustanon with the non-steroidal aromatase inhibitor letrozole and was not seen when the non-aromatisable androgen dihydrotestosterone was substituted for Sustanon. Oestrogen alone in gonadectomised and intact rats produced a marked increase in mitosis as expected. With the exception of a transient increase in response to a single high-dose injection of Sustanon in gonadectomised animals, apoptotic activity was unaffected by all of the above. This study suggests that pituitary mitotic activity is tonically inhibited by gonadal hormone production (at least in the short term) in adult male rats. The study also suggests that supraphysiological testosterone treatment – while unable to reduce anterior pituitary mitotic activity in untreated, intact animals –suppresses the early increase in mitotic activity induced by gonadectomy. Oestrogen, either exogenous or generated locally by aromatisation, stimulates anterior pituitary mitotic activity in a time-dependent manner.
Institut National de la Santé et de la Recherche Médicale U676, Hôpital Robert-Debré, 48 Boulevard Sérurier, F-75019 Paris, France
Department of Physiology and Pharmacology L334, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97201-3098, USA
Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique-Unité Mixte de Recherche, 6187 Pôle Biologie Santé, 40 Avenue du Recteur Pineau, 86022 Poitiers, France
Mental Retardation Research Center, University of California, Neurosciences Research Building, 655 Charles Young Drive South, Los Angeles, California 90095-7088, USA
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Institut National de la Santé et de la Recherche Médicale U676, Hôpital Robert-Debré, 48 Boulevard Sérurier, F-75019 Paris, France
Department of Physiology and Pharmacology L334, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97201-3098, USA
Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique-Unité Mixte de Recherche, 6187 Pôle Biologie Santé, 40 Avenue du Recteur Pineau, 86022 Poitiers, France
Mental Retardation Research Center, University of California, Neurosciences Research Building, 655 Charles Young Drive South, Los Angeles, California 90095-7088, USA
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Institut National de la Santé et de la Recherche Médicale U676, Hôpital Robert-Debré, 48 Boulevard Sérurier, F-75019 Paris, France
Department of Physiology and Pharmacology L334, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97201-3098, USA
Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique-Unité Mixte de Recherche, 6187 Pôle Biologie Santé, 40 Avenue du Recteur Pineau, 86022 Poitiers, France
Mental Retardation Research Center, University of California, Neurosciences Research Building, 655 Charles Young Drive South, Los Angeles, California 90095-7088, USA
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Institut National de la Santé et de la Recherche Médicale U676, Hôpital Robert-Debré, 48 Boulevard Sérurier, F-75019 Paris, France
Department of Physiology and Pharmacology L334, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97201-3098, USA
Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique-Unité Mixte de Recherche, 6187 Pôle Biologie Santé, 40 Avenue du Recteur Pineau, 86022 Poitiers, France
Mental Retardation Research Center, University of California, Neurosciences Research Building, 655 Charles Young Drive South, Los Angeles, California 90095-7088, USA
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Institut National de la Santé et de la Recherche Médicale U676, Hôpital Robert-Debré, 48 Boulevard Sérurier, F-75019 Paris, France
Department of Physiology and Pharmacology L334, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97201-3098, USA
Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique-Unité Mixte de Recherche, 6187 Pôle Biologie Santé, 40 Avenue du Recteur Pineau, 86022 Poitiers, France
Mental Retardation Research Center, University of California, Neurosciences Research Building, 655 Charles Young Drive South, Los Angeles, California 90095-7088, USA
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Institut National de la Santé et de la Recherche Médicale U676, Hôpital Robert-Debré, 48 Boulevard Sérurier, F-75019 Paris, France
Department of Physiology and Pharmacology L334, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97201-3098, USA
Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique-Unité Mixte de Recherche, 6187 Pôle Biologie Santé, 40 Avenue du Recteur Pineau, 86022 Poitiers, France
Mental Retardation Research Center, University of California, Neurosciences Research Building, 655 Charles Young Drive South, Los Angeles, California 90095-7088, USA
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. Neuroendocrinology 53 45 –51. Loren I , Emson PC, Fahrenkrug J, Bjorklund A, Alumets J, Hakanson R & Sundler F 1979 Distribution of vasoactive intestinal polypeptide in the rat and mouse brain. Neuroscience 4 1953 –1976
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College of Health and Biomedicine, The Florey Institute of Neuroscience and Mental Health, Department of Physiology, Centre for Chronic Disease Prevention and Management, Victoria University, St Albans Campus, PO Box 14428, Melbourne, Victoria 8001, Australia
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Modulation of the endocannabinoid system as an anti-obesity therapeutic is well established; however, the direct effects of cannabinoid receptor 1 (CB1) antagonism on renal function and structure in a model of diet-induced obesity (DIO) are unknown. The aim of this study was to characterise the renal effects of the CB1 antagonist AM251 in a model of DIO. Male Sprague–Dawley rats were fed a low- or high-fat diet (HFD: 40% digestible energy from lipids) for 10 weeks to elicit DIO (n=9). In a different cohort, rats were fed a HFD for 15 weeks. After 9 weeks consuming a HFD, rats were injected daily for 6 weeks with 3 mg/kg AM251 (n=9) or saline via i.p. injection (n=9). After 10 weeks consuming a HFD, CB1 and megalin protein expression were significantly increased in the kidneys of obese rats. Antagonism of CB1 with AM251 significantly reduced weight gain, systolic blood pressure, plasma leptin, and reduced albuminuria and plasma creatinine levels in obese rats. Importantly, there was a significant reduction in tubular cross-section diameter in the obese rats treated with AM251. An improvement in albuminuria was likely due to the reduction in tubular size, reduced leptinaemia and maintenance of megalin expression levels. In obese rats, AM251 did not alter diastolic blood pressure, sodium excretion, creatinine clearance or expression of the fibrotic proteins VEGFA, TGFB1 and collagen IV in the kidney. This study demonstrates that treatment with CB1 antagonist AM251 improves renal outcomes in obese rats.
Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, Wellcome Trust – MRC Institute of Metabolic Science, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, Wellcome Trust – MRC Institute of Metabolic Science, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, Wellcome Trust – MRC Institute of Metabolic Science, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, Wellcome Trust – MRC Institute of Metabolic Science, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, Wellcome Trust – MRC Institute of Metabolic Science, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, Wellcome Trust – MRC Institute of Metabolic Science, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, Wellcome Trust – MRC Institute of Metabolic Science, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark
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The incretin hormones glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from intestinal endocrine cells, the so-called L- and K-cells. The cells are derived from a common precursor and are highly related, and co-expression of the two hormones in so-called L/K-cells has been reported. To investigate the relationship between the GLP1- and GIP-producing cells more closely, we generated a transgenic mouse model expressing a fluorescent marker in GIP-positive cells. In combination with a mouse strain with fluorescent GLP1 cells, we were able to estimate the overlap between the two cell types. Furthermore, we used primary cultured intestinal cells and isolated perfused mouse intestine to measure the secretion of GIP and GLP1 in response to different stimuli. Overlapping GLP1 and GIP cells were rare (∼5%). KCl, glucose and forskolin+IBMX increased the secretion of both GLP1 and GIP, whereas bombesin/neuromedin C only stimulated GLP1 secretion. Expression analysis showed high expression of the bombesin 2 receptor in GLP1 positive cells, but no expression in GIP-positive cells. These data indicate both expressional and functional differences between the GLP1-producing ‘L-cell’ and the GIP-producing ‘K-cell’.
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Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands
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We showed previously that rats on a free-choice high-fat, high-sugar (fcHFHS) diet become rapidly obese and develop glucose intolerance within a week. Interestingly, neither rats on a free-choice high-fat diet (fcHF), although equally obese and hyperphagic, nor rats on a free-choice high-sugar (fcHS) diet consuming more sugar water, develop glucose intolerance. Here, we investigate whether changes in insulin sensitivity contribute to the observed glucose intolerance and whether this is related to consumption of saturated fat and/or sugar water. Rats received either a fcHFHS, fcHF, fcHS or chow diet for one week. We performed a hyperinsulinemic–euglycemic clamp with stable isotope dilution to measure endogenous glucose production (EGP; hepatic insulin sensitivity) and glucose disappearance (Rd; peripheral insulin sensitivity). Rats on all free-choice diets were hyperphagic, but only fcHFHS-fed rats showed significantly increased adiposity. EGP suppression by hyperinsulinemia in fcHF-fed and fcHFHS-fed rats was significantly decreased compared with chow-fed rats. One week fcHFHS diet also significantly decreased Rd. Neither EGP suppression nor Rd was affected in fcHS-fed rats. Our results imply that, short-term fat feeding impaired hepatic insulin sensitivity, whereas short-term consumption of both saturated fat and sugar water impaired hepatic and peripheral insulin sensitivity. The latter likely contributed to glucose intolerance observed previously. In contrast, overconsumption of only sugar water affected insulin sensitivity slightly, but not significantly, in spite of similar adiposity as fcHF-fed rats and higher sugar intake compared with fcHFHS-fed rats. These data imply that the palatable component consumed plays a role in the development of site-specific insulin sensitivity.
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To study in vivo the dynamics of the biosynthetic and secretory processes in a neuroendocrine cell, we use the proopiomelanocortin-producing intermediate pituitary melanotrope cells of Xenopus laevis. The activity of these cells can be simply manipulated by adapting the animal to a white or a black background, resulting in inactive and hyperactive cells respectively. Here, we applied differential display proteomics and field emission scanning electron microscopy (FESEM) to examine the changes in architecture accompanying the gradual transition of the inactive to the hyperactive melanotrope cells. The proteomic analysis showed differential expression of neuroendocrine secretory proteins, endoplasmic reticulum (ER)-resident chaperones, and housekeeping and metabolic proteins. The FESEM study revealed changes in the ultrastructure of the ER and Golgi and the number of secretory granules. We conclude that activation of neuroendocrine cells tunes their molecular machineries and organelles to become professional secretors.
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In rats, a shift from somatotroph dominance to lactotroph dominance during pregnancy and lactation is well reported. Somatotroph to lactotroph transdifferentiation and increased lactotroph mitotic activity are believed to account for this and associated pituitary hypertrophy. A combination of cell death and transdifferentiation away from the lactotroph phenotype has been reported to restore non-pregnant pituitary proportions after weaning. To attempt to confirm that a similar process occurs in mice, we generated and used a transgenic reporter mouse model (prolactin (PRL)-Cre/ROSA26-expression of yellow fluorescent protein (EYFP)) in which PRL promoter activity at any time resulted in permanent, stable, and highly specific EYFP. Triple immunochemistry for GH, PRL, and EYFP was used to quantify EYFP+ve, PRL−ve, and GH+ve cell populations during pregnancy and lactation, and for up to 3 weeks after weaning, and concurrent changes in cell size were estimated. At all stages, the EYFP reporter was expressed in 80% of the lactotrophs, but in fewer than 1% of other pituitary cell types, indicating that transdifferentiation from those lactotrophs where reporter expression was activated is extremely rare. Contrary to expectations, no increase in the lactotroph/somatotroph ratio was seen during pregnancy and lactation, whether assessed by immunochemistry for the reporter or PRL: findings confirmed by PRL immunochemistry in non-transgenic mice. Mammosomatotrophs were rarely encountered at the age group studied. Individual EYFP+ve cell volumes increased significantly by mid-lactation compared with virgin animals. This, in combination with a modest and non-cell type-specific estrogen-induced increase in mitotic activity, could account for pregnancy-induced changes in overall pituitary size.
Departments of Physiology and Pharmacology and
Cell and Developmental Biology, Oregon Health and Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA
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Departments of Physiology and Pharmacology and
Cell and Developmental Biology, Oregon Health and Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA
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Departments of Physiology and Pharmacology and
Cell and Developmental Biology, Oregon Health and Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA
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Departments of Physiology and Pharmacology and
Cell and Developmental Biology, Oregon Health and Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA
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The great writer and polyglot, W Somerset Maugham said, ‘I’ll give you my opinion of the human race in a nutshell...their heart’s in the right place, but their head is a thoroughly inefficient organ.’ If his words are applied to trafficking of the human pituitary gonadotropin-releasing hormone receptor, it turns out that he was more right than he knew. Paradoxically, the inefficiency of receptor trafficking to the plasma membrane can bring regulatory advantages to cells. Understanding the mechanism by which cells recognize correctly folded proteins in health and disease opens doors to new therapeutic approaches and provides a more accurate view of mechanisms of normal cell function than is presently available.
Center for Neuropharmacology and Neurosciences, Albany Medical College, Albany, New York 12208, USA
Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
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Center for Neuropharmacology and Neurosciences, Albany Medical College, Albany, New York 12208, USA
Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
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Center for Neuropharmacology and Neurosciences, Albany Medical College, Albany, New York 12208, USA
Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
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Ghrelin, leptin, and endogenous glucocorticoids play a role in appetite regulation, energy balance, and growth. The present study assessed the effects of dexamethasone (DEX) on these hormones, and on ACTH and pituitary proopiomelanocortin (POMC) and corticotropin-releasing hormone receptor-1 (CRHR1) mRNA expression, during a common metabolic stress – neonatal hypoxia. Newborn rats were raised in room air (21% O2) or under normobaric hypoxia (12% O2) from birth to postnatal day (PD) 7. DEX was administered on PD3 (0.5 mg/kg), PD4 (0.25 mg/kg), PD5 (0.125 mg/kg), and PD6 (0.05 mg/kg). Pups were studied on PD7 (24 h after the last dose of DEX). DEX significantly increased plasma leptin and ghrelin in normoxic pups, but only increased ghrelin in hypoxic pups. Hypoxia alone resulted in a small increase in plasma leptin. Plasma corticosterone and pituitary POMC mRNA expression were decreased 24 h following the last dose of DEX, whereas plasma ACTH and pituitary CRHR1 mRNA expression had already increased (normoxia and hypoxia). Hypoxia alone increased corticosterone, but had no effect on ACTH or pituitary POMC and CRHR1 mRNA expression. Neonatal DEX treatment, hypoxia, and the combination of both affect hormones involved in energy homeostasis. Pituitary function in the neonate was quickly restored following DEX-induced suppression of the hypothalamic–pituitary–adrenal axis. The changes in ghrelin, leptin, and corticosterone may be beneficial to the hypoxic neonate through the maintenance of appetite and shifts in intermediary metabolism.
Search for other papers by Esther Nuñez-Durán in
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Department of Metabolic Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
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Characterising the molecular networks that negatively regulate pancreatic β-cell function is essential for understanding the underlying pathogenesis and developing new treatment strategies for type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a critical regulator of ectopic fat storage, meta-inflammation, and fibrosis in liver and skeletal muscle. Here, we assessed the role of STK25 in control of progression of non-alcoholic fatty pancreas disease in the context of chronic exposure to dietary lipids in mice. We found that overexpression of STK25 in high-fat-fed transgenic mice aggravated diet-induced lipid storage in the pancreas compared with that of wild-type controls, which was accompanied by exacerbated pancreatic inflammatory cell infiltration, stellate cell activation, fibrosis and apoptosis. Pancreas of Stk25 transgenic mice also displayed a marked decrease in islet β/α-cell ratio and alteration in the islet architecture with an increased presence of α-cells within the islet core, whereas islet size remained similar between genotypes. After a continued challenge with a high-fat diet, lower levels of fasting plasma insulin and C-peptide, and higher levels of plasma leptin, were detected in Stk25 transgenic vs wild-type mice. Furthermore, the glucose-stimulated insulin secretion was impaired in high-fat-fed Stk25 transgenic mice during glucose tolerance test, in spite of higher net change in blood glucose concentrations compared with wild-type controls, suggesting islet β-cell dysfunction. In summary, this study unravels a role for STK25 in determining the susceptibility to diet-induced non-alcoholic fatty pancreas disease in mice in connection to obesity. Our findings highlight STK25 as a potential drug target for metabolic disease.
