Proopiomelanocortin-Deficient Mice Are Hypersensitive to the Adverse Metabolic Effects of Glucocorticoids

Abstract

Congenital lack of proopiomelanocortin (POMC) causes obesity and glucocorticoid deficiency. The responses of PomcϪ/Ϫ and wild-type mice to the administration of corticosterone were compared. In study 1, mice were given corticosterone-supplemented water (CORT) for 10 days, resulting in plasma CORT levels within the physiological range, with partial suppression of hypothalamic corticotropin-releasing hormone expression to a similar degree between genotypes. Body weight, fat mass, and food intake increased in CORT-treated Pomc Ϫ/Ϫ but not wild-type mice. CORT increased plasma insulin levels 50-fold in Pomc Ϫ/Ϫ versus 14-fold in wildtype mice (P < 0.01) and increased hypothalamic agouti-related protein (AgRP) expression by more than 200% in Pomc Ϫ/Ϫ versus 40% in wild type (P < 0.05). In study 2, mice were given CORT from weaning, and Pomc Ϫ/Ϫ but not wild-type mice developed hyperglycemia, ketonuria, and hepatic steatosis by 8 -12 weeks. Thus, Pomc Ϫ/Ϫ mice are hypersensitive to the adverse metabolic effects of glucocorticoids. Additionally, as the levels of plasma CORT achieved, especially in study 1, were not grossly supraphysiological, we conclude that glucocorticoid deficiency may afford Pomc Ϫ/Ϫ mice some protection from the full adverse consequences of melanocortin deficiency. This may occur through a mechanism involving the suppression of AgRP by the hypoadrenal state. Diabetes 54:2269 -2276, 2005 P roopiomelanocortin (POMC) is a polypeptide precursor that undergoes extensive, tissue-specific posttranslation modification to generate a range of smaller, biologically active peptides (1). These include ACTH and ␣-, ␤-, and ␥-melanocyte-stimulating hormone, collectively known as the melanocortins. Hypothalamic neurons expressing POMC are critically involved in the integration of nutritional and hormonal signals and the regulation of both appetite and energy expenditure (2). ACTH produced in the anterior pituitary is essential for adrenal steroidogenesis (3), and local production of melanocortins in the skin and hair follicles is critically involved in control of pigmentation (4,5). As expected, inactivating mutations of the POMC gene in humans and mice therefore result in a complex phenotype involving hyperphagia, obesity, glucocorticoid deficiency, and altered pigmentation (6 -9).Among murine models of obesity, Pomc-null mice are unusual in that obesity and hyperphagia develop in the absence of circulating glucocorticoid. Glucocorticoids have pleiotropic effects on metabolism, and in particular, changes in circulating levels of glucocorticoid can impact on the melanocortin system. For example, adrenalectomy is able to reverse the obese phenotype and restore hypothalamic melanocortin tone in leptin-deficient ob/ob mice (10). In addition, adrenalectomy alters the sensitivity of the central melanocortin system to the effects of the melanocortin antagonist agouti-related protein (AgRP), with the orexigenic effect of the latter being absent in adrenalectomized rats but restored with glucocorticoid supplementation (1...

Deletion of Hexose-6-phosphate Dehydrogenase Activates the Unfolded Protein Response Pathway and Induces Skeletal Myopathy

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Perinatal overfeeding in rats results in increased levels of plasma leptin but unchanged cerebrospinal leptin in adulthood

“…29,32 In situ hybridizations were performed as already reported previously. 11,29,31,32,34 To compare anatomically similar regions, the slides were matched according to the rat brain atlas of Paxinos and Watson. 35 The slides from control and treated animals, at each treatment time, were always exposed to the same autoradiographic film.…”

In vivo alternative assessment of the chemicals that interfere with anterior pituitary POMC expression and interrenal steroidogenesis in POMC: EGFP transgenic zebrafish

“…For instance, the processing of POMC in anterior pituitary corticotrophs results in the generation of pro-γ-MSH, ACTH, and β-LPH (Bicknell, 2008). These POMC-derived hormones regulate many physiological processes including steroidogenesis, skin pigmentation, food intake, and energy balance (Coll et al, 2004(Coll et al, , 2005Coll and Tung, 2009). ACTH is the most important pituitary-derived peptide-controlling steroidogenesis in the adult adrenal gland (Hinson and Raven, 2006;Coll and Tung, 2009).…”