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Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats.

ABSTRACT: OBJECTIVE:Obesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing's Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoid levels have been implicated in the development of the metabolic phenotype of obesity. Tissue glucocorticoid levels are regulated by 11?-hydroxysteroid dehydrogenase type1 (11?HSD1), which increases the local concentration of active glucocorticoids by the production of corticosterone from 11-dehydrocorticosterone. 11?HSD1 is expressed in the hypothalamic arcuate nucleus (ARC), a major weight and appetite-regulating centre, and therefore represents a target for novel anti-obesity therapeutic agents. Thus, we sought to investigate the effect of chronic alterations of ARC corticosterone levels (mediated by 11?HSD1) on food intake and body weight in adult male rats. METHODS:Recombinant adeno-associated virus particles bearing sense 11?HSD1 (rAAV-S11?HSD1) and small interfering 11?HSD1 (rAAV-si11?HSD1), respectively, were stereotactically injected into the ARC (bilaterally) of adult male Wistar rats. rAAV-GFP was injected into control groups of male Wistar rats. Food intake and body weight were measured three times a week for 70 days. Terminal brain, plasma and intrascapular brown adipose tissue (iBAT) samples were taken for measurement of mRNA expression and hormone levels. RESULTS:Compared to controls, rAAV-S11?HSD1 injection resulted in higher ARC corticosterone levels, hyperphagia and increased weight gain. Conversely, rAAV-si11?HSD1 injection (compared to controls) resulted in lower ARC corticosterone levels, higher iBAT uncoupling protein-1 mRNA expression and less weight gain despite similar food intake. CONCLUSIONS:Therefore ARC corticosterone, regulated by 11?HSD1, may play a role in food intake and body weight regulation. These data have important implications for the development of centrally-acting 11?HSD1 inhibitors, which are currently being developed for the treatment of obesity, metabolic disorders, and other conditions.

SUBMITTER: Izzi-Engbeaya C

PROVIDER: S-EPMC7132090 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats.

Izzi-Engbeaya Chioma C Ma Yue Y Buckley Niki W NW Ratnasabapathy Risheka R Richardson Errol E Counsell John R JR Fernandes-Freitas Isabel I Norton Mariana M Farooq Gala G Mirza Zainab Z Cai Mingzhu M Cheetham Sharon S Seckl Jonathan J Murphy Kevin K Dhillo Waljit S WS Gardiner James J

Molecular metabolism 20200306

<h4>Objective</h4>Obesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing's Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoid levels have been implicated in the development of the metabolic phenotype of obesity. Tissue glucocorticoid levels are regulated by 11β-hydro ...[more]

PMID: 32229097

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Project description:IntroductionThe action of nicotine to suppress body weight is often cited as a factor impacting smoking initiation and the failure to quit. Despite the weight-suppressant effects of nicotine, smokers and nonsmokers report equal daily caloric intake. The weight-suppressive effects of nicotine in animal models of smoking are poorly understood. Furthermore, the Food and Drug Administration has authority to implement a policy markedly reducing nicotine levels in cigarettes; such a reduction could reduce smoking behavior, but have detrimental effects on body weight. The aim of this investigation was to examine the effects of self-administered nicotine on body weight and food intake in rats.MethodsIn Experiment 1, rats with ad libitum access to chow responded for intravenous infusions of nicotine (60 µg/kg/infusion) or saline in daily 1-hour sessions; body weight and 24-hour food intake were measured. Experiment 2 tested the effects of subcutaneous injections of nicotine on food intake. In Experiment 3, rats were food restricted and self-administered nicotine across a range of doses (3.75-60 µg/kg/infusion) while body weight was measured. In Experiment 4, rats self-administered 60 µg/kg/infusion nicotine before reduction to one of several doses (1.875-15 µg/kg/infusion) for 50 days.ResultsSelf-administered nicotine suppressed weight gain independent of food intake. In food restricted rats, self-administered nicotine dose-dependently suppressed body weight gain. In rats self-administering 60 µg/kg/infusion nicotine, dose reduction increased body weight.ConclusionsSelf-administered nicotine, even at low doses, suppressed body independent of food intake; this may have important implications for nicotine reduction policy.ImplicationsThe results of the present studies demonstrate that self-administered nicotine suppresses body weight independent of food intake in rats. Further, the present studies establish that self-administered nicotine suppresses body weight even at very low doses and that reduction of nicotine dose results in weight gain. These results have important implications for nicotine reduction policy.

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Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats.

Publications

Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats.

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