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