SUN-112 Arcuate 11-Betahydroxysteroid Dehydrogenase Type1 Regulates Energy Homeostasis

Abstract

Introduction: Despite the ongoing increase in the prevalence of obesity, there are few licensed anti-obesity medications, and these therapies have limited efficacy and significant side effects. Therefore, new treatments are being developed, including 11-βhydroxysteroid dehydrogenase type1 (11βHSD1) inhibitors. In vivo, the enzyme 11-βhydroxysteroid dehydrogenase type1 (11βHSD1), converts the inactive glucocorticoid, 11-dehydrocorticosterone, to its active form (corticosterone). Tissue-specific 11βHSD1 has been reported to be important in the development of obesity. 11βHSD1 is expressed in the arcuate nucleus (ARC), a major hypothalamic centre which regulates energy homeostasis. We investigated the effect of modulation of intra-ARC 11βHSD1 expression on appetite and body weight in rodents. Methods: Experiments were performed using adult male Wistar rats fed a standard chow diet. In the overexpression experiment, recombinant adeno-associated virus (rAAV) encoding 11βHSD1 (rAAV-S11βHSD1) was injected bilaterally into the ARC of 12 rats and rAAV expressing green fluorescent protein (rAAV-GFP) was injected bilaterally into the ARC of 12 control rats. In the underexpression experiment, rAAV encoding small interfering RNA to 11βHSD1 (rAAV-si11βHSD1) was injected bilaterally into the ARC of 12 rats and rAAV-GFP injected into the ARC of 12 control rats. Starting 1 week post-surgery, body weight and food intake were measured three times a week for 10 weeks. At the end of the experiments, tissues and plasma were collected for gene expression and hormone analysis. Results and Conclusions: Compared to controls, ARC 11βHSD1 overexpression increased ARC corticosterone levels (iARC-S11βHSD1 243±34pg/mg vs iARC-GFP 89±39pg/mg, p<0.05), resulting in hyperphagia and 6% greater weight gain. ARC 11βHSD1 underexpression decreased ARC corticosterone levels by 47% (iARC-si11βHSD1 124.9±14.59pg/mg vs iARC-GFP 262.1±47.3pg/mg, p=0.01), resulting in 5% lower weight gain and a 1.7-fold increase in interscapular brown adipose tissue uncoupling protein-1 expression compared to controls. Corticosterone levels were unchanged in the neighbouring paraventricular nucleus. Additonally, systemic ACTH and corticosterone were unaffected by altered ARC 11βHSD1 expression. Our results suggest ARC 11βHSD1 plays a significant role in the regulation of energy homeostasis. Therefore, the novel class of therapies, 11βHSD1 inhibitors, may require central activity for maximal anti-obesity efficacy. Sources of Support: MRC MR/M004171/1, NIHR RP-2014-05-001, BBSRC BB/E52708X, FP7- HEALTH- 2009- 241592 EuroCHIP Grant