α/β-Hydrolase Domain 6 in the Ventromedial Hypothalamus Controls Energy Metabolism Flexibility

Abstract

Summary: α/β-Hydrolase domain 6 (ABHD6) is a monoacylglycerol hydrolase that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Although complete or peripheral ABHD6 loss of function is protective against diet-induced obesity and insulin resistance, the role of ABHD6 in the central control of energy balance is unknown. Using a viral-mediated knockout approach, targeted endocannabinoid measures, and pharmacology, we discovered that mice lacking ABHD6 from neurons of the ventromedial hypothalamus (VMHKO) have higher VMH 2-AG levels in conditions of endocannabinoid recruitment and fail to physiologically adapt to key metabolic challenges. VMHKO mice exhibited blunted fasting-induced feeding and reduced food intake, energy expenditure, and adaptive thermogenesis in response to cold exposure, high-fat feeding, and dieting (transition to a low-fat diet). Our findings identify ABHD6 as a regulator of the counter-regulatory responses to major metabolic shifts, including fasting, nutrient excess, cold, and dieting, thereby highlighting the importance of ABHD6 in the VMH in mediating energy metabolism flexibility. : Fisette et al. demonstrate that the endocannabinoid-degrading enzyme ABHD6 in ventromedial hypothalamus neurons is a regulator of VMH 2-AG accumulation and energy metabolism flexibility in response to homeostatic challenges. ABHD6 knockout in VMH neurons of adult mice impairs the feeding response to fasting and increases susceptibility to cold-induced hypothermia, diet-induced obesity, and resistance to diet-induced weight loss. Keywords: endocannabinoids, 2-arachidonoylglycerol, cannabinoid receptor 1, α/β-hydrolase-domain 6, ventromedial hypothalamus, energy homeostasis, thermogenesis, obesity