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

α/ß-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.

Long-term physiological and behavioral effects of exposure to a highly palatable diet during the perinatal and post-weaning periods.

Environmental conditions promote weight gain in children and adults, with early nutritional states and the availability of energy condensed/high-fat palatable diets appearing to facilitate the development of obesity. Little is known about the extent to which prenatal and postnatal dietary manipulations alter the response of the adult offspring to high-fat, highly palatable diets. Here we exposed rat dams to highly palatable diet (supplemental diet, SD), rich in fat and sugars, during pregnancy and lactation, and assessed the potential interactions with the effects of a similar diet offered post-weaning on a range of physiological and behavioral parameters in the adult male offspring. Post-weaning exposure to SD increased body weight, body fat, and plasma leptin levels, as well as the plasma glucose response to glucose challenge, compared to chow-fed rats. Combining perinatal SD with post-weaning exposure (SD/SD group) elevated fasting plasma glucose levels, and induced leptin resistance in the adult rats. The same treatment also resulted in sensitized locomotor response to an acute injection of amphetamine. The glucocorticoid response to stress was not affected by the dietary treatments. We conclude that exposure of mother and young to a highly palatable diet with high-fat and high sugar content during the critical perinatal period, increases the risk of developing an obesity-like condition in rats exposed to the same palatable diet post-weaning, and this effect may be accompanied by adaptations in the reward-related mesostriatal dopaminergic system.