title: α/β-Hydrolase Domain 6 in the Ventromedial Hypothalamus Controls Energy Metabolism Flexibility.
abstract: 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. VMHKOmice 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.
authors: CRCHUM and Montreal Diabetes Research Center, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Nutrition, Université de Montréal, Montreal, QC H3T1J4, Canada.
authors: Alexandre
authors: A
authors: Fisette
authors: CRCHUM and Montreal Diabetes Research Center, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Nutrition, Université de Montréal, Montreal, QC H3T1J4, Canada.
authors: Stephanie
authors: S
authors: Tobin
authors: CRCHUM and Montreal Diabetes Research Center, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Neuroscience, Université de Montréal, Montreal, QC H3T1J4, Canada.
authors: Léa
authors: L
authors: Décarie-Spain
authors: CRCHUM and Montreal Diabetes Research Center, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, QC H3T1J4, Canada.
authors: Khalil
authors: K
authors: Bouyakdan
authors: CRCHUM and Montreal Diabetes Research Center, Université de Montréal, Montreal, QC H3T1J4, Canada.
authors: Marie-Line
authors: ML
authors: Peyot
authors: CRCHUM and Montreal Diabetes Research Center, Université de Montréal, Montreal, QC H3T1J4, Canada.
authors: S R Murthy
authors: SRM
authors: Madiraju
authors: CRCHUM and Montreal Diabetes Research Center, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Nutrition, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, QC H3T1J4, Canada.
authors: Marc
authors: M
authors: Prentki
authors: CRCHUM and Montreal Diabetes Research Center, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Nutrition, Université de Montréal, Montreal, QC H3T1J4, Canada. Electronic address: stephanie.fulton@umontreal.ca.
authors: Stephanie
authors: S
authors: Fulton
authors: CRCHUM and Montreal Diabetes Research Center, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Medicine, Université de Montréal, Montreal, QC H3T1J4, Canada. Electronic address: thierry.alquier@umontreal.ca.
authors: Thierry
authors: T
authors: Alquier
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D003080:Cold Temperature; D059305:Diet, High-Fat; D063388:Endocannabinoids / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D017353:Gene Deletion; D005989:Glycerides / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D015203:Reproducibility of Results; D022722:Thermogenesis / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; C094503:glyceryl 2-arachidonate; C527261:ABHD6 protein, mouse; D008994:Monoacylglycerol Lipases
keywords: 2-arachidonoylglycerol; cannabinoid receptor 1; endocannabinoids; energy homeostasis; obesity; thermogenesis; ventromedial hypothalamus; α/β-hydrolase-domain 6