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Cell Rep. 2016 Oct 25;17(5):1217-1226. doi: 10.1016/j.celrep.2016.10.004.

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

Author information

1
CRCHUM and Montreal Diabetes Research Center, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Nutrition, Université de Montréal, Montreal, QC H3T1J4, Canada.
2
CRCHUM and Montreal Diabetes Research Center, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Neuroscience, Université de Montréal, Montreal, QC H3T1J4, Canada.
3
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.
4
CRCHUM and Montreal Diabetes Research Center, Université de Montréal, Montreal, QC H3T1J4, Canada.
5
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.
6
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.
7
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.

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. 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.

KEYWORDS:

2-arachidonoylglycerol; cannabinoid receptor 1; endocannabinoids; energy homeostasis; obesity; thermogenesis; ventromedial hypothalamus; α/β-hydrolase-domain 6

PMID:
27783937
DOI:
10.1016/j.celrep.2016.10.004
[Indexed for MEDLINE]
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