TY - JOUR
T1 - α/β-Hydrolase Domain 6 Deletion Induces Adipose Browning and Prevents Obesity and Type 2 Diabetes
AU - Zhao, Shangang
AU - Mugabo, Yves
AU - Ballentine, Gwynne
AU - Attane, Camille
AU - Iglesias, Jose
AU - Poursharifi, Pegah
AU - Zhang, Dongwei
AU - Nguyen, Thuy Anne
AU - Erb, Heidi
AU - Prentki, Raphael
AU - Peyot, Marie Line
AU - Joly, Erik
AU - Tobin, Stephanie
AU - Fulton, Stephanie
AU - Brown, J. Mark
AU - Madiraju, S. R.Murthy
AU - Prentki, Marc
N1 - Funding Information:
This study was supported by funds from Canadian Institutes of Health Research grants to M.P. and S.R.M.M. and by a NIH grant (R01-HL122283) to J.M.B. and a CIHR grant and New Investigator award to S.F. M.P. holds the Canada Research Chair in Diabetes and Metabolism. Y.M. is supported by a fellowship from Fond de recherche Santé Québec (FRSQ). We thank the core facilities of Cellular Physiology & Metabolomics and Rodent Phenotyping of CRCHUM/Montreal Diabetes Research Center for the many metabolic analyses performed in this study. We also thank Dr. Julie Lavoie, Dr. Ines Holzbaur, and Dr. Kathryn Skorey for critically reading the manuscript.
Publisher Copyright:
© 2016 The Authors.
PY - 2016/3/29
Y1 - 2016/3/29
N2 - Suppression of α/β-domain hydrolase-6 (ABHD6), a monoacylglycerol (MAG) hydrolase, promotes glucose-stimulated insulin secretion by pancreatic β cells. We report here that high-fat-diet-fed ABHD6-KO mice show modestly reduced food intake, decreased body weight gain and glycemia, improved glucose tolerance and insulin sensitivity, and enhanced locomotor activity. ABHD6-KO mice also show increased energy expenditure, cold-induced thermogenesis, brown adipose UCP1 expression, fatty acid oxidation, and white adipose browning. Adipose browning and cold-induced thermogenesis are replicated by the ABHD6 inhibitor WWL70 and by antisense oligonucleotides targeting ABHD6. Our evidence suggests that one mechanism by which the lipolysis derived 1-MAG signals intrinsic and cell-autonomous adipose browning is via PPARα and PPARγ activation, and that ABHD6 regulates adipose browning by controlling signal competent 1-MAG levels. Thus, ABHD6 regulates energy homeostasis, brown adipose function, and white adipose browning and is a potential therapeutic target for obesity and type 2 diabetes.
AB - Suppression of α/β-domain hydrolase-6 (ABHD6), a monoacylglycerol (MAG) hydrolase, promotes glucose-stimulated insulin secretion by pancreatic β cells. We report here that high-fat-diet-fed ABHD6-KO mice show modestly reduced food intake, decreased body weight gain and glycemia, improved glucose tolerance and insulin sensitivity, and enhanced locomotor activity. ABHD6-KO mice also show increased energy expenditure, cold-induced thermogenesis, brown adipose UCP1 expression, fatty acid oxidation, and white adipose browning. Adipose browning and cold-induced thermogenesis are replicated by the ABHD6 inhibitor WWL70 and by antisense oligonucleotides targeting ABHD6. Our evidence suggests that one mechanism by which the lipolysis derived 1-MAG signals intrinsic and cell-autonomous adipose browning is via PPARα and PPARγ activation, and that ABHD6 regulates adipose browning by controlling signal competent 1-MAG levels. Thus, ABHD6 regulates energy homeostasis, brown adipose function, and white adipose browning and is a potential therapeutic target for obesity and type 2 diabetes.
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U2 - 10.1016/j.celrep.2016.02.076
DO - 10.1016/j.celrep.2016.02.076
M3 - Article
C2 - 26997277
AN - SCOPUS:84961221399
SN - 2211-1247
VL - 14
SP - 2872
EP - 2888
JO - Cell Reports
JF - Cell Reports
IS - 12
ER -