title: α/β-Hydrolase Domain 6 Deletion Induces Adipose Browning and Prevents Obesity and Type 2 Diabetes.
abstract: 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.
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Shangang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Mugabo
authors.affiliation: Metanome Incorporated, Houston, TX 77046, USA.
authors.forename: Gwynne
authors.initials: G
authors.lastname: Ballentine
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Camille
authors.initials: C
authors.lastname: Attane
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Jose
authors.initials: J
authors.lastname: Iglesias
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Pegah
authors.initials: P
authors.lastname: Poursharifi
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Thuy Anne
authors.initials: TA
authors.lastname: Nguyen
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Heidi
authors.initials: H
authors.lastname: Erb
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Raphael
authors.initials: R
authors.lastname: Prentki
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Peyot
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Erik
authors.initials: E
authors.lastname: Joly
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tobin
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fulton
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada. Electronic address: murthy.madiraju@crchum.qc.ca.
authors.forename: S R Murthy
authors.initials: SR
authors.lastname: Madiraju
authors.affiliation: Departments of Nutrition and Biochemistry and Montreal Diabetes Research Center, CRCHUM and Université de Montréal, Montréal, QC H1W 4A4, Canada. Electronic address: marc.prentki@umontreal.ca.
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
mesh_terms: D041721:3T3-L1 Cells; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D059305:Diet, High-Fat; D004075:Diglycerides / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D022722:Thermogenesis; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D002219:Carbamates; D004075:Diglycerides; C584421:N-methyl-N-((3-(4-pyridinyl)phenyl)methyl)-4'-(aminocarbonyl)(1,1'-biphenyl)-4-yl ester, carbamic acid; D047493:PPAR alpha; D047495:PPAR gamma; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C044777:1-O-myristoyl-2-acetyl-glycerol; C527261:ABHD6 protein, mouse; D008994:Monoacylglycerol Lipases