α/β-Hydrolase Domain 6 Deletion Induces Adipose Browning and Prevents Obesity and Type 2 Diabetes

Cell Rep. 2016 Mar 29;14(12):2872-88. doi: 10.1016/j.celrep.2016.02.076. Epub 2016 Mar 17.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3-L1 Cells
  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Biphenyl Compounds / pharmacology
  • Carbamates / pharmacology
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / prevention & control
  • Diet, High-Fat
  • Diglycerides / pharmacology
  • Energy Metabolism / drug effects
  • Female
  • HEK293 Cells
  • Humans
  • Lipid Peroxidation / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Monoacylglycerol Lipases / genetics
  • Monoacylglycerol Lipases / metabolism*
  • Motor Activity / drug effects
  • Obesity / etiology
  • Obesity / genetics*
  • Obesity / metabolism
  • Obesity / prevention & control
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Thermogenesis
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / metabolism

Substances

  • Biphenyl Compounds
  • Carbamates
  • Diglycerides
  • N-methyl-N-((3-(4-pyridinyl)phenyl)methyl)-4'-(aminocarbonyl)(1,1'-biphenyl)-4-yl ester, carbamic acid
  • PPAR alpha
  • PPAR gamma
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • 1-O-myristoyl-2-acetyl-glycerol
  • ABHD6 protein, mouse
  • Monoacylglycerol Lipases