| Literature DB >> 24095738 |
Gwynneth Thomas1, Jenna L Betters1, Caleb C Lord1, Amanda L Brown1,2, Stephanie Marshall1,2, Daniel Ferguson1,2, Janet Sawyer1, Matthew A Davis1, John T Melchior1, Lawrence C Blume3, Allyn C Howlett3, Pavlina T Ivanova4, Stephen B Milne4, David S Myers4, Irina Mrak5, Vera Leber5, Christoph Heier5, Ulrike Taschler5, Jacqueline L Blankman6, Benjamin F Cravatt6, Richard G Lee7, Rosanne M Crooke7, Mark J Graham7, Robert Zimmermann5, H Alex Brown4, J Mark Brown1,2.
Abstract
The serine hydrolase α/β hydrolase domain 6 (ABHD6) has recently been implicated as a key lipase for the endocannabinoid 2-arachidonylglycerol (2-AG) in the brain. However, the biochemical and physiological function for ABHD6 outside of the central nervous system has not been established. To address this, we utilized targeted antisense oligonucleotides (ASOs) to selectively knock down ABHD6 in peripheral tissues in order to identify in vivo substrates and understand ABHD6's role in energy metabolism. Here, we show that selective knockdown of ABHD6 in metabolic tissues protects mice from high-fat-diet-induced obesity, hepatic steatosis, and systemic insulin resistance. Using combined in vivo lipidomic identification and in vitro enzymology approaches, we show that ABHD6 can hydrolyze several lipid substrates, positioning ABHD6 at the interface of glycerophospholipid metabolism and lipid signal transduction. Collectively, these data suggest that ABHD6 inhibitors may serve as therapeutics for obesity, nonalcoholic fatty liver disease, and type II diabetes.Entities:
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Year: 2013 PMID： 24095738 PMCID： PMC3833083 DOI： 10.1016/j.celrep.2013.08.047
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423