The Serine Hydrolase ABHD6 Is a Critical Regulator of the Metabolic Syndrome

Gwynneth Thomas, Jenna L. Betters, Caleb C. Lord, Amanda L. Brown, Stephanie Marshall, Daniel Ferguson, Janet Sawyer, Matthew A. Davis, John T. Melchior, Lawrence C. Blume, Allyn C. Howlett, Pavlina T. Ivanova, Stephen B. Milne, David S. Myers, Irina Mrak, Vera Leber, Christoph Heier, Ulrike Taschler, Jacqueline L. Blankman, Benjamin F. CravattRichard G. Lee, Rosanne M. Crooke, Mark J. Graham, Robert Zimmermann, H. Alex Brown, J. Mark Brown

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

The serine hydrolase α/β hydrolase domain 6 (ABHD6) has recently been implicated as a key lipasefor 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 inperipheral tissues in order to identify invivo 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 invivo lipidomic identification andinvitro 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

Original languageEnglish
Pages (from-to)508-520
Number of pages13
JournalCell Reports
Volume5
Issue number2
DOIs
StatePublished - 2013

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