@article{c7061545e95c4fbc90a1340118827555,
title = "The Serine Hydrolase ABHD6 Is a Critical Regulator of the Metabolic Syndrome",
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",
author = "Gwynneth Thomas and Betters, {Jenna L.} and Lord, {Caleb C.} and Brown, {Amanda L.} and Stephanie Marshall and Daniel Ferguson and Janet Sawyer and Davis, {Matthew A.} and Melchior, {John T.} and Blume, {Lawrence C.} and Howlett, {Allyn C.} and Ivanova, {Pavlina T.} and Milne, {Stephen B.} and Myers, {David S.} and Irina Mrak and Vera Leber and Christoph Heier and Ulrike Taschler and Blankman, {Jacqueline L.} and Cravatt, {Benjamin F.} and Lee, {Richard G.} and Crooke, {Rosanne M.} and Graham, {Mark J.} and Robert Zimmermann and Brown, {H. Alex} and Brown, {J. Mark}",
note = "Funding Information: We thank Larry Rudel, Paul Dawson, and Ryan Temel (Wake Forest School of Medicine) for insightful comments and suggestions. We also sincerely thank Marc Prentki and Murthy Madiraju (Montreal Diabetes Research Center) for critical review of this work. This work was supported by the Department of Pathology at Wake Forest School of Medicine, a pilot grant from the Wake Forest School of Medicine Venture Fund and a pilot grant awarded under the Wake Forest and Harvard Center for Botanical Lipids (P50-AT002782). These studies also received generous funding by the National Institute of General Medical Sciences LIPID MAPS (U54-GM069338 to H.A.B.) and National Institute of Diabetes and Digestive and Kidney Diseases (F32-DK084582 to J.L.B.). Richard Lee, Rosanne Crooke, and Mark Graham are employees at ISIS Pharmaceuticals, Inc. ",
year = "2013",
doi = "10.1016/j.celrep.2013.08.047",
language = "English",
volume = "5",
pages = "508--520",
journal = "Cell Reports",
issn = "2211-1247",
number = "2",
}