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

• ABHD6 inhibition reduces high-fat-diet-induced obesity/insulin resistance
• ABHD6 inhibition protects against high-fat-diet-induced hepatic steatosis
• ABHD6 is a critical regulator of hepatic de novo lipogenesis
• ABHD6 is both a monoacylglycerol lipase and a lysophospholipase

SummaryThe 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.

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