WWL70

WWL70 is an inhibitor of α/β-hydrolase domain-containing protein 6 (ABHD6; IC₅₀ = 70 nM).¹ It increases the expression of the adipose browning-related gene Ucp1 in differentiated 3T3-L1 mouse adipocytes and increases the oxygen consumption rate (OCR), an effect that can be blocked by the PPARα antagonist GW 6471 (Item No. 11697), when used at a concentration of 10 µM.² WWL70 (10 mg/kg per day) also increases the expression of the adipose browning-related genes Ucp1, Prdm16, Tmem26, and Tbx1 in visceral adipose tissue in mice fed a high-fat diet. WWL70 reduces adipose tissue mass and prevents glucose-intolerance and increases in body weight in mice fed a high-fat diet but does not reduce hepatic triacylglycerol levels.³ It increases brain levels of 2-arachidonoyl glycerol (2-AG; Item No. 62160) and decreases the severity of experimental autoimmune encephalomyelitis (EAE) in wild-type, but not cannabinoid (CB) receptor 2 (CB₂) knockout, mice when administered at a dose of 10 mg/kg per day starting at disease onset.⁴

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1. Li, W., Blankman, J.L., and Cravatt, B.F. A functional proteomic strategy to discover inhibitors for uncharacterized hydrolases. J. Am. Chem. Soc. 129(31), 9594-9595 (2007).

2. Zhao, S., Mugabo, Y., Ballentine, G., et al. α/β-Hydrolase domain 6 deletion induces adipose browning and prevents obesity and type 2 diabetes. Cell Rep. 14(12), 2872-28888 (2016).

3. Thomas, G., Betters, J.L., Lord, C.C., et al. The serine hydrolase ABHD6 Is a critical regulator of the metabolic syndrome. Cell Rep. 5(2), 508-520 (2013).

4. Wen, J., Ribeiro, R., Tanaka, M., et al. Activation of CB₂ receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis. Neuropharmacology 99, 196-209 (2015).

Lin, D.T.S., and Conibear, E. ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate turnover and subcellular localization. Elife 4, e11306 (2015).