Depletion of WWP1 Increases Adrb3 Expression and Lipolysis in White Adipose Tissue of Obese Mice

Obesity is defined as abnormal or excessive accumulation of body fat and contributes to several metabolic disorders. White adipose tissue (WAT) releases energy as free fatty acids and glycerol from triglycerides through a process called lipolysis. People with obesity have impaired catecholamine-stimulated lipolysis, but comprehensive understanding of this lipolysis is still unclear. We previously showed that expression of WW domain-containing E3 ubiquitin ligase 1 (WWP1), a member of the HECT-type E3 family of ubiquitin ligases, was increased in WAT of obese mice. In this study, we generated <i>Wwp1</i> knockout (KO) mice to evaluate the effect of WWP1 in WAT of obese mice. The mRNA levels of beta-3 adrenergic receptor (<i>Adrb3</i>), which were decreased with a high-fat diet, were increased by <i>Wwp1</i> KO in WAT. Moreover, <i>Wwp1</i> KO mice showed increased phosphorylated hormone-sensitive lipase levels in WAT. In contrast, noradrenaline and its metabolism were not altered in WAT of obese <i>Wwp1</i> KO mice. These findings indicate that WWP1, which is increased in adipocytes because of obesity, is a candidate for suppressing lipolysis independently of noradrenaline metabolism. We anticipate that inhibition of WWP1 is a promising approach for a new treatment of obesity and type-2 diabetes using Adrb3 agonists.