Adipose-specific knockout of ubiquitin-conjugating enzyme E2L6 (Ube2l6) reduces diet-induced obesity, insulin resistance, and hepatic steatosis.

Ubiquitin/ISG15-conjugating enzyme E2 L6 (UBE2L6/Ube2l6) catalyzes protein ISGylation and ubiquitylation, post-translational modifications which regulate protein stability. Ube2l6 plays a role in promoting in vitro adipogenesis; however, its mechanism(s) of action and in vivo effects remain unknown. Here, we discovered that UBE2L6 levels were upregulated, and UBE2L6 and adipose triglyceride lipase (ATGL/Atgl) levels were negatively correlated, in white adipose tissue (WAT) from obese humans and obese mice. Therefore, we employed adipose-specific Ube2l6 knockout (Ube2l6AKO) mice and age-matched Ube2l6flox/flox controls to assess adipocyte Ube2l6's role in high-fat diet (HFD)-induced obesity, insulin resistance, and hepatic steatosis. HFD-fed Ube2l6AKO mice displayed lower subcutaneous and visceral WAT mass levels relative to controls. HFD-fed Ube2l6AKO mice also showed WAT adipocyte hypoplasia and hypotrophy as well as enhanced whole-body metabolic activity relative to controls. Furthermore, glucose intolerance, insulin resistance, compensatory hyperinsulinemia, hypercholesterolemia, and hepatic steatosis were lower in HFD-fed Ube2l6AKO mice as compared to controls. Mechanistically, we found that Atgl protein expression and Atgl-mediated lipolysis were negatively regulated by Ube2l6's promotion of Atgl protein ubiquitylation. Collectively, adipocyte Ube2l6 functions as a negative regulator of Atgl protein stability and, consequently, promotes HFD-induced obesity, insulin resistance, and hepatic steatosis.

Wei W ，Li Y ，Li Y ，Li D ... -  《-》

Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice.

Schoiswohl G ，Stefanovic-Racic M ，Menke MN ，Wills RC ，Surlow BA ，Basantani MK ，Sitnick MT ，Cai L ，Yazbeck CF ，Stolz DB ，Pulinilkunnil T ，O'Doherty RM ，Kershaw EE ... -  《-》

Identification of a loss-of-function mutation in Ube2l6 associated with obesity resistance.

Marcelin G ，Liu SM ，Schwartz GJ ，Chua SC Jr ... -  《-》

Adipose HuR protects against diet-induced obesity and insulin resistance.

Li J ，Gong L ，Liu S ，Zhang Y ，Zhang C ，Tian M ，Lu H ，Bu P ，Yang J ，Ouyang C ，Jiang X ，Wu J ，Zhang Y ，Min Q ，Zhang C ，Zhang W ... -  《Nature Communications》

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity.

Schreiber R ，Hofer P ，Taschler U ，Voshol PJ ，Rechberger GN ，Kotzbeck P ，Jaeger D ，Preiss-Landl K ，Lord CC ，Brown JM ，Haemmerle G ，Zimmermann R ，Vidal-Puig A ，Zechner R ... -  《-》