Inactivation of Minar2 in Mice Hyperactivates mTOR Signaling and Results in Obesity.

Obesity is a complex disorder and is linked to chronic diseases such as type 2 diabetes. Major intrinsically disordered NOTCH2-associated receptor2 (MINAR2) is an understudied protein with an unknown role in obesity and metabolism. To examine its physiological role in adipocytes, we generated Minar2 knockout (KO) mice and demonstrated that its inactivation results in increased body fat with hypertrophic adipocytes. Minar2 KO mice on a high-fat diet develop obesity and impaired glucose tolerance and metabolism. Mechanistically, Minar2 interacts with raptor, a specific and essential component of mammalian TOR complex 1 (mTORC1) and inhibits mTOR activation. mTOR is hyperactivated in the adipocytes deficient for Minar2 and over-expression of Minar2 in HEK-293 cells inhibited mTOR activation and phosphorylation of mTORC1 substrates, including S6 kinase, and 4E-BP1. These results suggest that Minar2 is a physiological negative regulator of mTORC1 with a key role in obesity and metabolic disorders. Impaired expression of MINAR2 could lead to obesity and obesity-associated diseases.