Beigeing of white adipose tissue has potential anti-obesity and anti-diabetes effects, yet the underlying signaling mechanisms remain to be fully elucidated. Here we show that adipose-specific knockout of Rheb, an upstream activator of mTORC1, protects mice from high fat diet-induced obesity and insulin resistance. Rheb deficiency in adipose tissue reduced mTORC1 signaling, increased lipolysis, and promoted beigeing and energy expenditure. On the other hand, overexpression of Rheb in primary adipocytes significantly inhibited CREB phosphorylation and UCP1 expression. Mechanistically, fat-specific knockout of Rheb increased cAMP levels, PKA activity, and UCP1 expression in subcutaneous white adipose tissue. Interestingly, treating primary adipocytes with rapamycin only partially alleviated the suppressing effect of Rheb on UCP1 expression, suggesting the presence of a novel mechanism underlying the inhibitory effect of Rheb on thermogenic gene expression. Consistent with this notion, overexpression of Rheb stabilizes the expression of cAMP-specific phosphodiesterase-4D5 in adipocytes, whereas knockout of Rheb greatly reduced cellular levels of phosphodiesterase-4D5, concurrently with increased cAMP levels, PKA activation, and UCP1 expression. Taken together, our findings reveal Rheb as an important negative regulator of beige fat development and thermogenesis. In addition, Rheb is able to suppress the beigeing effect through an mTORC1-independent mechanism.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0886/-/DC1.
- Received July 25, 2016.
- Accepted December 14, 2016.
- © 2017 by the American Diabetes Association.