The Nuclear Factor (Erythroid-Derived 2)-Like 2 Activator TBE-31 Influences Body Weight by Affecting White Adipose Tissue in High Fat Diet-Induced Obesity Mice.

Abstract

The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system plays an important role in defense against oxidative stress, and its involvement has been implicated in body weight reduction under obese conditions. While the effect on white adipose tissue (WAT) has been intensely studied, focusing on the anti-inflammatory and anti-oxidative stress effects exerted by Nrf2 activation, the involvement of skeletal muscle has not been investigated. We assessed the body weight changes induced by Nrf2 activation by comparing its effect on WAT with those on skeletal muscle. We evaluated TBE-31, a potent Nrf2 activator, in a high-fat diet (HFD)-induced obesity model. Notably, TBE-31 significantly suppressed HFD-induced body weight gain compared with vehicle treatment. While treatment with TBE-31 induced a significant WAT weight decrease compared with vehicle, skeletal muscle weight was not affected. In addition, body weight changes were significantly correlated with WAT but not with skeletal muscle. Lipid deposition was remarkably improved in the adipose tissue, but muscle histology was not affected. A gene expression analysis revealed that Ucp-1 was upregulated and Il-6 downregulated by TBE-31 treatment in an Nrf2-dependent manner. Taken together, these findings suggest that pharmacological activation of Nrf2 suppressed HFD-induced body weight gain by affecting WAT.