Nrf2 induces Ucp1 expression in adipocytes in response to β3-AR stimulation and enhances oxygen consumption in high-fat diet-fed obese mice

Cold-induced norepinephrine activates beta 3-adrenergic receptors (beta 3-AR) to stimulate the kinase cascade and cAMP-response element-binding protein, leading to the induction of themiogenic gene expression including uncoupling protein 1 (Ucp1). Here, we showed that stimulation of the beta 3-AR by its agonists isoproterenol and CL316,243 in adipocytes increased the expression of Ucp1 and Heme Oxygenase 1 (Hmox1), the principal Nr12 target gene, suggesting the functional interaction of Nrf2 with beta 3-AR signaling. The activation of Nr12 by tert-butylhydroquinone and reactive oxygen species (ROS) production by glucose oxidase induced both Ucp1 and Hmox1 expression. The increased expression of Ucp1 and Hmox1 was significantly reduced in the presence of a Nrf2 chemical inhibitor or in Nrf2-deleted (knockout) adipocytes. Furthermore, Nrf2 directly activated the Ucp1 promoter, and this required DNA regions located at -3.7 and -2.0 kb of the transcription start site. The CL316,243-induced Ucp1 expression in adipocytes and oxygen consumption in obese mice were partly compromised in the absence of Nrf2 expression. These data provide additional insight into the role of Nrf2 in beta 3-AR-mediated Ucpl expression and energy expenditure, further highlighting the utility of Nrf2-mediated theimogenic stimulation as a therapeutic approach to diet-induced obesity.

Automated summary

Research demonstrates that stimulation of beta 3-adrenergic receptors (beta 3-AR) in adipocytes can increase the expression of Ucp1 and Hmox1, indicating a functional interaction between Nrf2 and beta 3-AR signaling. Nrf2 directly activates the Ucp1 promoter and inhibiting Nrf2 results in decreased expression of Ucp1 and Hmox1.