Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis

Acute cold exposure leads to norepinephrine release in brown adipose tissue (BAT) and activates uncoupling protein (UCP)1-mediated nonshivering thermogenesis. Chronic sympathetic stimulation is known to initiate mitochondrial biogenesis, UCP1 expression, hyperplasia of BAT, and recruitment of brown adipocytes in white adipose tissue (WAT) depots. Despite distinct functions of BAT and WAT in energy balance, only a few genes are exclusively expressed in either tissue. We identified NUR77 (Nr4a1), an orphan receptor, to be induced transiently in brown adipocytes in response to beta-adrenergic stimulation and in BAT of cold-exposed mice. Subsequent reporter gene assays demonstrated an inhibitory action of NUR77 on basal and peroxisome proliferator-activated receptor (PPAR)gamma/retinoid X receptor (RXR)alpha-mediated transactivation of the Ucp1 enhancer in heterologous cotransfection experiments. Despite this function of NUR77 in the control of Ucp1 gene expression, nonshivering thermogenesis was not affected in Nur77 knockout mice. However, we observed a superinduction of Nor1 in BAT of cold-exposed knockout mice. We conclude that NUR77 is a cold-induced negative regulator of Ucp1, but phenotypic consequences in knockout mice are compensated by functional redundancy of Nor1.