Funktionsanalyse des Waisenrezeptors Nur77 im braunen Fettgewebe

Acute cold exposure leads to noradrenaline release in brown adipose tissue (BAT) and activates UCP1-mediated non-shivering thermogenesis. Chronic sympathetic stimulation is also 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. Nur77, an orphan receptor, was identified to be induced transiently in brown adipocytes in response to * adrenergic stimulation and in BAT of cold exposed mice. In WAT Nur77 expression could not be detected. Subsequent reporter gene assays demonstrated an inhibitory action of Nur77 on basal and PPARg/RXRa mediated transactivation of the Ucp1 enhancer in heterologous cotransfection experiments. Chromatin immuno-precipitation (ChIP) in brown adipocytes revealed specific interaction of Nur77 with the endogenous enhancer. This strongly suggests a function of Nur77 as a negative regulator of UCP1 expression. Interestingly, Nur77 was constitutively expressed early during adipogenesis in brown but not in white adipocytes In this phase of adipogenesis UCP1 expression cannot be induced by * adrenergic stimulation despite the presence of essential factors like PPARg and RXRa. Despite this function of Nur77 in the control of Ucp1 gene expression, non-shivering thermogenesis was not affected in Nur77-knockout mice. However, we observed induction of Nurr1 and Nor1 after cold exposure and even a superinduction of Nor1 in BAT of cold exposed homozygous knockout mice. We therefore conclude that Nur77 is a cold-induced negative regulator of Ucp1, but phenotypic consequences in knockout mice are compensated by functional redundancy of Nor1.