Endocrine Abstracts

Adaptation of oxidative metabolism is essential for meeting different energy demands in different tissues, or altered energy demands in response to stressors, such as exposure to cold. The orphan nuclear receptor ERRα (estrogen-related receptor alpha) is implicated in the regulation of energy metabolism. ERRα expression is high in tissues with high oxidative capacity and increased at physiologic states of increased energy demand. Moreover, ERRα activity and expression are regulated by the co-activators PGC-1α and PGC-1β, which integrate signals indicating changing energy demands. Gain- and loss-of function studies in vitro show that ERRα is a crucial downstream effector of PGC-1α and PGC-1β in the regulation of several facets of mitochondrial metabolism, including mitochondrial biogenesis and oxidative capacity. To address the physiologic function of ERRα in vivo we have studied mice lacking ERRα and shown that they are defective in adaptive thermogenesis. The impaired thermogenic function is not due to defects in the acute transcriptional induction of ‘thermogenic’ genes, suggesting that ERRα is dispensable for some subsets of PGC-1α-controlled programs. Rather, ERRα is needed for the high levels of mitochondrial biogenesis and oxidative capacity characteristic of brown adipose tissue, and thus for providing the energy necessary for thermogenesis. ERRα fulfils this role by binding directly and enhancing the expression of genes important for fatty acid oxidation, TCA cycle, and oxidative phosphorylation, acting parallel to other transcription factors that control mitochondrial gene expression, such as NRF1 and NRF2/GABPA. These findings demonstrate that ERRα is an important component of the network that controls adaptive mitochondrial biogenesis and function in vivo, and essential for survival in situations of high energy demand. The physiologic consequences of ERRα lack of function in other tissues and the extent to which other members of the ERR family compensate for the lack of ERRα will be discussed.