Regulators of adipocyte oxidative metabolism

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PROJECT SUMMARY Adipose oxidative metabolism is central to human health. Defects in adipocyte mitochondria are linked to adipocyte dysfunction and insulin resistance, whereas lifestyle interventions and pharmacological agents that promote adipocyte oxidative capacity promote metabolic health and insulin sensitivity. Studies over several years have identified important regulators of adipocyte oxidative metabolism, such as members of the PGC-1 coactivator family, and nuclear receptors of the PPAR (peroxisome proliferator-activated receptor) and ERR (Estrogen-related receptor) subfamilies. These transcription factors exert their effects on gene expression and cellular function by both direct and indirect regulation of hundreds of genes that coordinately promote mitochondrial biogenesis and oxidative metabolism. Mining of genes regulated by PGC-1s and ERRs, coupled to bioinformatic approaches to determine associations of PGC-1/ERR targets with PPAR pathways and metabolism, has led us to identify a new and poorly characterized protein, Mcrip2, as highly associated with adipocyte oxidative metabolism. The premise of this proposal is that Mcrip2, a protein of unknown cellular and molecular function, that has not been linked yet to metabolism or physiology, is induced by PGC-1, PPAR and ERR factors, acts to enhance basal and adrenergically stimulated expression of oxidative metabolism genes, and is thus a critical element of the regulatory networks that control adipocyte oxidative metabolism. Interactions of Mcrip2 with proteins involved in mRNA processing and turnover suggest that Mcrip2 exerts its function by regulating gene expression at the post-transcriptional level. Notably, we know little about mechanisms controlling post- transcriptional steps in adipocyte oxidative metabolism pathways. The proposed work will define the role of Mcrip2 in adipocyte basal oxidative metabolism and adrenergic responses, using gain- and loss-of function approaches in primary brown and inguinal adipocytes, and delineate the level at which Mcrip2 impacts gene expression. It will also determine the physiologic significance of Mcrip2 for mitochondrial function and adaptive thermogenesis, using a mouse model. Finally, the studies will elucidate the mechanism by which Mcrip2 impacts adipocyte biology, by defining Mcrip2 protein domains required for function and critical Mcrip2 interacting partners in basal and adrenergically stimulated adipocytes. In sum, the work will give first insights into post-transcriptional regulation of adipocyte oxidative function, and may suggest new targets and avenues for therapeutic intervention in diseases that can benefit from increases in oxidative capacity, such as obesity and obesity-related diseases.