The short isoform of PGC-1alpha in the control of brown adipose tissue thermogenesis

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 DESCRIPTION (provided by applicant): Obesity is a global health epidemic associated with metabolic disorders such as type 2 diabetes. While white adipose tissue accumulates fat as energy storage, brown adipose tissue (BAT) dissipates energy as heat by mitochondrial uncoupling protein 1 (UCP1). Studies in rodents have shown that activation of non-shivering thermogenesis in BAT increases energy expenditure and protects against obesity. Adult humans also have functional BAT whose thermogenic capacity increases with cold exposure and decreases with age and body fat mass, suggesting that activation of BAT might be useful for treating human obesity. Efficient mitochondrial respiration through the electron transport chain (ETC) is essential for BAT thermogenesis since it provides the energy required for UCP1-mediated heat production. The ETC consists of four large multisubunit complexes (I- IV). The majority of ETC complex subunits are encoded by nuclear DNA and are imported into mitochondria, but 11 essential subunits of ETC complexes I, III, and IV are encoded by mitochondrial DNA (mtDNA). Thus, coordinated regulation of nuclear and mitochondrial genomes in response to cold is critically important for the biogenesis of functional ETC complexes. Although the basal transcription machinery of mitochondria has been identified and characterized, the regulatory mechanisms involved in mitochondrial gene expression remains an open question. We recently discovered a short isoform of PGC-1a (designated NT-PGC-1a) that is produced by alternative splicing of the PGC-1a gene. NT-PGC-1a is a functional transcriptional coactivator and its expression is highly induced by cold in BAT. Cold-induced NT-PGC-1a translocates to the nucleus and drives the expression of UCP1 and a number of mitochondrial genes. Surprisingly, while PGC-1a resides in the nucleus, a small fraction of NT-PGC-1a localizes to mitochondria and is recruited to the mtDNA, raising the possibility that mitochondrial NT-PGC-1a directly regulates mtDNA transcription to increase mtDNA-encoded ETC gene expression in response to cold. In this research project, we aim to test our hypothesis that simultaneous localization of NT-PGC-1a in both nucleus and mitochondria is the mechanism that coordinates nuclear and mitochondrial gene expression, contributing to cold-induced mitochondrial adaptation and thermogenesis. Aim 1 is to evaluate the role of NT-PGC-1a in the regulation of mtDNA transcription. Aim 2 is to determine the mechanism by which NT-PGC-1a activity is increased in the nucleus and mitochondria during cold stress. Aim 3 is to evaluate the effects of NT-PGC-1a deletion on mitochondrial respiratory activity and adaptive thermogenesis in vivo. This research will uncover the previously unappreciated role of NT-PGC-1a in regulating mitochondrial transcription in brown adipocytes and will highlight the importance of this process for adaptive thermogenesis and energy expenditure in BAT.