Role of energy metabolism in the brown fat program

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

? DESCRIPTION (provided by applicant): We propose that mitochondrial respiration is a potent transcriptional regulator of oxidative and thermogenic genes expression. This proposal will define the biological relevance of this transcriptional control, the signals that mitochondria use o govern transcription and the subsequent transcriptional events in the nucleus that regulate oxidative and thermogenic gene expression. Due to its fat burning capacity, brown/beige adipose tissue (hereafter referred to as brown fat) may prove promising in controlling obesity and type 2 diabetes. Fueled by lipid oxidation, mitochondria are engines of heat that exploit uncoupled respiration via induction and activation of oxidative and thermogenic gene programs. Under thermoneutral conditions, brown fat adopts a lipid storage phenotype, but when activated by cold or beta-agonists, it adopts a thermogenic phenotype. The transcriptional pathways that govern these two metabolic states are under intense study in order to identify novel pathways amenable to therapeutic application. From a biochemical perspective, mitochondrial respiration plays a crucial role in determining the metabolic state of brown fat. Our preliminary data indicate that the role of mitochondrial respiration extends well beyond biochemical metabolic control. We hypothesize that the status of mitochondrial respiratory capacity governs transcription of oxidative and thermogenic genes. Specifically, we propose that impaired respiratory capacity is a transcriptional checkpoint for oxidative and thermogenic gene expression, whereas increased respiratory capacity is a transcriptional trigger. Our preliminary data has also identified the signal that mitochondrial respiration uses to control nuclear transcription. Because perturbation of the mitochondrial signal may differ depending on how mitochondrial respiration is impaired, our findings may explain why some respiratory defects have differential effects on thermogenic gene expression. Finally, we have identified key transcription factors that are influenced by the mitochondrial signal. Two Specific Aims will test our hypothesis: (1) Determine the biological and therapeutic implications of mitochondrial respiratory capacity in oxidative and thermogenic gene control; (2) Determine how the mitochondrial respiratory checkpoint signals and dictates oxidative and thermogenic gene expression.