PGC-1 coactivators in the control of energy metabolism

Chronic disruption of energy balance, where energy intake exceeds expenditure, is a major risk factor for the development of metabolic syndrome. The latter is characterized by a constellation of symptoms including obesity, dyslipidemia, insulin resistance, hypertension, and nonalcoholic fatty liver disease. Altered expression of genes involved in glucose and lipid metabolism as well as mitochondrial oxidative phosphorylation has been implicated in the pathogenesis of these disorders. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators is emerging as a hub linking nutritional and hormonal signals and energy metabolism. PGC-1 alpha and PGC-1 beta are highly responsive to environmental cues and coordinate metabolic gene programs through interaction with transcription factors and chromatin-remodeling proteins. PGC-1 alpha has been implicated in the pathogenic conditions including obesity, type 2 diabetes, neurodegeneration, and cardiomyopathy, whereas PGC-1 beta plays an important role in plasma lipoprotein homeostasis and serves as a hepatic target for niacin, a potent hypotriglyceridemic drug. Here, we review recent advances in the identification of physiological and pathophysiological contexts involving PGC-1 coactivators, and also discuss their implications for therapeutic development.