PPARGC1 and Metabolic Disorders

The escalating global epidemic of overweight and obesity predicts a tremendous increase in the prevalence of type 2 diabetes (T2DM) in the near future. Obesity, specifically visceral obesity, is associated with insulin resistance, dyslipemia, hypertension and fatty liver. The clustering of these metabolic disturbances is termed the metabolic syndrome (MS) which is a major risk factor of coronary artery disease and stroke. Many studies in independent populations indicate that genetic factors play an important role in the etiology of obesity, T2DM and MS, but the specific factors causing the disorders and/or the modes of action are incompletely defined. Peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1a (PGC-1a, PPARGC1A) and PGC-1ß (PPARGC1B) are pivotal transcriptional regulators of key physiological pathways that coordinate mammalian energy metabolism. Like other coactivators, PGC-1a and PGC-1ß do not bind to DNA directly, but interact with nuclear receptors and/or a diverse array of other factors to control gene transcription in a tissue-specific manner and in response to various cellular signals. In rodents, PGC-1a and PGC-1ß have complementary functions in transcriptional programs of thermogenesis, gluconeogenesis, fatty acid oxidation, hepatic lipid metabolism and lipoprotein biosynthesis and mitochondrial biogenesis. Our goal is to identify specific regulatory mechanisms, whereby PGC-1a and PGC-1ß contribute to the pathogenesis of obesity, T2DM, MS, dyslipemia and hepatic steatosis. By associating the mRNA expression profile of PPARGC1A and PPARGC1B with known or putative targets in human skeletal muscle, intra- and extra- peritoneal adipose tissues and liver from slender and obese patients with or without the above metabolic disorders, potential regulatory pathways may be identified and substantiated by studies in cultured cells. Furthermore, preliminary evidence shows that liver- and skeletal muscle-specific PPARGC1A transcripts exist as well as alternatively spliced forms of PPARGC1B. We will examine the role of these alternative splice variants in the regulation of target genes and study their expression in relation to metabolic disorders. Finally, we will identify functional sequence substitutions in regulatory regions of PPARGC1s and/or their variant transcripts and examine their relevance with respect to disease phenotypes. These studies are expected to i) identify genetic factors that cause or predispose to common metabolic disorders, ii) delineate diagnostic methods for the detection of such defects, and iii) provide rational approaches for the treatment of such disorders.

The escalating global epidemic of overweight and obesity predicts a tremendous increase in the prevalence of type 2 diabetes (T2DM) in the near future. Obesity, specifically visceral obesity, is associated with insulin resistance, dyslipemia, hypertension and fatty liver. The clustering of these metabolic disturbances is termed the metabolic syndrome (MS) which is a major risk factor of coronary artery disease and stroke. Many studies in independent populations indicate that genetic factors play an important role in the etiology of obesity, T2DM and MS, but the specific factors causing the disorders and/or the modes of action are incompletely defined. Peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1a (PGC-1a, PPARGC1A) and PGC-1ß (PPARGC1B) are pivotal transcriptional regulators of key physiological pathways that coordinate mammalian energy metabolism. Like other coactivators, PGC-1a and PGC-1ß do not bind to DNA directly, but interact with nuclear receptors and/or a diverse array of other factors to control gene transcription in a tissue-specific manner and in response to various cellular signals. In rodents, PGC-1a and PGC-1ß have complementary functions in transcriptional programs of thermogenesis, gluconeogenesis, fatty acid oxidation, hepatic lipid metabolism and lipoprotein biosynthesis and mitochondrial biogenesis. Our goal is to identify specific regulatory mechanisms, whereby PGC-1a and PGC-1ß contribute to the pathogenesis of obesity, T2DM, MS, dyslipemia and hepatic steatosis. By associating the mRNA expression profile of PPARGC1A and PPARGC1B with known or putative targets in human skeletal muscle, intra- and extra- peritoneal adipose tissues and liver from slender and obese patients with or without the above metabolic disorders, potential regulatory pathways may be identified and substantiated by studies in cultured cells. Furthermore, preliminary evidence shows that liver- and skeletal muscle-specific PPARGC1A transcripts exist as well as alternatively spliced forms of PPARGC1B. We will examine the role of these alternative splice variants in the regulation of target genes and study their expression in relation to metabolic disorders. Finally, we will identify functional sequence substitutions in regulatory regions of PPARGC1s and/or their variant transcripts and examine their relevance with respect to disease phenotypes. These studies are expected to i) identify genetic factors that cause or predispose to common metabolic disorders, ii) delineate diagnostic methods for the detection of such defects, and iii) provide rational approaches for the treatment of such disorders.