Expression of the thermogenic nuclear hormone receptor coactivator PGC-1α is reduced in the adipose tissue of morbidly obese subjects

Abstract

Peroxisome proliferator-activated receptor gamma coactivator 1a (PGC1a) is an accessory protein which can potentiate the transcriptional activation function of many nuclear hormone receptors. Its tissue distribution and physiological studies suggest that its principal in vivo roles are to promote cold-induced thermogenesis, mitochondrial biogenesis, hepatic gluconeogenesis, and fatty acid b-oxidation. It is expressed in the white adipose tissue of both humans and rodents, and in rodents it has been suggested to mediate in part the leptin-induced conversion of white adipocytes from fat storing to fat oxidising cells. In this study, quantitative real-time PCR has been used in human tissue to demonstrate that (1) PGC1a mRNA levels in subcutaneous fat are three-fold lower in morbidly obese than in slim subjects; (2) there are no differences in PGC1a mRNA between omental and subcutaneous mature adipocytes; (3) there is a robust induction of PGC1a expression during subcutaneous human preadipocyte differentiation ex vivo. Whether low PGC1a expression is a prelude to the development of obesity, or a consequence of that obesity, attempts to upregulate endogenous white adipose tissue expression may prove a valuable new avenue to explore in obesity therapy. Keywords: PGC1; white adipose tissue; preadipocyte; adipocyte; obesity Peroxisome proliferator-activated receptor gamma coactivator 1a (PGC1a) was first identified as a coactivator of PPARg in vitro, 1 although subsequent studies have revealed it to be promiscuous in such systems, able to coactivate PPARa, PPARd, the oestrogen receptor, thyroid hormone receptor, and hepatic nuclear factor 4a (HNF4a) among others. It is most highly expressed in brown adipose tissue, the heart and skeletal muscle, and has been shown to be upregulated during cold exposure in rodents. Further functional studies have elucidated its central role in coordinating adaptive thermogenesis through increased mitochondrial biogenesis and uncoupled oxidative metabolism. 2 More recently, initial rodent expression data were added to by the demonstration of a strong induction of PGC1a expression in the liver during fasting, when it has been shown to act in concert with the glucocorticoid receptor, CREB, and HNF4a to stimulate gluconeogenesis, 3,4 and with CREB and HNF4a to stimulate fatty acid oxidation. 5 Thus, altering PGC1a activity has emerged as a parsimonious strategy for influencing complex programmes of gene expression in response to external stimuli in a cell-and tissue-specific manner.PGC1a expression in white adipose tissue is low in both rodents and humans, where it is around 10% of that in liver. Although the small index study found relative suppression of PGC1a mRNA in the skeletal muscle of obese humans, no difference was found in WAT expression. 6 However, recent work in rodents has shown that hyperleptinaemia results in a dramatic decrease of white adipose tissue due to increased b oxidation, attributed to increased expression of Moreover, using a range of transgenic, pharmacological, a...

Development of insulin resistance in mice lacking PGC-1α in adipose tissues

“…Individuals with type 2 diabetes exhibit reduced PGC-1α gene expression in adipose tissue (25,26). Whether this downregulation is a consequence of the disease or actively contributes to disease pathogenesis has not been clear.…”

“…In addition, reduced adipose PGC-1α and an association between reduced PGC-1α mRNA levels and insulin resistance have been found in human subjects (25,26). Adipose mitochondria play an important role in fatty acid oxidation (FAO) and adaptive thermogenesis, key adipose-specific metabolic pathways that are regulated by PGC-1α (27).…”

Obesity and polymorphisms in genes regulating human adipose tissue

“…125 PGC1A is expressed at low levels in human adipose tissue and mRNA levels are reduced in morbid obesity. 126,127 SNPs in the PGC1A gene have been reported to be associated with obesity in Austrian women. 128 PPARG coactivator 1B (PGC1B) is a recently discovered homologue of PGC1A, which, like PGC1A, in experimental animals induces expression of genes involved in oxidative phosphorylation.…”

Lipodystrophy in HIV 1-infected patients: lessons for obesity research

“…The expression of the master regulator of mitochondriogenesis, peroxisome proliferator-activated receptor-coactivator-1a (PGC-1a), has been reported to be reduced in adipose tissue from obese patients. 26 Other authors found a downregulation of expression of mitochondrial electron transport (OXPHOS) genes preferentially in visceral adipose tissue of obese patients developing type 2 diabetes. 27 In mice, weight gain has been associated with the downregulation of OXPHOS genes in visceral adipose tissue, 28 and in ob/ob mice, an animal model of obesity, there is reduced mtDNA in visceral adipose tissue.…”