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...

OBJECTIVES: Uncoupling protein 2 (UCP2) is a recently described homologue of the uncoupling protein of brown adipocytes (UCP1), which is expressed at high levels in human white adipose tissue. Studies were undertaken (1) to establish whether the expression of UCP2 mRNA varies in a depot-related manner in isolated human adipocytes, (2) to determine whether thiazolidinedione exposure in¯uences the expression of UCP2 mRNA in cultured human preadipocytes, and (3) to determine whether human UCP2 is targeted to mitochondria when transfected into mammalian cells. SUBJECTS: Abdominal subcutaneous and omental adipose tissue biopsies were obtained from adult patients undergoing elective intra-abdominal surgical procedures. MEASUREMENTS: A competitive reverse transcriptase-polymerase chain reaction (RT-PCR) was used to quantify UCP2 mRNA expression in human omental and subcutaneous adipocytes, and in cultured human preadipocytes differentiated in vitro using the thiazolidinedione, BRL49653. Chinese hamster ovary cells were transfected with a vector expressing human UCP2, and its cellular localization was determined by confocal immuno¯uorescence microscopy. RESULTS: Adipocytes isolated from human omentum consistently expressed more UCP2 mRNA than did subcutaneous adipocytes from the same subjects (mean fold difference 2.92 AE 0.44 P`0.001, n 11) with no effect of gender or body mass index being seen. BRL49653 treatment of subcutaneously, but not omentally, derived preadipocytes stimulated expression of UCP2 mRNA (5.1 AE 1.1 fold). Transfected human UCP2 was detected exclusively in mitochondria of CHO cells. CONCLUSIONS: Increased expression of UCP2 in human omental adipose tissue relative to subcutaneous adipose tissue is related to the expression levels in adipocytes per se, a ®nding which may relate to the particular functional attributes of this sub-population of adipocytes. Furthermore, BRL 49653 has site-speci®c effects of on the expression of UCP2 in human preadipocytes, a ®nding which may be relevant to the therapeutic effects of such compounds. Finally we present evidence for the mitochondrial localisation of human UCP2.

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