Depot-Specific Differences in Adipose Tissue Gene Expression in Lean and Obese Subjects Anne-Marie Lefebvre, Martine Laville, Nathalie Vega, Jean Paul Riou, Luc van Gaal, Johan Auwerx, and Hubert Vidal Intra-abdominal and subcutaneous adipose tissue dis- play important metabolic differences that underlie the association of visceral, but not subcutaneous, fat with obesity-related cardiovascular and metabolic problems. Because the molecular mechanisms contributing to these differences are not yet defined, we compared by reverse transcription-polymerase chain reaction the expression of 15 mRNAs that encode proteins of known importance in adipocyte function in paired omental and subcutaneous abdominal biopsies. No difference in mRNA expression between omental and subcutaneous adipose tissue was observed for hormone sensitive lipase, lipoprotein lipase, 6-phosphofructo-l-kinase, insulin receptor substrate 1, p85a regulatory subunit of phosphatidylinositol-3-kinase, and Rad. Total amount of insulin receptor expression was significantly higher in omental adipose tissue. Most of this increase was accounted for by expression of the differentially spliced insulin receptor lacking exon 11, which is con- sidered to transmit the insulin signal less efficiently than the insulin receptor with exon 11. Perhaps consis- tent with a less efficient insulin signaling, a twofold reduction in GLUT4, glycogen synthase, and leptin mRNA expression was observed in omental adipose tis- sue. Finally peroxisome proliferator activated recep- tor-Y (PPAR-Y) mRNA levels were significantly lower in visceral adipose tissue in subjects with a BMI <30 kg/m 2 , but not in obese subjects, indicating that relative PPAR-Y expression is increased in omental fat in obe- sity. This suggests that altered expression of PPAR-Y might play a role in adipose tissue distribution and expansion. Diabetes 47:98-103, 1998 I ntra-abdominal body fat accumulation is an indepen- dent risk factor of obesity-related health problems, including NIDDM, cardiovascular disease, hyperten- sion, and hyperlipidemia, and is associated with a significant increase in overall morbidity and mortality (1,2). From INSERM U.325, Departement d'Athe"rosclerose (A.-M.L, J.A.), Insti- tut Pasteur, Lille; INSERM U.449 and Centre de Recherche en Nutrition Humaine de Lyon (M.L., N.V., J.P.R., H.V.), Faculty de Medecine R. Laennec, Lyon, France; and University Hospital UIA (L.V.G.), Edegen, Belgium. Address correspondence and reprint requests to Dr. Hubert Vidal, INSERM U 449, Faculte" de Medecine R. Laennec, Rue G. paradin, F-69373 Lyon Cedex 08, France. E-mail: vidal@cimac-res.univ-lyonl.fr. Received for publication 8 August 1997 and accepted in revised form 24 September 1997. GS, glycogen synthase; HSL, hormone sensitive lipase; IRS-1, insulin receptor substrate 1; LPL, lipoprotein lipase; PCR, polymerase chain reac- tion; PFK-1, 6-phosphofructo-l-kinase; PI, phosphatidylinositol; PPAR, per- oxisome proliferator activated receptor; Rad, protein Ras associated with diabetes; RT, reverse transcription. The mechanisms responsible for the association between intra-abdominal fat accumulation and health outcomes are not well known, but several possible factors might be implicated. Visceral fat (mesenteric and omental adipose tissues) is drained into the portal venous system, leading to a direct supply of free fatty acids and other secreted products of adipocytes to the liver (3). In addition to the localization of the tissue, the metabolic consequences of visceral obesity might be related to specific differences in the properties of the adipocytes. Several lines of evidence indicate that adipocytes can function as endocrine cells, producing not only fatty acids but also several bioactive peptides (4). Production of such secreted signaling molecules might be profoundly dif- ferent between adipocytes in different adipose tissue depots. For example, omental adipocytes were recently shown to express more plasminogen activator inhibitor 1 than subcu- taneous adipocytes, providing a possible link between visceral fat and vascular disease (5,6). Moreover, leptin, the adipocyte-specific product of ob gene that plays a major role in the control of body weight in rodents (7), is expressed more in adipocytes from the subcutaneous depots (8,9). Finally, metabolism is also somewhat different in adipocytes that originate from superficial or visceral depots. For example, omental adipocytes have been shown to possess higher cat- echolamine-induced lipolytic activity than subcutaneous cells (10,11). In addition, resistance to the antilipolytic action of insulin is more pronounced in omental adipocytes (12), a difference that has been attributed, at least in part, to a decrease in insulin receptor affinity (12). Although depot-specific differences in the intrinsic prop- erties of adipocytes are well established (5,6,8-12), little is known regarding the mechanisms leading to these differ- ences. Distinct regulations of specific key genes could be involved. In the present study, we compared the levels of 15 mRNAs that encode proteins of known importance in adipocyte metabolism and function in paired omental and abdominal subcutaneous adipose tissue biopsies from lean and obese humans. We specifically investigated the expres- sion of the genes that code for 1) the lipoprotein lipase (LPL) and the hormone sensitive lipase (HSL), two key enzymes controlling important aspects of fatty acid metabolism in adipocytes; 2) the insulin-sensitive GLUT 4, glycogen synthase (GS), and 6-phosphofructo-l-kinase (PFK-1) that catalyze important steps of intracellular glucose metabolism; 3) the two insulin receptor variants (with and without exon 11), insulin receptor substrate 1 (IRS-1), the p85a regulatory sub- unit of phosphatidylinositol (PI) 3-kinase (PI 3-kinase), and the protein Ras associated with diabetes (Rad), that represent some of the main components of the insulin signaling cascade; and 4) leptin, which is already known to be less expressed in 98 DIABETES, VOL. 47, JANUARY 1998