Adipose Triglyceride Lipase Gene Expression in Human Visceral Obesity

Abstract

In comparison to subcutaneous (SC) fat, visceral adipose tissue is more sensitive to catecholamine-induced lipolysis and less sensitive to the antilipolytic effects of insulin. Variation in the expression of lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) have been reported. We therefore hypothesized that expression of adipose triglyceride lipase (ATGL) is different in visceral and SC depot and investigated whether ATGL mRNA expression is related to obesity, fat distribution and insulin sensitivity. ATGL, LPL, and HSL mRNA expression was measured in 85 paired samples of omental and subcutaneous adipose tissue in normal glucose tolerant lean and obese individuals. In addition, we included a subgroup of obese (BMI >30 kg/m²) individuals with either impaired or preserved insulin sensitivity determined by euglycemic-hyperinsulinemic clamps. ATGL mRNA levels are significantly decreased in insulin resistant obese subjects. Independently of body fat mass, omental ATGL mRNA correlates with fasting insulin concentration, glucose uptake during the steady state of the clamp and HSL mRNA expression. In obese, but not in lean subjects, LPL and HSL mRNA expression was significantly higher in omental compared to SC fat. In both depots, HSL mRNA was significantly lower in obese individuals. Visceral HSL mRNA expression is closely related to adipocyte size and fasting plasma insulin concentrations, whereas visceral fat area significantly predicts visceral LPL mRNA expression. ATGL mRNA expression is not significantly different between omental and SC fat. HSL, but not ATGL mRNA expression is closely related to individual and regional differences in adipocyte size. Impaired insulin sensitivity was associated with decreased ATGL and HSL mRNA expression, independently of body fat mass and fat distribution.

Key words

LPL - HSL - ATGL - visceral obesity - type 2 diabetes

References

• 1 Arner P, Langin D. The role of neutral lipases in human adipose tissue lipolysis.  Curr Opin Lipidol. 2007;  18 246-250
• 2 Berger JJ, Barnard RJ. Effect of diet on fat cell size and hormone-sensitive lipase activity.  J Appl Phys. 1999;  87 227-232
• 3 Berndt J, Klöting N, Kralisch S, Kovacs P, Fasshauer M, Schon MR, Stumvoll M, Blüher M. Plasma visfatin concentrations and fat depot-specific mRNA expression in humans.  Diabetes. 2005;  54 2911-2916
• 4 Blüher M, Unger R, Rassoul F, Richter V, Paschke R. Relation between glycaemic control, hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or type II diabetes.  Diabetologia. 2002;  45 210-216
• 5 Bolinder J, Kager L, Ostman J, Arner P. Differences at the receptor and postreceptor levels between human omental and subcutaneous adipose tissue in the action of insulin on lipolysis.  Diabetes. 1983;  32 117-123
• 6 Czech MP. Cellular basis of insulin insensitivity in large rat adipocytes.  J Clin Invest. 1976;  57 1523-1532
• 7 Fronzo RA De, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance.  Am J Phys. 1979;  237 214-223
• 8 Fischer J, Lefevre C, Morava E, Mussini JM, Laforet P, Negre-Salvayre A, Lathrop M, Salvayre R. The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy.  Nat Genet. 2007;  39 28-30
• 9 Frayn KN, Coppack SW, Fielding BA, Humphreys SM. Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo: implications for the control of fat storage and fat mobilization.  Adv Enzyme Regul. 1995;  35 163-178
• 10 Frayn KN, Shadid S, Hamlani R, Humphreys SM, Clark ML, Fielding BA, Boland O, Coppack SW. Regulation of fatty acid movement in human adipose tissue in the postabsorptive-to-postprandial transition.  Am J Phys. 1994;  266 E308-E317
• 11 Fried SK, Kral JG. Sex differences in regional distribution of fat cell size and lipoprotein lipase activity in morbidly obese patients.  Int J Obes. 1987;  11 129-140
• 12 Fried SK, Russell CD, Grauso NL, Brolin RE. Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men.  J Clin Invest. 1993;  92 2191-2198
• 13 Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, Kratky D, Wagner EF, Klingenspor M, Hoefler G, Zechner R. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase.  Science. 2006;  312 734-737
• 14 Jocken JW, Langin D, Smit E, Saris WH, Valle C, Hul GB, Holm C, Arner P, Blaak EE. Adipose triglyceride lipase and hormone-sensitive lipase protein expression is decreased in the obese insulin-resistant state.  J Clin Endocrinol Metab. 2007;  92 2292-2299
• 15 Kershaw EE, Hamm JK, Verhagen LA, Peroni O, Katic M, Flier JS. Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin.  Diabetes. 2006;  55 148-157
• 16 Kralisch S, Klein J, Lossner U, Blüher M, Paschke R, Stumvoll M, Fasshauer M. Isoproterenol, TNF, and insulin downregulate adipose triglyceride lipase in 3T3-L1 adipocytes.  Mol Cell Endocrinol. 2005;  240 43-49
• 17 Laborda J. 36B4 cDNA used as an estradiol-independent mRNA control is the cDNA for human acidic ribosomal phosphoprotein PO.  Nucl Acids Res. 1991;  19 3998
• 18 Langin D, Dicker A, Tavernier G, Hoffstedt J, Mairal A, Ryden M, Arner E, Sicard A, Jenkins CM, Viguerie N, Harmelen V van, Gross RW, Holm C, Arner P. Adipocyte lipases and defect of lipolysis in human obesity.  Diabetes. 2005;  54 3190-3197
• 19 Large V, Reynisdottir S, Langin D, Fredby K, Klannemark M, Holm C, Arner P. Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects.  J Lipid Res. 1999;  40 2059-2066
• 20 Lass A, Zimmermann R, Haemmerle G, Riederer M, Schoiswohl G, Schweiger M, Kienesberger P, Strauss JG, Gorkiewicz G, Zechner R. Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome.  Cell Metab. 2006;  3 309-319
• 21 Lefebvre AM, Laville M, Vega N, Riou JP, Gaal L van, Auwerx J, Vidal H. Depot-specific differences in adipose tissue gene expression in lean and obese subjects.  Diabetes. 1998;  47 98-103
• 22 Mairal A, Langin D, Arner P, Hoffstedt J. Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity.  Diabetologia. 2006;  49 1629-1636
• 23 Marin P, Andersson B, Ottosson M, Olbe L, Chowdhury B, Kvist H, Holm G, Sjostrom L, Bjorntorp P. The morphology and metabolism of intraabdominal adipose tissue in men.  Metabolism. 1992;  41 1242-1248
• 24 Montague CT, O'Rahilly S. The perils of portliness: causes and consequences of visceral adiposity.  Diabetes. 2000;  49 883-888
• 25 Montague CT, Prins JB, Sanders L, Zhang J, Sewter CP, Digby J, Byrne CD, O'Rahilly S. Depot-related gene expression in human subcutaneous and omental adipocytes.  Diabetes. 1998;  47 1384-1391
• 26 Ramis JM, Bibiloni B, Moreiro J, Garcia-Sanz JM, Salinas R, Proenza AM, Llado I. Tissue leptin and plasma insulin are associated with lipoprotein lipase activity in severely obese patients.  J Nutr Biochem. 2005;  16 279-285
• 27 Ramis JM, Salinas R, Garcia-Sanz JM, Moreiro J, Proenza AM, Llado I. Depot- and gender-related differences in the lipolytic pathway of adipose tissue from severely obese patients.  Cell Phys Biochem. 2006;  17 173-180
• 28 Rebuffe-Scrive M, Andersson B, Olbe L, Bjorntorp P. Metabolism of adipose tissue in intraabdominal depots of nonobese men and women.  Metabolism. 1989;  38 453-458
• 29 Reynisdottir S, Dauzats M, Thorne A, Langin D. Comparison of hormone-sensitive lipase activity in visceral and subcutaneous human adipose tissue.  J Clin Endocrinol Metab. 1997;  82 4162-4166
• 30 Ryden M, Jocken J, Harmelen V van, Dicker A, Hoffstedt J, Wiren M, Blomqvist L, Mairal A, Langin D, Blaak E, Arner P. Comparative studies of the role of hormone-sensitive lipase and adipose triglyceride lipase in human fat cell lipolysis.  Am J Physiol Endocrinol Metab. 2007;  292 E1847-1855
• 31 Schoenborn V, Heid IM, Vollmert C, Lingenhel A, Adams TD, Hopkins PN, Illig T, Zimmermann R, Zechner R, Hunt SC, Kronenberg F. The ATGL gene is associated with free fatty acids, triglycerides, and type 2 diabetes.  Diabetes. 2006;  55 1270-1275
• 32 Steinberg GR, Kemp BE, Watt MJ. Adipocyte triglyceride lipase expression in human obesity.  Am J Physiol Endocrinol Metab. 2007; 
• 33 Tchernof A, Belanger C, Morisset AS, Richard C, Mailloux J, Laberge P, Dupont P. Regional differences in adipose tissue metabolism in women: minor effect of obesity and body fat distribution.  Diabetes. 2006;  55 1353-1360
• 34 Vidal H. Gene expression in visceral and subcutaneous adipose tissues.  Ann Med. 2001;  33 547-555
• 35 Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome.  Endocr Rev. 2000;  21 697-738
• 36 Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase.  Science. 2004;  19 ((306)) 1383-1386

Correspondence