Differential Gene Expression Between Visceral and Subcutaneous Fat Depots

Abstract

Abdominal obesity has been linked to the development of insulin resistance and Type 2 diabetes mellitus (DM2). By surgical removal of visceral fat (VF) in a variety of rodent models, we prevented insulin resistance and glucose intolerance, establishing a cause-effect relationship between VF and the metabolic syndrome. To characterize the biological differences between visceral and peripheral fat depots, we obtained perirenal visceral (VF) and subcutaneous (SC) fat from 5 young rats. We extracted mRNA from the fat tissue and performed gene array hybridization using Affymetrix technology with a platform containing 9 000 genes. Out of the 1 660 genes that were expressed in fat tissue, 297 (17.9 %) genes show a two-fold or higher difference in their expression between the two tissues. We present the 20 genes whose expression is higher in VF fat (by 3 - 7 fold) and the 20 genes whose expression is higher in SC fat (by 3 - 150 fold), many of which are predominantly involved in glucose homeostasis, insulin action, and lipid metabolism. We confirmed the findings of gene array expression and quantified the changes in expression in VF of genes involved in insulin resistance (PPARγ leptin) and its syndrome (angiotensinogen and plasminogen activating inhibitor-1, PAI-1) by real-time PCR (qRT-PCR) technology. Finally, we demonstrated increased expression of resistin in VF by around 12-fold and adiponectin by around 4-fold, peptides that were not part of the gene expression platform. These results indicate that visceral fat and subcutaneous fat are biologically distinct.

Key words

Visceral Fat - Subcutaneous Fat - Leptin - Angiotensinogen - Resistin - PPARγ - Adiponectin (ACRP30) - Plasminogen Activating Inhibitor-1 (PAI-1)

References

• 1 Carey D G, Jenkins A B, Campbell L V, Freund J, Chisholm D J. Abdominal fat and insulin resistance in normal and overweight women: Direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM.  Diabetes. 1996;  45 633-638
• 2 Coon P J, Rogus E M, Drinkwater D, Muller D C, Goldberg A P. Role of body fat distribution in the decline in insulin sensitivity and glucose tolerance with age.  J Clin Endocrinol Metab. 1992;  75 1125-1132
• 3 O’Shaughnessy I M, Myers T J, Stepniakowski K, Nazzaro P, Kelly T M, Hoffmann R G, Egan B M, Kissebah A H. Glucose metabolism in abdominally obese hypertensive and normotensive subjects.  Hypertension. 1995;  26 186-192
• 4 Bjorntorp P. “Portal” adipose tissue as a generator of risk factors for cardiovascular disease and diabetes.  Arteriosclerosis. 1990;  10 493-496
• 5 Barzilai N, She L, Liu B Q, Vuguin P, Cohen P, Wang J, Rossetti L. Surgical removal of visceral fat reverses hepatic insulin resistance.  Diabetes. 1999;  48 94-98
• 6 Gabriely I, Ma X H, Yang X M, Atzmon G, Rajala M W, Berg A H, Scherer P, Rossetti L, Barzilai N. Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process?.  Diabetes. 2002;  51 2951-2958
• 7 Barzilai N, Wang J, Massilon D, Vuguin P, Hawkins M, Rossetti L. Leptin selectively decreases visceral adiposity and enhances insulin action.  J Clin Invest. 1997;  100 3105-3110
• 8 Barzilai N, Banerjee S, Hawkins M, Chen W, Rossetti L. Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat.  J Clin Invest. 1998;  101 1353-1361
• 9 Baker T K, Carfagna M A, Gao H, Dow E R, Li Q, Searfoss G H, Ryan T P. Temporal gene expression analysis of monolayer cultured rat hepatocytes.  Chem Res Toxicol. 2001;  14 1218-1231
• 10 Jacob S, Stumvoll M, Becker R, Koch M, Nielsen M, Loblein K, Maerker E, Volk A, Renn W. et al . the PPARγ2 polymorphism Pro 12 Ala is associated with better insulin sensitivity in the offspring of type 2 diabetic subjects.  Horm Metab Res. 2000;  32 413-416
• 11 Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandarino L J, DeFronzo R A. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients.  J Clin Endocrinol Metab. 2002;  87 2784-2791
• 12 Montague C T, Prins J B, Sanders L, Zhang J, Sewter C P, Digby J, Byrne C D, O’Rahilly S. Depot-related gene expression in human subcutaneous and omental adipocytes.  Diabetes. 1998;  47 1384-1391
• 13 Lefebvre A-M, Alville M, Vega N, Riou J P, van Gaal L, Auwerx J, Vidal H. Depot specific differences in adipose tissue gene expression in lean and obese subjects.  Diabetes. 1998;  47 98-103
• 14 Hansen T B, Vahl N, Jorgensen J O, Christiansen J S, Hagen C. Whole body and regional soft tissue changes in growth hormone deficient adults after one year of growth hormone treatment: a double-blind, randomized, placebo-controlled study.  Clin Endocrinol (Oxf). 1995;  43 689-696
• 15 Brummer R JM, Lonn L, Kvist H, Grangard U, Bengtsson B-A, Sjostrom L. Adipose tissue and muscle volume determination by computed tomography in acromegaly before and one year after adenomectomy. Eur.  J Clin Invest. 1993;  23 199-205
• 16 Patsch W, Oberkofler H, Esterbauer H, Breban D, Winkler C, Hell E, Krempler F. Uncoupling protein-1 mRNA expression: relation to obesity and sequence variations at the UCP-1 gene locus. Eighth international congress on obesity (Paris, France, August 29 - September 3, 1998).  Int J Obes. 1998;  22 (Suppl. 2) O19-PS6
• 17 Barzilai N, She L, Liu L, Wang J, Hu M, Vuguin P, Rossetti L. Decreased visceral adiposity accounts for leptin effect on hepatic but not peripheral insulin action.  Am J Physiol. 1999;  277 E291-E298
• 18 Gabriely I, Ma X H, Yang X M, Rossetti L, Barzilai N. Leptin resistance during aging is independent of fat mass.  Diabetes. 2002;  51 1016-1021
• 19 Ma X H, Muzumdar R, Yang X M, Gabriely I, Berger R, Barzilai N. Aging is associated with resistance to effects of leptin on fat distribution and insulin action.  J Gerontol A Biol Sci Med Sci. 2002;  57 B225-B231
• 20 Gabriely I, Yang X M, Cases J A, Ma X H, Rossetti L, Barzilai N. Hyperglycemia modulates angiotensinogen gene expression.  Am J Physiol Regul Integr Comp Physiol. 2001;  281 R795-R802
• 21 Giachetti G, Faloia E, Mariniello B, Sardu C, Camilloni M A, Guerrieri M, Montero F. Overexpression of the renin-angiotensin system in human visceral adipose tissue in normal and overweight subjects.  Am J Hypertens. 2002;  15 381-388
• 22 Alessi M C, Peiretti F, Morange P, Henry M, Nalbone G, Juhanvague I. Production of plasminogen activator inhibitor-1 by human adipose tissue. Possible link between visceral fat accumulation and vascular disease.  Diabetes. 1997;  46 860-867
• 23 Calles Escandon J, Mirza S A, Sobel B E, Schnieder D J. Induction of hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia increases plasminogen activator inhibitor-1 in blood of normal human subjects.  Diabetes. 1998;  47 290-293
• 24 Mertens I, van der Planken M, Corthouts B, Wauters M, Peiffer F, Leeuw I, van Gaal L. Visceral fat is a determinant of PAI-1 activity in diabetic and non-diabetic overweight and obese women.  Horm Metab Res. 2001;  33 602-607
• 25 Gabriely I, Yang X M, Cases J A, Ma X H, Rossetti L, Barzilai N. Hyperglycemia induces PAI-1 gene expression in adipose tissue by activation of the hexosamine biosynthetic pathway.  Atherosclerosis. 2002;  160 115-122
• 26 Steppan C M, Bailey S T, Bhat S, Brown E J, Banerjee R R, Wright C M, Patel H R, Ahima R S, Lazar M A. The hormone resistin links obesity to diabetes.  Nature. 2001;  409 307-312
• 27 Janke J, Engeli S, Gorzelniak K, Lift F C, Sharma A M. Resistin gene expression in human adipocytes is not related to insulin resistance.  Obes Res. 2002;  10 1-5
• 28 Scherer P E, Williams S, Fogliano M, Baldini G, Lodish H F. A novel serum protein similar to C1q, produced exclusively in adipocytes.  J Biol Chem. 1995;  270 26 746-26 749
• 29 Berg A H, Combs T P, Du X, Brownlee M, Scherer P E. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action.  Nat Med. 2001;  7 947-953
• 30 Combs T P, Berg A H, Obici S, Scherer P E, Rossetti L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30.  J Clin Invest. 2001;  108 1875-1881