Differences in Adiponectin Protein Expression: Effect of Fat Depots and Type 2 Diabetic Status

Abstract

Adiponectin is an adipocyte-derived hormone associated with insulin sensitivity and atherosclerotic risk. As central rather than gluteofemoral fat is known to increase the risk of type 2 diabetes and cardiovascular disease, we investigated the mRNA and protein expression of adiponectin in human adipose tissue depots. RNA was extracted from 46 human adipose tissue samples from non-diabetic subjects aged 44.33 ± 12.4 with a BMI of 28.3 ± 6.0 (mean ± SD). The samples were as follows: 21 abdominal subcutaneous, 13 omentum, 6 thigh; samples were also taken from diabetic subjects aged 66.6 ± 7.5 with BMI 28.9 ± 3.17; samples were: 6 abdominal subcutaneous; 3 thigh. Quantitative PCR and Western analysis was used to determine adiponectin content. Protein content studies determined that when compared with non-diabetic abdominal subcutaneous adipose tissue (Abd Sc AT) (values expressed as percentage relative to Abd Sc AT -100 %). Adiponectin protein content was significantly lower in non-diabetic omental AT (25 ± 1.6 %; p < 0.0001, n = 6) and in Abd Sc AT from diabetic subjects (36 ± 1.5 %; p < 0.0001, n = 4). In contrast, gluteal fat maintained high adiponectin protein content from non-diabetic patients compared with diabetic patients. An increase in BMI was associated with lower adiponectin protein content in obese ND Abd Sc AT (25 ± 0.4 %; p < 0.0001). These findings were in agreement with the mRNA expression data. In summary, this study indicates that adiponectin protein content in non-diabetic subjects remains high in abdominal subcutaneous fat, including gluteal fat, explaining the high serum adiponectin levels in these subjects. Omental fat, however, expresses little adiponectin. Furthermore, abdominal and gluteal subcutaneous fat appears to express significantly less adiponectin once diabetic status is reached. In conclusion, the adipose tissue depot-specific expression of adiponectin may influence the pattern of serum adiponectin concentrations and subsequent disease risk.

AdipoQ - Acrp30 - Adipose Tissue - Abdominal - Gluteal - Type 2 Diabetes

References

• 1 Haffner S M, Karhappa P, Mykkanen L, Laasko M. Insulin resistance, body fat distrubtion, and sex hormones in men.  Diabetes. 1994;  43 212-219
• 2 Despres J P, Moorjani S, Luipen P J, Tremblay A, Nadeau A, Bouchard C. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease.  Arteriosclerosis. 1990;  10 497-511
• 3 Matthaei S, Stumvoll M, Kellerer M, Haring H U. Pathophysiology and pharmacological treatment of insulin resistance.  Endocr Rev. 2000;  21 585-618
• 4 Spiegelman B M, Flier J S. Obesity and the regulation of energy balance.  Cell. 2001;  104 531-543
• 5 Kappes A, Loffler G. Influences of Ionomycin, dibutyryl-cycloAMP and tumour necrosis factors-alpha on intracellular amount of secretion of apM1 in differentiating primary human preadipocytes.  Horm Metab Res. 2000;  32 548-554
• 6 Saltiel A R, Kahn C R. Insulin signalling and the regulation of glucose and lipid metabolism.  Nature. 2001;  414 799-806
• 7 Bastelica D, Morange P, Berhet B, Borghi H, Lacroix O, Grino M, Juhan-Vague I, Alessi M C. Stromal cells are the main plasminogen activator inhibitor-1-producing cells in human fat: evidence of differences between visceral and subcutaneous deposits.  Arterioscler Thromb Vasc Biol. 2002;  22 173-178
• 8 Hotamisligil G S, Arner P, Caro J F, Atkinson R L, Spiegelman B M. Increased adipose tissue expression of tumor necrosis factor α in human obesity and insulin resistance.  J Clin Invest. 1995;  95 2409-2415
• 9 Freidman J M, Halaas J L. Leptin and the regulation of body weight in mammals.  Nature. 1998;  395 763-770
• 10 Folli F, Kahn C R, Hansen H, Bouchie J L, Feener E P. Angiotensin II inhibits insulin signalling in aortic smooth muscle cells at multiple levels. A potential role for serine phosphorylation in insulin/angiotensin II crosstalk.  J Clin Invest. 1997;  100 2158-2169
• 11 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
• 12 Berg A H, Combs T P, Scherer P E. ACRP30/adiponectin: An adipokine regulating glucose and lipid metabolism.  Trends Endocrinol Metab. 2002;  13 84-89
• 13 Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (Adipose Most abundant gene Transcript 1).  Biochem Biophys Res Commun. 1996;  221 286-289
• 14 Shapiro L, Scherer P E. The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor.  Curr Biol. 1998;  8 335-338
• 15 Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahasi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Murguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanfusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.  Arterioscler Thromb Vas Biol. 2000;  20 1595-1599
• 16 Lindsay R S, Funahashi T, Hanson R L, Matsuzawa Y, Tanaka S, Tataranni P A, Knowler W C, Krakoff J. Adiponectin and development of type 2 diabetes in the Pima Indian population.  Lancet. 2002;  360 57-58
• 17 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyako K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.  Biochem Biophys Res Commun. 1999;  257 79-83
• 18 Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin.  Circulation. 1999;  100 2473-2476
• 19 Okamoto Y, Artia Y, Nishida M, Muraguchi M, Ouchi N, Takahashi M, Igura T, Inui Y, Kihara S, Nakamura T, Yamashita S, Miyagawa J, Funahashi T, Matsuzawa Y. An adipocyte-derived plasma protein adiponectin adheres to injured vascular walls.  Horm Metab Res. 2000;  32 47-50
• 20 Fruebis J, Tsao T S, Javorschi S, Ebbts-Reed D, Erickson M R, Yen F T, Bihain B E, Lodish H F. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.  Proc Natl Acad Sci USA. 2001;  98 2005-2010
• 21 Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota H, Hara K, Mori Y, Ide T, Murakami K, Tsubiyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Retman M L, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipotrophy and obesity.  Nat Med. 2001;  7 941-946
• 22 Berg A H, Combs T P, Du X, Brownless M, Scherer P E. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action.  Nat Med. 2001;  7 947-953
• 23 Combs T P, Berg A H, Obici S, Scherer P E, Rossetti L J. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30.  Clin Invest. 2001;  108 1875-1881
• 24 Scherer P E, Williams S, Fogliano M, Baldini G, Lodish H F. A novel serum protein similar to Clq, produced exclusively in adipocytes.  J Biol Chem. 1995;  270 26746-26749
• 25 Nakano Y, Tobe T, Choi-Miura N H, Mazda T, Tomita M. Isolation and characterisation of GBP28, a novel gelatain-binding protein purified from human plasma.  J Biochem. 1996;  120 803-812
• 26 Statnick M A, Beavers L S, Conner L J, Corominola H, Johnson D, Hammond C D, Rafaeloff-Phail R, Seng T, Suter T M, Sluka J P, Ravussin E, Gadski R A, Caro J F. Decreased expression of apM1 in omental and subcutaneous adipose tissue of humans with type 2 diabetes.  Int J Exp Diabetes Res. 2000;  1 81-88
• 27 Halleux C M, Takahashi M, Delporte M L, Detry R, Funahashi T, Matsuzawa Y, Brichard S M. Secretion of adiponectin and regulation of apM1 gene expression in human visceral adipose tissue.  Biochem Bipohys Res Comm. 2001;  288 1102-1107
• 28 McTernan P G, McTernan C L, Chetty R, Jenner K, Fisher f M, Lauer M N, Crocker J, Barnett A H, Kumar S. Increased resistin gene and protein expression in human abdominal adipose tissue.  J Clin Endocrinol Metab. 2002;  87 2407-2410
• 29 Bradford M M. A rapid and sensitive method for the quantitation of microgram quantities of protein utlising the principle of protein-dye binding.  Anal Biochem. 1976;  72 807-811
• 30 McTernan P G, Sheppard M C, Williams G R. Hormone-induced changes in nuclear receptor stoichiometry in HL60 cells correlate with induction of monocyte or neutrophil differentiation.  J Endocrinol. 1998;  156 135-148
• 31 McTernan P G, Harte A L, Anderson L A, Green A, Holder J, Smith S A, Barnett A H, Eggo M, Kumar S. Insulin and rosiglitazone regulation of lipolysis and lipogenesis in human adipose tissue in vitro.  Diabetes. 2002;  51 1493-1498
• 32 McTernan C L, McTernan P G, Harte A L, Levick P, Barnett A H, Kumar S. Resistin-The link between central obesity and type 2 diabetes.  Lancet. 2002;  35 46-47
• 33 Maeda N, Takahashi M, Funahashi T, Kihara S, Nishzawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein.  Diabetes. 2001;  50 2904-2909
• 34 Kissebath A H, Sonnenberg G E, Myklebust J, Goldstein M, Broman K, James R G, Marks J A, Krakower G R, Jocob H J, Weber J, Martin L, Blangero J, Commuzzie A G. Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome.  Proc Natl Acad Sci USA. 2001;  97 14 478-14 483
• 35 Kondo H, Shimoura I, Matsukawa Y, Kumada M, Takahashi M, Matsuda M, Ouchi N, Kihara S, Kawamoto T, Sumitsuji S, Funahashi T, Matsuzawa Y. Association of adiponectin mutation with type 2 diabetes. A candidate gene for the insulin resistance syndrome.  Diabetes. 2002;  50 2325-2328
• 36 Hu E, Liang P, Spiegelman B M. AdipoQ is a novel adipose-specific gene dysregulated in obesity.  J Biol Chem. 2002;  271 10 697-10 703
• 37 Stefan N, Vozarova B, Funahashi T, Matsuzawa Y, Weyer C, Lindsay R S, Youngren J F, Havel P J, Prately R E, Bogardus C, Tataranni P A. Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans.  Diabetes. 2002;  50 1884-1888
• 38 Depres J P, Moorjani S, Luipen P J, Tremblay A, Nadeau A, Bouchard C. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease.  Arteriosclerosis. 1990;  10 497-511