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Obesity and metabolic disease: is adipose tissue the culprit?

Published online by Cambridge University Press:  07 March 2007

Keith N. Frayn
Keith N. Frayn
Affiliation:
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford,Oxford OX3 7LJ, UK
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Abstract

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Obesity is a risk factor for the development of type 2 diabetes and CVD. Is adipose tissue the culprit in the relationship between obesity and metabolic disease? It iscertainly possible to argue that adipose tissue function is disturbed in obesity in sucha way that adverse consequences may follow. For instance, lipolysis is down regulated, the sensitivity of lipolysis to insulin is reduced and there are disturbances in the regulation of adipose tissue blood flow. However, when examined critically these changes canbe seen as adaptations to the increased adipose tissue mass, making the situation betterrather than worse. In terms of the many peptide and other factors now known to be secreted from adipose tissue, it is easier to argue that adipose tissue is the culprit. However, for no single ‘adipokine’ is there as yet unequivocal evidence of a link between adipose tissue secretion and adverse metabolic events in other tissues. The bestdocumented of these adipokines in relation to insulin resistance is adiponectin. Here, unusually, adiponectin confers insulin sensitivity, and its secretion is down regulated in obesity. It could be again that adipose tissue has down regulated its function in an attempt to compensate for itsincreased mass, although certainly that down-regulation is too extreme. On balance, it is clear that adipose tissue is a link in the chain of events leading to metabolic disease, but in many respects it is an innocent intermediary trying to deal with the consequences of positive energy balance, the real culprit.

Keywords

Adipose tissueBlood flowInsulin resistanceLipolysis
Type
Symposium on ‘Obesity and metabolic diseases’
Information
Proceedings of the Nutrition Society , Volume 64 , Issue 1 , February 2005 , pp. 7 - 13
Copyright
Copyright © The Nutrition Society 2005

References

Aitman, TJ, Godsland, IF, Farren, B, Crook, D, Wong, HJ & Scott, J (1997) Defects of insulin action on fatty acid and carbohydrate metabolism in familial combined hyperlipidemia. Arteriosclerosis, Thrombosis and Vascular Biology 17, 748–754.CrossRefGoogle ScholarPubMed
Arita, Y, Kihara, S, Ouchi, N, Takahashi, M, Maeda, K & Miyagawa, J et al. (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochemical and Biophysical Research Communications 257, 79–83.CrossRefGoogle ScholarPubMed
Boden, G, Chen, X, Ruiz, J, White, JV & Rossetti, L (1994) Mechanisms of fatty acid-induced inhibition of glucose uptake. Journal of Clinical Investigation 93, 2438–2446.CrossRefGoogle ScholarPubMed
Boden, G, Cheung, P, Stein, TP, Kresge, K & Mozzoli, M (2002) FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. American Journal of Physiology 283, E12–E19.Google ScholarPubMed
Bogardus, C, Lillioja, S, Mott, DM, Hollenbeck, C & Reaven, G (1985) Relationship between degree of obesity and in vivo insulin action in man. American Journal of Physiology 248, E286–E291.Google ScholarPubMed
Campbell, PJ, Carlson, MG & Nurjhan, N (1994) Fat metabolism in human obesity. American Journal of Physiology 266, E600–E605.Google ScholarPubMed
Carpentier, A, Mittelman, SD, Lamarche, B, Bergman, RN, Giacca, A & Lewis, GF (1999) Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation. American Journal of Physiology 276, E1055–E1066.Google ScholarPubMed
Charles, MA, Eschwege, E, Thibult, N, Claude, JR, Warnet, JM, Rosselin, GE, Girard, J & Balkau, B (1997) The role of non-esterified fatty acids in the deterioration of glucose tolerance in Caucasian subjects: results of the Paris Prospective Study. Diabetologia 40, 1101–1106.CrossRefGoogle ScholarPubMed
Clausen, JO, Borch-Johnsen, K, Ibsen, H, Bergman, RN, Hougaard, P, Winther, K & Pedersen, O (1996) Insulin sensitivity index, acute insulin response, and glucose effectiveness in a population-based sample of 380 young healthy Caucasians. Analysis of the impact of gender, body fat, physical fitness, and life-style factors. Journal of Clinical Investigation 98, 1195–1209.CrossRefGoogle Scholar
Considine, RV, Sinha, MK, Heiman, ML, Kriauciunas, A, Stephens, TW, Nyce, MR, Ohannesian, JP, Marco, CC, McKee, LJ, Bauer, TL & Caro, JF (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New England Journal of Medicine 334, 292–295.CrossRefGoogle ScholarPubMed
Eriksson, JW, Smith, U, Waagstein, F, Wysocki, M & Jansson, PA (1999) Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients: is cellular insulin resistance a secondary phenomenon? Diabetes 48, 1572–1578.CrossRefGoogle ScholarPubMed
Ferrannini, E, Barrett, EJ, Bevilacqua, S & DeFronzo, RA (1983) Effect of fatty acids on glucose production and utilization in man. Journal of Clinical Investigation 72, 1737–1747.CrossRefGoogle ScholarPubMed
Ferrannini, E, Buzzigoli, G, Bonadonna, R, Giorico, MA, Oleggini, M, Graziadei, L, Pedrinelli, R, Brandi, L & Bevilacqua, S (1987) Insulin resistance in essential hypertension. New England Journal of Medicine 317, 350–357.CrossRefGoogle ScholarPubMed
Flatt, J-P (1972) Role of the increased adipose tissue mass in the apparent insulin insensitivity of obesity. American Journal of Clinical Nutrition 25, 1189–1192.CrossRefGoogle ScholarPubMed
Frayn, KN (2001) Adipose tissue and the insulin resistance syndrome. Proceedings of the Nutrition Society 60, 375–380.CrossRefGoogle ScholarPubMed
Frayn, KN (2002) Adipose tissue as a buffer for daily lipid flux. Diabetologia 45, 1201–1210.CrossRefGoogle ScholarPubMed
Frayn, KN, Williams, CM & Arner, P (1996) Are increased plasma non-esterified fatty acid concentrations a risk marker for coronary heart disease and other chronic diseases? Clinical Science 90, 243–253.CrossRefGoogle ScholarPubMed
Frühbeck, G, Gomez-Ambrosi, J, Muruzabal, FJ & Burrell, MA (2001) The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. American Journal of Physiology 280, E827–E847.Google Scholar
Frühbeck, G & Salvador, J (2000) Relation between leptin and the regulation of glucose metabolism. Diabetologia 43, 3–12.Google ScholarPubMed
Haffner, SM, Miettinen, H, Gaskill, SP & Stern, MP (1996) Metabolic precursors of hypertension. The San Antonio Heart Study. Archives of Internal Medicine 156, 1994–2000.CrossRefGoogle ScholarPubMed
Hokanson, JE & Austin, MA (1996) Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. Journal of Cardiovascular Risk 3, 213–219.CrossRefGoogle Scholar
Hotamisligil, GS (2003) The irresistible biology of resistin. Journal of Clinical Investigation 111, 173–174.CrossRefGoogle ScholarPubMed
Hotta, K, Funahashi, T, Arita, Y, Takahashi, M, Matsuda, M & Okamoto, Y et al. (2000) Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arteriosclerosis, Thrombosis and Vascular Biology 20, 1595–1599.CrossRefGoogle ScholarPubMed
Hotta, K, Funahashi, T, Bodkin, NL, Ortmeyer, HK, Arita, Y, Hansen, BC & Matsuzawa, Y (2001) Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50, 1126–1133.CrossRefGoogle ScholarPubMed
Insel, PA, Liljenquist, JE, Tobin, JD, Sherwin, RS, Watkins, P, Andres, R & Berman, M (1975) Insulin control of glucose metabolism in man. A new kinetic analysis. Journal of Clinical Investigation 55, 1057–1066.CrossRefGoogle Scholar
Jansson, PA, Larsson, A & Lonnroth, PN (1998) Relationship between blood pressure, metabolic variables and blood flow in obese subjects with or without non-insulin-dependent diabetes mellitus. European Journal of Clinical Investigation 28, 813–818.CrossRefGoogle ScholarPubMed
Kamohara, S, Burcelin, R, Halaas, JL, Friedman, JM & Charron, MJ (1997) Acute stimulation of glucose metabolism in mice by leptin. Nature 389, 374–377.CrossRefGoogle ScholarPubMed
Karpe, F, Fielding, BA, Ilic, V, Macdonald, IA, Summers, LKM & Frayn, KN (2002) Impaired postprandial adipose tissue blood flow response is related to aspects of insulin sensitivity. Diabetes 51, 2467–2473.CrossRefGoogle ScholarPubMed
Kelley, DE, Goodpaster, BH & Storlien, L (2002) Muscle triglyceride and insulin resistance. Annual Review of Nutrition 22, 325–346.CrossRefGoogle ScholarPubMed
Kern, PA, Ranganathan, S, Li, C, Wood, L & Ranganathan, G (2001) Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. American Journal of Physiology 280, E745–E751.Google ScholarPubMed
Koistinen, HA, Bastard, JP, Dusserre, E, Ebeling, P, Zegari, N & Andreelli, F et al. (2000) Subcutaneous adipose tissue expression of tumour necrosis factor-α is not associated with whole body insulin resistance in obese nondiabetic or in type-2 diabetic subjects. European Journal of Clinical Investigation 30, 302–310.CrossRefGoogle Scholar
Kubota, N, Terauchi, Y, Yamauchi, T, Kubota, T, Moroi, M & Matsui, J et al. (2002) Disruption of adiponectin causes insulin resistance and neointimal formation. Journal of Biological Chemistry 277, 25863–25866.CrossRefGoogle ScholarPubMed
Large, V, Reynisdottir, S, Langin, D, Fredby, K, Klannemark, M, Holm, C & Arner, P (1999) Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. Journal of Lipid Research 40, 2059–2066.CrossRefGoogle ScholarPubMed
Lehrke, M & Lazar, MA (2004) Inflamed about obesity. Nature Medicine 10, 126–127.CrossRefGoogle ScholarPubMed
Lind, L, Fugmann, A, Branth, S, Vessby, B, Millgård, J, Berne, C & Lithell, H (2000) The impairment in endothelial function induced by non-esterified fatty acids can be reversed by insulin. Clinical Science 99, 169–174.CrossRefGoogle ScholarPubMed
Ma, K, Cabrero, A, Saha, PK, Kojima, H, Li, L, Chang, BH-J, Paul, A & Chan, L (2002) Increased β-oxidation but no insulin resistance or glucose intolerance in mice lacking adiponectin. Journal of Biological Chemistry 277, 34658–34661.CrossRefGoogle ScholarPubMed
Maeda, N, Shimomura, I, Kishida, K, Nishizawa, H, Matsuda, M & Nagaretani, H et al. (2002) Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nature Medicine 8, 731–737.CrossRefGoogle ScholarPubMed
Mohamed-Ali, V, Goodrick, S, Rawesh, A, Katz, DR, Miles, JM, Yudkin, JS, Klein, S & Coppack, SW (1997) Subcutaneous adipose tissue secretes interleukin-6 but not tumor necrosis-factor-a in vivo. Journal of Clinical Endocrinology and Metabolism 82, 4196–4200.Google ScholarPubMed
Mohamed-Ali, V, Pinkney, JH & Coppack, SW (1998) Adipose tissue as an endocrine and paracrine organ. International Journal of Obesity 22, 1145–1158.CrossRefGoogle ScholarPubMed
Opie, LH & Walfish, PG (1963) Plasma free fatty acid concentrations in obesity. New England Journal of Medicine 268, 757–760.CrossRefGoogle ScholarPubMed
Oral, EA, Simha, V, Ruiz, E, Andewelt, A, Premkumar, A, Snell, P, Wagner, AJ, DePaoli, AM, Reitman, ML, Taylor, SI, Gorden, P & Garg, A (2002) Leptin-replacement therapy for lipodystrophy. New England Journal of Medicine 346, 570–578.CrossRefGoogle ScholarPubMed
Pallett, AL, Morton, NM, Cawthorne, MA & Emilsson, V (1997) Leptin inhibits insulin secretion and reduces insulin mRNA levels in rat isolated pancreatic islets. Biochemical and Biophysical Research Communications 238, 267–270.CrossRefGoogle ScholarPubMed
Pankow, JS, Duncan, BB, Schmidt, MI, Ballantyne, CM, Couper, DJ, Hoogeveen, RC & Golden, SH (2004) Fasting plasma free fatty acids and risk of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes Care 27, 77–82.CrossRefGoogle ScholarPubMed
Paolisso, G, Tataranni, PA, Foley, JE, Bogardus, C, Howard, BV & Ravussin, E (1995) A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM. Diabetologia 38, 1213–1217.CrossRefGoogle ScholarPubMed
Perez, C, Fernandez, Galaz, C, Fernandez, Agullo, T, Arribas, C, Andres, A, Ros, M & Carrascosa, JM (2004) Leptin impairs insulin signaling in rat adipocytes. Diabetes 53, 347–353.CrossRefGoogle ScholarPubMed
Petersen, KF, Oral, EA, Dufour, S, Befroy, D, Ariyan, C, Yu, C, Cline, GW, DePaoli, AM, Taylor, SI, Gorden, P & Shulman, GI (2002) Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. Journal of Clinical Investigation 109, 1345–1350.CrossRefGoogle ScholarPubMed
Pittas, AG, Joseph, NA & Greenberg, AS (2004) Adipocytokines and insulin resistance. Journal of Clinical Endocrinology and Metabolism 89, 447–452.CrossRefGoogle ScholarPubMed
Prentice, AM, Black, AE, Coward, WA, Davies, HL, Goldberg, GR, Murgatroyd, PR, Ashford, J, Sawyer, M & Whitehead, RG (1986) High levels of energy expenditure in obese women. British Medical Journal 292, 983–987.CrossRefGoogle ScholarPubMed
Randle, PJ, Garland, PB, Hales, CN & Newsholme, EA (1963) The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet i, 785–789.CrossRefGoogle Scholar
Riemens, SC, Sluiter, WJ & Dullaart, RPF (2000) Enhanced escape of non-esterified fatty acids from tissue uptake: its role in impaired insulin-induced lowering of total rate of appearance in obesity and Type II diabetes mellitus. Diabetologia 43, 416–426.CrossRefGoogle ScholarPubMed
Ruan, H & Lodish, HF (2004) Regulation of insulin sensitivity by adipose tissue-derived hormones and inflammatory cytokines. Current Opinion in Lipidology 15, 297–302.CrossRefGoogle ScholarPubMed
Ryysy, L, Häkkinen, A-M, Goto, T, Vehkavaara, S, Westerbacka, J, Halavaara, J, Yki-Järvinen, H (2000) Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49, 749–758.CrossRefGoogle ScholarPubMed
Saghizadeh, M, Ong, JM, Garvey, WT, Henry, RR & Kern, PA (1996) The expression of TNFα by human muscle. Relationship to insulin resistance. Journal of Clinical Investigation 97, 1111–1116.CrossRefGoogle ScholarPubMed
Samra, JS, Simpson, EJ, Clark, ML, Forster, CD, Humphreys, SM, Macdonald, IA & Frayn, KN (1996) Effects of epinephrine infusion on adipose tissue: interactions between blood flow and lipid metabolism. American Journal of Physiology 271, E834–E839.Google ScholarPubMed
Scherer, PE, Williams, S, Fogliano, M, Baldini, G & Lodish, HF (1995) A novel serum protein similar to C1q, produced exclusively in adipocytes. Journal of Biological Chemistry 270, 26746–26749.CrossRefGoogle ScholarPubMed
Seppälä Lindroos, A, Vehkavaara, S, Häkkinen, A-M, Goto, T, Westerbacka, J, Sovijarvi, A, Halavaara, J & Yki-Järvinen, H (2002) Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. Journal of Clinical Endocrinology and Metabolism 87, 3023–3028.CrossRefGoogle ScholarPubMed
Starkie, R, Ostrowski, SR, Jauffred, S, Febbraio, M & Pedersen, BK (2003) Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB Journal 17, 884–886.CrossRefGoogle ScholarPubMed
Steensberg, A, Fischer, CP, Sacchetti, M, Keller, C, Osada, T, Schjerling, P, van Hall, G, Febbraio, MA & Pedersen, BK (2003) Acute interleukin-6 administration does not impair muscle glucose uptake or whole-body glucose disposal in healthy humans. Journal of Physiology 548, 631–638.CrossRefGoogle ScholarPubMed
Steinberg, HO, Paradisi, G, Hook, G, Crowder, K, Cronin, J & Baron, AD (2000) Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes 49, 1231–1238.CrossRefGoogle ScholarPubMed
Steppan, CM, Bailey, ST, Bhat, S, Brown, EJ, Banerjee, RR, Wright, CM, Patel, HR, Rexford, SA & Lazar, MA (2001) The hormone resistin links obesity to diabetes. Nature 409, 307–312.CrossRefGoogle ScholarPubMed
Summers, LKM, Fielding, BA, Herd, SL, Ilic, V, Clark, ML, Quinlan, PT & Frayn, KN (1999) Use of structured triacylglycerols containing predominantly stearic and oleic acids to probe early events in metabolic processing of dietary fat. Journal of Lipid Research 40, 1890–1898.CrossRefGoogle ScholarPubMed
Summers, LKM, Fielding, BA, Ilic, V, Quinlan, PT & Frayn, KN (1998) The effect of triacylglycerol-fatty acid positional distribution on postprandial metabolism in subcutaneous adipose tissue. British Journal of Nutrition 79, 141–147.CrossRefGoogle ScholarPubMed
Summers, LKM, Samra, JS, Humphreys, SM, Morris, RJ & Frayn, KN (1996) Subcutaneous abdominal adipose tissue blood flow: variation within and between subjects and relationship to obesity. Clinical Science 91, 679–683.CrossRefGoogle ScholarPubMed
Virtanen, KA, Lönnroth, P, Parkkola, R, Peltoniemi, P, Asola, M, Viljanen, T, Tolvanen, T, Knuuti, J, Rönnemaa, T, Huupponen, R & Nuutila, P (2002) Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans. Journal of Clinical Endocrinology and Metabolism 87, 3902–3910.CrossRefGoogle ScholarPubMed
Weisberg, SP, McCann, D, Desai, M, Rosenbaum, M, Leibel, RL, Ferrante, AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. Journal of Clinical Investigation 112, 1796–1808.CrossRefGoogle ScholarPubMed
Weyer, C, Funahashi, T, Tanaka, S, Hotta, K, Matsuzawa, Y, Pratley, RE & Tataranni, PA (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. Journal of Clinical Endocrinology and Metabolism 86, 1930–1935.CrossRefGoogle ScholarPubMed
Xu, H, Barnes, GT, Yang, Q, Tan, G, Yang, D, Chou, CJ, Sole, J, Nichols, A, Ross, JS, Tartaglia, LA & Chen, H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. Journal of Clinical Investigation 112, 1821–1830.CrossRefGoogle Scholar
Yamauchi, T, Kamon, J, Waki, H, Terauchi, Y, Kubota, N & Hara, K et al. (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Medicine 7, 941–946.CrossRefGoogle ScholarPubMed
Yaspelkis, BB 3rd singh, MK, Krisan, AD, Collins, DE, Kwong, CC, Bernard, JR & Crain, AM (2004) Chronic leptin treatment enhances insulin-stimulated glucose disposal in skeletal muscle of high-fat fed rodents. Life Sciences 74, 1801–1816.CrossRefGoogle ScholarPubMed
Zhang, Y, Proenca, R, Maffei, M, Barone, M, Leopold, L & Friedman, JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.CrossRefGoogle ScholarPubMed
Zhou, YP & Grill, V (1995) Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans. Journal of Clinical Endocrinology and Metabolism 80, 1584–1590.Google ScholarPubMed