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Adipose tissue and the insulin resistance syndrome

Published online by Cambridge University Press:  05 March 2007

Keith N. Frayn*
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Infirmary, Oxford OX2 6HE, UK
Corresponding Author: Professor Keith Frayn, fax +44 1865 224652, email
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Obesity is associated with insulin resistance. Insulin resistance underlies a constellation of adverse metabolic and physiological changes (the insulin resistance syndrome) which is a strong risk factor for development of type 2 diabetes and CHD. The present article discusses how accumulation of triacylglycerol in adipocytes can lead to deterioration of the responsiveness of glucose metabolism in other tissues. Lipodystrophy, lack of adipose tissue, is also associated with insulin resistance. Any plausible explanation for the link between excess adipose tissue and insulin resistance needs to be able to account for this observation. Adipose tissue in obesity becomes refractory to suppression of fat mobilization by insulin, and also to the normal acute stimulatory effect of insulin on activation of lipoprotein lipase (involved in fat storage). The net effect is as though adipocytes are ‘full up’ and resisting further fat storage. Thus, in the postprandial period especially, there is an excess flux of circulating lipid metabolites that would normally have been ‘absorbed’ by adipose tissue. This situation leads to fat deposition in other tissues. Accumulation of triacylglycerol in skeletal muscles and in liver is associated with insulin resistance. In lipodystrophy there is insufficient adipose tissue to absorb the postprandial influx of fatty acids, so these fatty acids will again be directed to other tissues. This view of the link between adipose tissue and insulin resistance emphasises the important role of adipose tissue in ‘buffering’ the daily influx of dietary fat entering the circulation and preventing excessive exposure of other tissues to this influx.

Symposium on ‘New perspectives on adipose tissue function’
Copyright © The Nutrition Society 2001


Banerji, MA, Buckley, MC, Chaiken, RL, Gordon, D, Lebovitz, HE & Kral, JG (1995) Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM. International Journal of Obesity 19, 846850.Google Scholar
Björntorp, P (1994) Fatty acids, hyperinsulinemia, and insulin resistance: which comes first? Current Opinion in Lipidology 5, 166174.Google Scholar
Björntorp, P (1995) Liver triglycerides and metabolism. International Journal of Obesity 19, 839840.Google Scholar
Blaak, EE, Van Baak, MA, Kemerink, GJ, Pakbiers, MT, Heidendal, GA & Saris, WH (1994) β-adrenergicstimulation of energy expenditure and forearm skeletal muscle metabolism in lean and obese men. American Journal of Physiology 267, E306E315.Google Scholar
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, 24382446.Google Scholar
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, E286E291.Google Scholar
Brunzell, JD & Hokanson, JE (1999) Dyslipidemia of central obesity and insulin resistance. Diabetes Care 22, Suppl. 3, C10C13.Google Scholar
Campbell, PJ, Carlson, MG & Nurjhan, N (1994) Fat metabolism in human obesity. American Journal of Physiology 266, E600E605.Google Scholar
Cao, H & Hegele, RA (2000) Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Human and Molecular Genetics 9, 109112.Google Scholar
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, E1055E1066.Google Scholar
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, 11951209.Google Scholar
Colberg, SR, Simoneau, J-A, Thaete, FL & Kelley, DE (1995) Skeletal muscle utilization of free fatty acids in women with visceral obesity. Journal of Clinical Investigation 95, 18461853.Google 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, 292295.Google Scholar
Coppack, SW, Evans, RD, Fisher, RM, Frayn, KN, Gibbons, GF, Humphreys, SM, Kirk, MJ, Potts, JL & Hockaday, TDR (1992) Adipose tissue metabolism in obesity: lipase action in vivo before and after a mixed meal. Metabolism 41, 264272.Google Scholar
Coppack, SW, Fisher, RM, Gibbons, GF, Humphreys, SM, McDonough, MJ, Potts, JL & Frayn, KN (1990) Postprandial substrate deposition in human forearm and adipose tissues in vivo. Clinical Science 79, 339348.Google Scholar
Eckel, RH (1987) Adipose tissue lipoprotein lipase. In Lipoprotein Lipase, pp. 79132 [Borensztajn, J, editor]. Chicago, IL: Evener.Google Scholar
Eckel, RH (1992) Insulin resistance: an adaptation for weight maintenance. Lancet 340, 14521453.Google Scholar
Ellis, BA, Poynten, A, Lowy, AJ, Furler, SM, Chisholm, DJ, Kraegen, EW & Cooney, GJ (2000) Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle. American Journal of Physiology 279, E554E560.Google Scholar
Farese, RV, Yost, TJ & Eckel, RH (1991) Tissue-specific regulation of lipoprotein lipase activity by insulin/glucose in normal-weight humans. Metabolism 40, 214216.Google Scholar
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, 17371747.Google Scholar
Flatt, J-P (1972) Role of the increased adipose tissue mass in the apparent insulin insensitivity of obesity. American Journal of Clinical Nutrition 25, 11891192.Google Scholar
Flatt, JP (1988) Importance of nutrient balance in body weight regulation. Diabetes/Metabolism Reviews 4, 571581.Google Scholar
Forouhi, NG, Jenkinson, G, Thomas, EL, Mullick, S, Mierisova, S, Bhonsle, U, McKeigue, PM & Bell, JD (1999) Relation of triglyceride stores in skeletal muscle cells to central obesity and insulin sensitivity in European and South Asian men. Diabetologia 42, 932935.Google Scholar
Frayn, KN (1993) Insulin resistance and lipid metabolism. Current Opinion in Lipidology 4, 197204.Google Scholar
Frayn, KN, Coppack, SW, Humphreys, SM, Fisher, RM & Allman, RFC (1991) Adipose tissue insulin resistance in obesity: protective mechanism or risk factor for heart disease? International Journal of Obesity 15, Suppl. 1, 55 Abstr.Google Scholar
Ganda, OP (2000) Lipoatrophy, lipodystrophy, and insulin resistance. Annals of Internal Medicine 133, 304306.Google Scholar
Gavrilova, O, Marcus Samuels, B, Graham, D, Kim, JK, Shulman, GI, Castle, AL, Vinson, C, Eckhaus, M & Reitman, ML (2000) Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. Journal of Clinical Investigation 105, 271278.Google Scholar
Goto, T, Onuma, T, Takebe, K & Kral, JG (1995) The influence of fatty liver on insulin clearance and insulin resistance in non-diabetic Japanese subjects. International Journal of Obesity 19, 841845.Google Scholar
Grill, V & Qvigstad, E (2000) Fatty acids and insulin secretion. British Journal of Nutrition 83, Suppl. 1, S79S84.Google Scholar
Hauner, H, Bender, M, Haastert, B & Hube, F (1998) Plasma concentrations of soluble TNF-alpha receptors in obese subjects. International Journal of Obesity 22, 12391243.Google Scholar
Himsworth, HP (1936) Diabetes mellitus. Its differentiation into insulin-sensitive and insulin-insensitive types. Lancet i, 127130.Google Scholar
Hofmann, C, Lorenz, K, Braithwaite, SS, Colca, JR, Palazuk, BJ, Hotamisligil, GS & Spiegelman, BM (1994) Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance. Endocrinology 134, 264270.Google Scholar
Hotamisligil, GS & Spiegelman, BM (1994) Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 43, 12711278.Google Scholar
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, 10571066.Google Scholar
Jeppesen, J, Hollenbeck, CB, Zhou, M-Y, Coulston, AM, Jones, C, Chen, Y-DI, & Reaven, GM (1995) Relation between insulin resistance, hyperinsulinemia, postheparin plasma lipoprotein lipase activity, and postprandial lipemia. Arteriosclerosis, Thrombosis and Vascular Biology 15, 320324.Google Scholar
Kalant, D, Phélis, S, Fielding, BA, Frayn, KN, Cianflone, K & Sniderman, AD (2001) Increased postprandial fatty acid trapping in subcutaneous adipose tissue in obese women. Journal of Lipid Research 41, 19631968.Google Scholar
Kaplan, NM (1989) The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Archives of Internal Medicine 149, 15141520.Google Scholar
Karam, JH, Grodsky, GM & Forsham, PH (1963) Excessive insulin response to glucose in obese subjects as measured by immunochemical assay. Diabetes 12, 197204.Google Scholar
Kim, JK, Gavrilova, O, Chen, Y, Reitman, ML & Shulman, GI (2000) Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. Journal of Biological Chemistry 275, 84568460.Google Scholar
Koistinen, HA, Bastard, JP, Dusserre, E, Ebeling, P, Zegari, N, Andreelli, F, Jardel, C, Donner, M, Meyer, L, Moulin, P, Hainque, B, Riou, JP, Laville, M, Koivisto, VA & Vidal, H (2000) Subcutaneous adipose tissue expression of tumour necrosis factor-a is not associated with whole body insulin resistance in obese nondiabetic or in type-2 diabetic subjects. European Journal of Clinical Investigation 30, 302310.Google Scholar
Koyama, K, Chen, G, Lee, Y & Unger, RH (1997) Tissue triglycerides, insulin resistance, and insulin production: implications for hyperinsulinemia of obesity. American Journal of Physiology 273, E708E713.Google Scholar
Landin, K, Stigendal, L, Eriksson, E, Krotkiewski, M, Risberg, B, Tengborn, L & Smith, U (1990) Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1. Metabolism 39, 10441048.Google Scholar
Lewis, GFO, Meara, NM, Soltys, PA, Blackman, JD, Iverius, PH, Druetzler, AF, Getz, GS & Polonsky, KS (1990) Postprandial lipoprotein metabolism in normal and obese subjects: comparison after the vitamin A fat-loading test. Journal of Clinical Endocrinology and Metabolism 71, 10411050.Google Scholar
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, 169174.Google Scholar
Miesenböck, G & Patsch, JR (1992) Postprandial hyperlipidemia: the search for the atherogenic lipoprotein. Current Opinion in Lipidology 3, 196201.Google Scholar
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, 41964200.Google Scholar
Mohamed-Ali, V, Pinkney, JH & Coppack, SW (1998) Adipose tissue as an endocrine and paracrine organ. International Journal of Obesity 22, 11451158.Google Scholar
Ong, JM & Kern, PA (1989) Effect of feeding and obesity on lipoprotein lipase activity, immunoreactive protein, and messenger RNA levels in human adipose tissue. Journal of Clinical Investigation 84, 305311.Google Scholar
Opie, LH & Walfish, PG (1963) Plasma free fatty acid concentrations in obesity. New England Journal of Medicine 268, 757760.Google Scholar
Patsch, JR, Prasad, S, Gotto, AMJ & Bengtsson-Olivecrona, G (1984) Postprandial lipemia. A key for the conversion of high density lipoprotein2 into high density lipoprotein3 by hepatic lipase. Journal of Clinical Investigation 74, 20172023.Google Scholar
Phillips, DIW, Caddy, S, Ilic, V, Fielding, BA, Frayn, KN, Borthwick, AC & Taylor, R (1996) Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in non-diabetic subjects. Metabolism 45, 947950.Google Scholar
Rabinowitz, D & Zierler, KL (1961) Forearm metabolism in obesity and its response to intra-arterial insulin. Evidence for adaptive hyperinsulinism. Lancet i, 690692.Google Scholar
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, 785789.Google Scholar
Reaven, GM (1988) Role of insulin resistance in human disease. Diabetes 37, 15951607.Google Scholar
Sadur, CN & Eckel, RH (1982) Insulin stimulation of adipose tissue lipoprotein lipase. Use of the euglycemic clamp technique. Journal of Clinical Investigation 69, 11191125.Google Scholar
Saghizadeh, M, Ong, JM, Garvey, WT, Henry, RR & Kern, PA (1996) The expression of TNFa by human muscle. Relationship to insulin resistance. Journal of Clinical Investigation 97, 11111116.Google Scholar
Shackleton, S, Lloyd, DJ, Jackson, SN, Evans, R, Niermeijer, MF, Singh, BM, Schmidt, H, Brabant, G, Kumar, S, Durrington, PN, Gregory, S, O'Rahilly, S & Trembath, RC (2000) LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nature Genetics 24, 153156.Google Scholar
Shimabukuro, M, Koyama, K, Chen, G, Wang, M-Y, Trieu, F, Lee, Y, Newgard, CB & Unger, RH (1997) Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proceedings of the National Academy of Sciences, USA 94, 46374641.Google Scholar
Sniderman, AD, Cianflone, K, Summers, LKM, Fielding, BA & Frayn, KN (1997) The acylation-stimulating protein pathway and regulation of postprandial metabolism. Proceedings of the Nutrition Society 56, 703712.Google Scholar
Spiegelman, BM & Flier, JS (1996) Adipogenesis and obesity: rounding out the big picture. Cell 87, 377389.Google Scholar
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, 12311238.Google Scholar
Steinberg, HO, Tarshoby, M, Monestel, R, Hook, G, Cronin, J, Johnson, A, Bayazeed, B & Baron, AD (1997) Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. Journal of Clinical Investigation 100, 12301239.Google Scholar
Tooke, JE & Hannemann, MM (2000) Adverse endothelial function and the insulin resistance syndrome. Journal of Internal Medicine 247, 425431.Google Scholar
Unger, RH (1995) Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44, 863870.Google Scholar