Hostname: page-component-7c8c6479df-ws8qp Total loading time: 0 Render date: 2024-03-27T16:28:37.368Z Has data issue: false hasContentIssue false

Fatty acid metabolism in obesity and type 2 diabetes mellitus

Published online by Cambridge University Press:  05 March 2007

E. E. Blaak*
Affiliation:
Dept of Human Biology, Nutrition Research Centre, Maastricht University, PO Box 6166200, MD, Maastricht, The Netherlands
*
Corresponding author: Dr E. E. Blaak, fax 3143 3670976, E.Blaak@HB.Unimaas.nl
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Disturbances in pathways of lipolysis and fatty acid handling are of importance in the aetiology of obesity and type 2 diabetes mellitus. There is evidence that a lowered catecholamine-mediated lipolytic response may play a role in the development and maintenance of increased adipose tissue stores. Increased adipose tissue stores, a disturbed insulin-mediated regulation of lipolysis and subnormal skeletal muscle non-esterified fatty acid (NEFA) uptake under conditions of high lipolytic rate may increase circulating NEFA concentrations, which may promote insulin resistance and cardiovascular complications. In addition, a disturbance of NEFA uptake by adipose tissue postprandially is also a critical determinant of plasma NEFA concentration. Furthermore, evidence is increasing that insulin-resistant muscle is characterised by a lowered ability to oxidise fatty acids. A dysbalance between fatty acid uptake and fatty acid oxidation may in turn be a factor promoting accumulation of lipid intermediates and triacylglycerols within skeletal muscle, which is strongly associated with skeletal muscle insulin resistance. The present review describes the reported disturbances in pathways of lipolysis and skeletal muscle fatty acid handling, and discusses underlying mechanisms and metabolic consequences of these disturbances.

Type
Meeting Report
Copyright
Copyright © The Nutrition Society 2003

References

Aitman, TJ, Glazier, AM, Wallace, CA, Cooper, LD, Norsworthy, PJ, Wahid, FN, Al-Majali, KM, Trembling, PM, Mann, CJ, Shoulders, CC, Graf, D, St Lezin, E, Kurtz, TW, Kren, V, Pravenec, M, Ibrahimi, A, Abumrad, NA, Stanton, LW & Scott, J (1999) Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nature Genetics 21, 7683.CrossRefGoogle ScholarPubMed
Astrup, A, Buemann, B, Toubro, S & Raben, A (1996) Defects in substrate oxidation involved in the predisposition to obesity. Proceedings of the Nutrition Society 55, 817828.CrossRefGoogle ScholarPubMed
Blaak, EE, Glatz, JF & Saris, WH, (2001a) Increase in skeletal muscle fatty acid binding protein (FABPC) content is directly related to weight loss and to changes in fat oxidation following a very low calorie diet. Diabetologia 44, 20132177.CrossRefGoogle ScholarPubMed
Blaak, EE, Van Aggel-Leijssen, DP, Wagenmakers, AJ, Saris, WH & Van Baak, MA (2000a) Impaired oxidation of plasma-derived fatty acids in type 2 diabetic subjects during moderate-intensity exercise. Diabetes 49, 21022107.CrossRefGoogle ScholarPubMed
Blaak, EE, Van Baak, MA, Kemerink, GJ, Pakbiers, MT, Heidendal, GA & Saris, WH (1994a) Beta-adrenergic stimulation of energy expenditure and forearm skeletal muscle metabolism in lean and obese men. American Journal of Physiology 267, E306E315.Google ScholarPubMed
Blaak, EE, Van Baak, MA, Kemerink, GJ, Pakbiers, MT, Heidendal, GA & Saris, GA (1994b) beta-Adrenergic stimulation of skeletal muscle metabolism in relation to weight reduction in obese men. American Journal of Physiology 267, E316E322.Google ScholarPubMed
Blaak, EE, Wagenmakers, AJ, Glatz, JF, Wolffenbuttel, BH, Kemerink, GJ, Langenberg, CJ, Heidendal, GA & Saris, WH (2000b) Plasma FFA utilization and fatty acid-binding protein content are diminished in type 2 diabetic muscle. American Journal of Physiology 279, E146E154.Google ScholarPubMed
Blaak, EE, Wolffenbuttel, BH, Saris, WH, Pelsers, MM & Wagenmakers, AJ, (2001b) Weight reduction and the impaired plasma-derived free fatty acid oxidation in type 2 diabetic subjects. Journal of Clinical Endocrinology and Metabolism 86, 16381644.Google ScholarPubMed
Boden, G (1999) Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proceedings of the Association of American Physicians 111, 241248.CrossRefGoogle ScholarPubMed
Clifford, GM, Londos, C, Kraemer, FB, Vernon, RG & Yeaman, SJ (2000) Translocation of hormone-sensitive lipase and perilipin upon lipolytic stimulation of rat adipocytes. Journal of Biological Chemistry 275, 50115015.CrossRefGoogle ScholarPubMed
Coburn, CT, Knapp, FF Jr, Febbraio, M, Beets, AL, Silverstein, RL & Abumrad, NA (2000) Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. Journal of Biological Chemistry 275, 3252332529.CrossRefGoogle ScholarPubMed
Colberg, SR, Simoneau, JA, Thaete, FL & Kelley, DE (1995) Skeletal muscle utilization of free fatty acids in women with visceral obesity. Journal of Clinical Investigation 95, 18461853.CrossRefGoogle ScholarPubMed
Connacher, AA, Bennet, WM, Jung, RT, Bier, DM, Smith, CC, Scrimgeour, CM & Rennie, MJ (1991) Effect of adrenaline infusion on fatty acid and glucose turnover in lean and obese human subjects in the post-absorptive and fed states. Clinical Science 81, 635644.CrossRefGoogle ScholarPubMed
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 ScholarPubMed
Enoksson, S, Degerman, E, Hagstrom-Toft, E Large, V Arner, P (1998) Various phosphodiesterase subtypes mediate the in vivo antilipolytic effect of insulin on adipose tissue and skeletal muscle in man. Diabetologia 41, 560568.CrossRefGoogle ScholarPubMed
Ezell, DM, Geiselman, PJ, Anderson, AM, Dowdy, ML, Womble, LG, Greenway, FL & Zachwieja, JJ (1999) Substrate oxidation and availability during acute exercise in non-obese, obese, and post-obese sedentary females. International Journal of Obesity and Related Disorders 23, 10471056.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, 243253.CrossRefGoogle ScholarPubMed
Froidevaux, F, Schutz, Y, Christin, L & Jequier, E (1993) Energy expenditure in obese women before and during weight loss, after refeeding, and in the weight-relapse period. American Journal of Clinical Nutrition 57, 3542.CrossRefGoogle ScholarPubMed
Geerling, BJ, Alles, MS, Murgatroyd, PR, Goldberg, GR, Harding, M & Prentice, AM (1994) Fatness in relation to substrate oxidation during exercise. International Journal of Obesity and Related Disorders 18, 453459.Google ScholarPubMed
Glatz, JF, Luiken, JJ & Bonen, A (2001a) Involvement of membrane-associated proteins in the acute regulation of cellular fatty acid uptake. Journal of Molecular Neuroscience 16, 123132.CrossRefGoogle ScholarPubMed
Glatz, JF, Luiken, JJ & Bonen, A (2001b) Involvement of membrane-associated proteins in the acute regulation of cellular fatty acid uptake (Discussion). Journal of Molecular Neuroscience 16, 151157.CrossRefGoogle Scholar
Hagstrom-Toft, E, Thorne, A, Reynisdottir, S, Moberg, E, Rossner, S, Bolinder, J & Arner, P (2001) Evidence for a major role of skeletal muscle lipolysis in the regulation of lipid oxidation during caloric restriction in vivo. Diabetes 50, 16041611.CrossRefGoogle Scholar
Hajri, T, Ibrahimi, A, Coburn, CT, Knapp, FF Jr, Kurtz, T, Pravenec, M & Abumrad, NA (2001) Defective fatty acid uptake in the spontaneously hypertensive rat is a primary determinant of altered glucose metabolism, hyperinsulinemia, and myocardial hypertrophy. Journal of Biological Chemistry 276, 2366123666.CrossRefGoogle ScholarPubMed
He, J, Watkins, S & Kelley, DE (2001) Skeletal muscle lipid content and oxidative enzyme activity in relation to muscle fiber type in type 2 diabetes and obesity. Diabetes 50, 817823.CrossRefGoogle ScholarPubMed
Helge, JW, Fraser, AM, Kriketos, AD, Jenkins, AB, Calvert, GD, Ayre, KJ & Storlien, LH (1999) Interrelationships between muscle fibre type, substrate oxidation and body fat. International Journal of Obesity and Related Disorders 23, 986991.CrossRefGoogle ScholarPubMed
Hellstrom, L, Langin, D, Reynisdottir, S, Dauzats, M & Arner, P (1996) Adipocyte lipolysis in normal weight subjects with obesity among first-degree relatives. Diabetologia 39, 921928.CrossRefGoogle ScholarPubMed
Hennes, MM, Dua, A & Kissebah, AH (1997) Effects of free fatty acids and glucose on splanchnic insulin dynamics. Diabetes 46, 5762.CrossRefGoogle ScholarPubMed
Holm, C, Osterlund, T, Laurell, H & Contreras, JA (2000) Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Annual Review of Nutrition 20, 365393.CrossRefGoogle ScholarPubMed
Horowitz, JF & Klein, S (2000) Oxidation of nonplasma fatty acids during exercise is increased in women with abdominal obesity. Journal of Applied Physiology 89, 22762282.CrossRefGoogle ScholarPubMed
Ishiyama-Shigemoto, S, Yamada, K, Yuan, X, Ichikawa, F & Nonaka, K (1999) Association of polymorphisms in the beta2-adrenergic receptor gene with obesity, hypertriglyceridaemia, and diabetes mellitus. Diabetologia 42, 98101.CrossRefGoogle ScholarPubMed
Itani, SI, Ruderman, NB, Schmieder, F & Boden, G (2002) Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 51, 20052011.CrossRefGoogle ScholarPubMed
Jensen, MD, Haymond, MW, Rizza, RA, Cryer, PE & Miles, JM (1989) Influence of body fat distribution on free fatty acid metabolism in obesity. Journal of Clinical Investigation 83, 11681173.CrossRefGoogle ScholarPubMed
Kelley, DE, Goodpaster, B, Wing, RR & Simoneau, JA (1999) Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. American Journal of Physiology 277, E1130E1141.Google ScholarPubMed
Kelley, DE & Mandarino, LJ (2000) Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 49, 677683.CrossRefGoogle ScholarPubMed
Kelley, DE & Simoneau, JA (1994) Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus. Journal of Clinical Investigation 94, 23492356.CrossRefGoogle ScholarPubMed
Kempen, KP, Saris, WH, Kuipers, H, Glatz, JF, Van Der Vusse, GJ (1998) Skeletal muscle metabolic characteristics before and after energy restriction in human obesity: fibre type, enzymatic beta-oxidative capacity and fatty acid-binding protein content. European Journal of Clinical Investigation 28, 10301037.CrossRefGoogle ScholarPubMed
Kim, JY, Hickner, RC, Cortright, RL, Dohm, GL Houmard, JA (2000) Lipid oxidation is reduced in obese human skeletal muscle. American Journal of Physiology 279, E1039E1044.Google ScholarPubMed
Klannemark, M, Orho, M, Langin, D, Laurell, H, Holm, C, Reynisdottir, S, Arner, P & Groop, L (1998) The putative role of the hormone-sensitive lipase gene in the pathogenesis of Type II diabetes mellitus and abdominal obesity. Diabetologia 41, 15161522.CrossRefGoogle ScholarPubMed
Langfort, J, Ploug, T, Ihlemann, J, Enevoldsen, LH, Stallknecht, B, Saldo, M, Kjaer, M, Holm, C & Galbo, H (1998) Hormone-sensitive lipase (HSL) expression and regulation in skeletal muscle. Advances in Experimental Medicine and Biology 441, 219228.CrossRefGoogle ScholarPubMed
Langfort, J, Ploug, T, Ihlemann, J, Saldo, M, Holm, C & Galbo, H (1999) Expression of hormone-sensitive lipase and its regulation by adrenaline in skeletal muscle. Biochemical Journal 340, 459465.CrossRefGoogle ScholarPubMed
Large, V, Hellstrom, L, Reynisdottir, S, Lonnqvist, F, Eriksson, P, Lannfelt, L & Arner, P (1997) Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associated with altered adipocyte beta-2 adrenoceptor function. Journal of Clinical Investigation 100, 30053013.CrossRefGoogle ScholarPubMed
Levin, K, Daa Schroeder, H Alford, FP Beck-Nielsen, H (2001) Morphometric documentation of abnormal intramyocellular fat storage and reduced glycogen in obese patients with Type II diabetes. Diabetologia 44, 824833.Google ScholarPubMed
Magre, J, Laurell, H, Fizames, C, Antoine, PJ, Dib, C, Vigouroux, C, Bourut, C, Capeau, J, Weissenbach, J & Langin, D (1998) Human hormone-sensitive lipase: genetic mapping, identification of a new dinucleotide repeat, and association with obesity and NIDDM. Diabetes 47, 284286.CrossRefGoogle ScholarPubMed
Malenfant, P, Tremblay, A, Doucet, E, Imbeault, P, Simoneau, JA & Joanisse, DR (2001) Elevated intramyocellular lipid concentration in obese subjects is not reduced after diet and exercise training. American Journal of Physiology 280, E632E639.Google Scholar
Mandarino, LJ, Consoli, A, Jain, A & Kelley, DE (1996) Interaction of carbohydrate and fat fuels in human skeletal muscle: impact of obesity and NIDDM. American Journal of Physiology 270, E463E4670.Google ScholarPubMed
Meirhaeghe, A, Helbecque, N, Cottel, D & Amouyel, P (2000) Impact of polymorphisms of the human beta2-adrenoceptor gene on obesity in a French population. International Journal of Obesity and Related Disorders 24, 382387.CrossRefGoogle Scholar
Mensink, M, Blaak, EE, Van Baak, MA, Wagenmakers, AJ & Saris, WH (2001) Plasma free fatty acid uptake and oxidation are already diminished in subjects at high risk for developing type 2 diabetes. Diabetes 50, 25482554.CrossRefGoogle ScholarPubMed
Miyaoka, K, Kuwasako, T, Hirano, K, Nozaki, S, Yamashita, S & Matsuzawa, Y (2001) CD36 deficiency associated with insulin resistance. Lancet 357, 686687.CrossRefGoogle ScholarPubMed
Nozaki, S, Tanaka, T, Yamashita, S, Sohmiya, K, Yoshizumi, T, Okamoto, F, Kitaura, Y, Kotake, C, Nishida, H, Nakata, A, Nakagawa, T, Matsumoto, K, Kameda-Takemura, K, Tadokoro, S, Kurata, Y, Tomiyama, Y, Kawamura, K & Matsuzawa, Y (1999) CD36 mediates long-chain fatty acid transport in human myocardium: complete myocardial accumulation defect of radiolabeled long-chain fatty acid analog in subjects with CD36 deficiency. Molecular and Cellular Biochemistry 192, 129135.CrossRefGoogle ScholarPubMed
Pan, DA, Lillioja, S, Kriketos, AD, Milner, MR, Baur, LA, Bogardus, C, Jenkins, AB & Storlien, LH (1997) Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 46, 983–938.CrossRefGoogle ScholarPubMed
Pelsers, MM, Lutgerink, JT, Nieuwenhoven, FA, Tandon, NN, van der Vusse, GJ, Arends, JW, Hoogenboom, HR & Glatz, JF (1999) A sensitive immunoassay for rat fatty acid translocase (CD36) using phage antibodies selected on cell transfectants: abundant presence of fatty acid translocase/CD36 in cardiac and red skeletal muscle and up-regulation in diabetes. Biochemical Journal 337, 407414.CrossRefGoogle ScholarPubMed
Pihlajamaki, J, Valve, R, Karjalainen, L, Karhapaa, P, Vauhkonen, I & Laakso, M (2001) The hormone sensitive lipase gene in familial combined hyperlipidemia and insulin resistance. European Journal of Clinical Investigation 31, 302308.CrossRefGoogle ScholarPubMed
Pravenec, M, Landa, V, Zidek, V, Musilova, A, Kren, V, Kazdova, L, Aitman, TJ, Glazier, AM, Ibrahimi, A, Abumrad, NA, Qi, N, Wang, JM, St Lezin, EM & Kurtz, TW (2001) Transgenic rescue of defective Cd36 ameliorates insulin resistance in spontaneously hypertensive rats. Nature Genetics 27, 156158.CrossRefGoogle ScholarPubMed
Prentki, M & Corkey, BE (1996) Are β-cell signalling molecules malonyl CoA and cytosolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM. Diabetes 45, 273283.CrossRefGoogle ScholarPubMed
Randle, PJ (1998) Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metabolism Reviews 14, 263283.3.0.CO;2-C>CrossRefGoogle Scholar
Ranneries, C, Bulow, J, Buemann, B, Christensen, NJ, Madsen, J & Astrup, A (1998) Fat metabolism in formerly obese women. American Journal of Physiology 274, E155E161.Google ScholarPubMed
Reynisdottir, S, Ellerfeldt, K, Wahrenberg, H, Lithell, H & Arner, P (1994) Multiple lipolysis defects in the insulin resistance (metabolic) syndrome. Journal of Clinical Investigation 93, 25902599.CrossRefGoogle ScholarPubMed
Reynisdottir, S, Langin, D, Carlstrom, K, Holm, C, Rossner, S & Arner, P (1995) Effects of weight reduction on the regulation of lipolysis in adipocytes of women with upper-body obesity. Clinical Science 89, 421429.CrossRefGoogle ScholarPubMed
Roden, M, Krssak, M, Stingl, H, Gruber, S, Hofer, A, Furnsinn, C, Moser, E & Waldhausl, W (1999) Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans. Diabetes 48, 358364.CrossRefGoogle ScholarPubMed
Roden, M, Price, TB, Perseghin, G, Petersen, KF, Rothman, DL, Cline, GW & Shulman, GI (1996) Mechanism of free fatty acid-induced insulin resistance in humans. Journal of Clinical Investigation 97, 28592865.CrossRefGoogle ScholarPubMed
Saha, AK, Vavvas, D, Kurowski, TG, Apazidis, A, Witters, LA, Shafrir, E & Ruderman, NB (1997) Malonyl-CoA regulation in skeletal muscle: its link to cell citrate and the glucose-fatty acid cycle. American Journal of Physiology 272, E641E648.Google ScholarPubMed
Schiffelers, SL, Saris, WH, Boomsma, F & Van Baak, MA (2001) beta(1)-and beta(2)-Adrenoceptor-mediated thermogenesis and lipid utilization in obese and lean men. Journal of Clinical Endocrinology and Metabolism 86, 21912199.Google Scholar
Simoneau, JA, Colberg, SR, Thaete, FL & Kelley, DE (1995) Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women. FASEB Journal 9, 273278.CrossRefGoogle ScholarPubMed
Simoneau, JA, Veerkamp, JH, Turcotte, LP & Kelley, DE (1999) Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. FASEB Journal 13, 20512060.CrossRefGoogle ScholarPubMed
Souza, SC, de Vargas, LM, Yamamoto, MT, Lien, P, Franciosa, MD, Moss, LG & Greenberg, AS (1998) Overexpression of perilipin A and B blocks the ability of tumor necrosis factor alpha to increase lipolysis in 3T3-L1 adipocytes. Journal of Biological Chemistry 273, 2466524669.CrossRefGoogle Scholar
Svedberg, J, Bjorntorp, P, Smith, U & Lonnroth, P (1990) Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes. Diabetes 39, 570574.CrossRefGoogle ScholarPubMed
Tuomilehto, J, Lindstrom, J, Eriksson, JG, Valle, TT, Hamalainen, H, Ilanne-Parikka, P, Keinanen-Kiukaanniemi, S, Laakso, M, Louheranta, A, Rastas, M, Salminen, V & Uusitupa, M, for the Finnish Diabetes Prevention Study Group (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New England Journal of Medicine 344, 13431350.CrossRefGoogle ScholarPubMed
Ukkola, O, Rankinen, T, Weisnagel, SJ, Sun, G, Perusse, L, Chagnon, YC, Despres, JP & Bouchard, C (2000) Interactions among the alpha2-, beta2-, and beta3-adrenergic receptor genes and obesity-related phenotypes in the Quebec Family Study. Metabolism 49, 10631070.CrossRefGoogle ScholarPubMed
van der Vusse, GJ, Van Bilsen, M, Glatz, JF, Hasselbaink, DM & Luiken, JJ (2002) Critical steps in cellular fatty acid uptake and utilization. Molecular and Cellular Biochemistry 239, 915.CrossRefGoogle ScholarPubMed
Wade, AJ, Marbut, MM & Round, JM (1990) Muscle fibre type and aetiology of obesity. Lancet 335, 805808.CrossRefGoogle ScholarPubMed
Zurlo, F, Lillioja, S, Esposito-Del Puente, A, Nyomba, BL, Raz, I, Saad, MF, Swinburn, BA, Knowler, WC, Bogardus, C & Ravussin, E (1990) Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ. American Journal of Physiology 259, E650E657.Google ScholarPubMed