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Basic disturbances in skeletal muscle fatty acid metabolism in obesity and type 2 diabetes mellitus

Published online by Cambridge University Press:  05 March 2007

E. E. Blaak
E. E. Blaak*
Affiliation:
Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
*
*Corresponding author: Dr E. E. Blaak Fax: +31 43 3670976, Email: E.Blaak@HB.Unimaas.nl
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Abstract

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The present article addresses the hypothesis that disturbances in skeletal muscle fatty acid handling in abdominal obesity and type 2 diabetes mellitus may play a role in the aetiology of increased adipose tissue stores, increased triacylglycerol storage in skeletal muscle and skeletal muscle insulin resistance. The uptake and/or oxidation of fatty acids have been shown to be impaired during post-absorptive conditions in abdominally-obese subjects and/or subjects with type 2 diabetes. Also, human studies have shown that muscle of subjects that are (abdominally) obese and/or have type 2 diabetes is characterized by an inability to increase fatty acid uptake and/or fatty acid oxidation during β-adrenergic stimulation and exercise. This disturbance in fat oxidation may promote, on one hand, the development of increased adipose tissue stores and obesity. On the other hand, fatty acids that are taken up by muscle and not oxidized may increase triacylglycerol storage in muscle, which has been associated with skeletal-muscle insulin resistance. Disturbances in the capacity to increase fat oxidation during post-absorptive conditions, β-adrenergic stimulation and exercise in subjects who are obese and/or have type 2 diabetes persist after weight reduction, indicating that the diminished fat oxidation may be a primary factor leading to the obese and/or insulin-resistant state rather than an adaptational response. Clearly, the precise sequence of events leading to an increased adiposity and insulin resistance in obesity and type 2 diabetes mellitus is not yet fully understood.

Keywords

Fatty acid metabolismSkeletal muscleObesityType 2 diabetes
Type
Symposium 4: New methodologies and insights in the regulation of fat metabolism during exercise
Information
Proceedings of the Nutrition Society , Volume 63 , Issue 2 , May 2004 , pp. 323 - 330
Copyright
Copyright © The Nutrition Society 2004

References

Aitman, TJ, Glazier, AM, Wallace, CA, Cooper, LD, Norsworthy, PJ, Wahid, FN, et al. (1999) Identification of Cd36 (fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nature Genetics 21, 76–83.Google Scholar
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, 2102–2107.Google Scholar
Blaak, EE, Van Baak, MA, Kemerink, GJ, Pakbiers, MT, Heidendal, GA & Saris, WH (1994) beta-Adrenergic stimulation of skeletal muscle metabolism in relation to weight reduction in obese men. American Journal of Physiology 267, E316–E322.Google Scholar
Blaak, EE & Wagenmakers, AJ (2002) The fate of [U-(13)C]palmitate extracted by skeletal muscle in subjects with type 2 diabetes and control subjects. Diabetes 51, 784–789.Google Scholar
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, E146–E154.Google Scholar
Blaak, EE, Wolffenbuttel, BH, Saris, WH, Pelsers, MM & Wagenmakers, AJ (2001) Weight reduction and the impaired plasma-derived free fatty acid oxidation in type 2 diabetic subjects. Journal of Clinical Endocrinology and Metabolism 86, 1638–1644.Google Scholar
Boden, G, Lebed, B, Schatz, M, Homko, C & Lemieux, S (2001) Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes 50, 1612–1617.Google Scholar
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, 32523–32529.Google Scholar
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, 1846–1853.Google Scholar
Dagenais, GR, Tancredi, RG & Zierler, KL (1976) Free fatty acid oxidation by forearm muscle at rest, and evidence for an intramuscular lipid pool in the human forearm. Journal of Clinical Investigation 58, 421–431.Google Scholar
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 Metabolic Disorders 23, 1047–1056.Google Scholar
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, 35–42.Google Scholar
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 Metabolic Disorders 18, 453–459.Google Scholar
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, 123–132.Google Scholar
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, 151–157.Google Scholar
Glatz, JF, Schaap, FG, Binas, B, Bonen, A, van der Vusse, GJ & Luiken, JJ (2003) Cytoplasmic fatty acid-binding protein facilitates fatty acid utilization by skeletal muscle. Acta Physiologica Scandinavica 178, 367–371.Google 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, 1604–1611.Google 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, 23661–23666.Google Scholar
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 Metabolic Disorders 23, 986–991.Google Scholar
Horowitz, JF & Klein, S (2000) Oxidation of nonplasma fatty acids during exercise is increased in women with abdominal obesity. Journal of Applied Physiology 89, 2276–2282.Google Scholar
Hulver, MW, Berggren, JR, Cortright, RN, Dudek, RW, Thompson, RP, Pories, WJ, MacDonald, KG, Cline, GW, Shulman, GI, Dohm, GL & Houmard, JA (2003) Skeletal muscle lipid metabolism with obesity. American Journal of Physiology 284, E741–E747.Google Scholar
Jong-Yeon, K, Hickner, RC, Dohm, GL & Houmard, JA (2002) Long- and medium-chain fatty acid oxidation is increased in exercise-trained human skeletal muscle. Metabolism 51, 460–464.Google Scholar
Kelley, DE & Goodpaster, BH (2001) Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance. Diabetes Care 24, 933–941.Google Scholar
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, E1130–E1141.Google Scholar
Kelley, DE & Mandarino, LJ (2000) Fuel selection in human skeletal muscle in insulin resistance: a re-examination. Diabetes 49, 677–683.Google Scholar
Kelley, DE & Simoneau, JA (1994) Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus. Journal of Clinical Investigation 94, 2349–2356.Google Scholar
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, E1039–E1044.Google Scholar
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, 219–228.Google Scholar
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, 459–465.Google Scholar
Luiken, JJ, Arumugam, Y, Bell, RC, Calles-Escandon, J, Tandon, NN, Glatz, JF & Bonen, A (2002a) Changes in fatty acid transport and transporters are related to the severity of insulin deficiency. American Journal of Physiology 283, E612–E621.Google Scholar
Luiken, JJ, Arumugam, Y, Dyck, DJ, Bell, RC, Pelsers, MM, Turcotte, LP, Tandon, NN, Glatz, JF & Bonen, A (2001) Increased rates of fatty acid uptake and plasmalemmal fatty acid transporters in obese Zucker rats. Journal of Biological Chemistry 276, 40567–40573.Google Scholar
Luiken, JJ, Coort, SL, Willems, J, Coumans, WA, Bonen, A, van der Vusse, GJ & Glatz, JF (2003) Contraction-induced fatty acid translocase/CD36 translocation in rat cardiac myocytes is mediated through AMP-activated protein kinase signaling. Diabetes 52, 1627–1634.Google Scholar
Luiken, JJ, Dyck, DJ, Han, XX, Tandon, NN, Arumugam, Y, Glatz, JF & Bonen, A (2002b) Insulin induces the translocation of the fatty acid transporter FAT/CD36 to the plasma membrane. American Journal of Physiology 282, E491–E495.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, E463–E470.Google 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, 2548–2554.Google Scholar
Mensink, M, Blaak, EE, Vidal, H De Bruin, TW, Glatz, JF & Saris, WH (2003a) Lifestyle changes and lipid metabolism gene expression and protein content in skeletal muscle of subjects with impaired glucose tolerance. Diabetologia 46, 1082–1089.Google Scholar
Mensink, M, Corpeleijn, E, Feskens, EJ, Kruijshoop, M, Saris, WH, de Bruin, TW & Blaak, EE (2003b) Study on lifestyle-intervention and impaired glucose tolerance Maastricht (SLIM): design and screening results. Diabetes Research and Clinical Practice 61, 49–58.Google Scholar
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, 983–988.Google Scholar
Randle, PJ (1998) Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes/Metabolism Reviews 14, 263–283.Google 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, E155–E161.Google Scholar
Rasmussen, BB, Holmback, UC, Volpi, E, Morio-Liondore, B, Paddon-Jones, D & Wolfe, RR (2002) Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle. Journal of Clinical Investigation 110, 1687–1693.Google Scholar
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, 2859–2865.Google Scholar
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, E641–E648.Google Scholar
Schrauwen, P, Van Aggel-Leijssen, DP, Hul, G, Wagenmakers, AJ, Vidal, H, Saris, WH & Van Baak, MA (2002) The effect of a 3-month low-intensity endurance training program on fat oxidation and acetyl-CoA carboxylase-2 expression. Diabetes 51, 2220–2226.Google Scholar
Sidossis, LS & Wolfe, RR (1996) Glucose and insulin-induced inhibition of fatty acid oxidation; the glucose-fatty acid cycle reversed. American Journal of Physiology 270, E733–E738.Google Scholar
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, 2051–2060.Google Scholar
Stumvoll, M, Jacob, S, Wahl, HG, Hauer, B, Loblein, K, Grauer, P, Becker, R, Nielsen, M, Renn, W & Haring, H (2000) Suppression of systemic, intramuscular, and subcutaneous adipose tissue lipolysis by insulin in humans. Journal of Clinical Endocrinology and Metabolism 85, 3740–3745.Google Scholar
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 (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New England Journal of Medicine 344, 1343–1350.Google Scholar
Turpeinen, AK, Takala, TO, Nuutila, P, Axelin, T, Luotolahti, M, Haaparanta, M, Bergman, J, Hamalainen, H, Iida, H, Maki, M, Uusitupa, MI & Knuuti, J (1999) Impaired free fatty acid uptake in skeletal muscle but not in myocardium in patients with impaired glucose tolerance: studies with PET and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Diabetes 48, 1245–1250.Google Scholar
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, 9–15.CrossRefGoogle ScholarPubMed
Wade, AJ, Marbut, MM & Round, JM (1990) Muscle fibre type and aetiology of obesity. Lancet 335, 805–808.Google Scholar
Watt, MJ, Stellingwerff, T, Heigenhauser, GJ & Spriet, LL (2003) Effects of plasma adrenaline on hormone-sensitive lipase at rest and during moderate exercise in human skeletal muscle. Journal of Physiology 550, 325–332.Google Scholar
Wilmsen, HM, Ciaraldi, TP, Carter, L, Reehman, N, Mudaliar, SR & Henry, RR (2003) Thiazolidinediones upregulate impaired fatty acid uptake in skeletal muscle of type 2 diabetic subjects. American Journal of Physiology 285, E354–E362.Google Scholar
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, E650–E657.Google Scholar