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Metabolic flexibility

Published online by Cambridge University Press:  05 March 2007

Len Storlien*
AstraZeneca R&D, Pepparedsleden 3, Mölndal 431 83, Sweden
Nick D. Oakes
AstraZeneca R&D, Pepparedsleden 3, Mölndal 431 83, Sweden
David E. Kelley
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh 15213, USA
*Corresponding author: Professor Len Storlien Fax: +46 31 776 3704, Email:
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Human physiology needs to be well adapted to cope with major discontinuities in both the supply of and demand for energy. This adaptability requires ‘a clear capacity to utilize lipid and carbohydrate fuels and to transition between them’ ( Kelley et al. 2002b). Such capacities characterize the healthy state and can be termed ‘metabolic flexibility’. However, increasing evidence points to metabolic inflexibility as a key dysfunction of the cluster of disease states encompassed by the term ‘metabolic syndrome’. In obese and diabetic individuals this inflexibility is manifest in a range of metabolic pathways and tissues including: (1) failure of cephalic-phase insulin secretion (impaired early-phase prandial insulin secretion concomitant with failure to suppress hepatic glucose production and NEFA efflux from adipose tissue); (2) failure of skeletal muscle to appropriately move between use of lipid in the fasting state and use of carbohydrate in the insulin-stimulated prandial state; (3) impaired transition from fatty acid efflux to storage in response to a meal. Finally, it is increasingly clear that reduced capacity for fuel usage in, for example, skeletal muscle, as indicated by reduced mitochondrial size and density, is characteristic of the metabolic syndrome state and a fundamental component of metabolic inflexibility. Key questions that remain are how metabolic flexibility is lost in obese and diabetic individuals and by what means it may be regained.

Symposium 6: Adipose tissue–liver–muscle interactions leading to insulin resistance
Copyright © The Nutrition Society 2004


Bruce, DG, Chisholm, DJ, Storlien, LH & Kraegen, EW (1988) Physiological importance of deficiency in early prandial insulin secretion in non-insulin-dependent diabetes. Diabetes 37, 736744.CrossRefGoogle ScholarPubMed
Coppack, SW, Evans, RD, Fisher, RM, Frayn, KN, Gibbons, GF, Humphreys, SM, Kirk, ML, Potts, JL & Hockaday, TDR (1992) Adipose tissue metabolism in obesity: lipase action in vivo before and after a mixed meal. Metabolism 41, 264272.CrossRefGoogle ScholarPubMed
Dodt, C, Lönnroth, P, Wellhöner, JP, Fehm, HL & Elam, M (2003) Sympathetic control of white adipose tissue in lean and obese humans. Acta Physiologica Scandinavica 177, 351357.Google Scholar
English, PJ, Coughlin, SR, Hayden, K, Malik, IA & Wilding, JPH (2003) Plasma adiponectin increases postprandially in obese, but not in lean, subjects. Obesity Research 11, 839844.Google Scholar
Frayn, KN (2002) Adipose tissue as a buffer for daily lipid flux. Diabetologia 45, 12011210.CrossRefGoogle ScholarPubMed
Goto, M, Terada, S, Kato, M, Katoh, M, Yokozeki, T, Tabata, I & Shimokawa, T (2000) cDNA cloning and mRNA analysis of PGC-1 in epitrochlearis muscle in swimming-exercised rats. Biochemical and Biophysical Research Communications 274, 350354.Google Scholar
Holmes, L, Storlien, LH & Smythe, GA (1989) Hypothalamic monoamines associated with the cephalic phase insulin response. American Journal of Physiology 256, E236E241.Google ScholarPubMed
Kelley, DE, Goodpaster, B, Wing, RR & Simoneau, J-A (1999) Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity and weight loss. American Journal of Physiology 277, E1130E1141.Google Scholar
Kelley, DE, Goodpaster, BH & Storlien, LH (2002 a) Muscle triglycerides and insulin resistance. Annual Review of Nutrition 22, 325346.CrossRefGoogle Scholar
Kelley, DE, He, J, Menshikova, EV & Ritov, VB (2002 b) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 29442950.CrossRefGoogle ScholarPubMed
Kelley, DE & Mandarino, LJ (2000) Fuel selection in human skeletal muscle in insulin resistance. Diabetes 49, 677683.Google Scholar
Kern, PA, Di Gregorio, GB, Lu, T, Rassouli, N & Ranganathan, G (2003) Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-α expression. Diabetes 52, 17791785.Google Scholar
Lin, J, Wu, H, Tarr, PT, et al. (2002) Transcriptional co-activator PGC-1alpha drives the formation of slow-twitch muscle fibres. Nature 418, 797801.Google Scholar
Meirhaeghe, A, Crowley, V, Lenaghan, C, et al. (2003) Characterization of the human, mouse and rat PGC1β (peroxisome-proliferator-activated receptor-γ co-activator 1β) gene in vitro and in vivo. Biochemical Journal 373, 155165.Google Scholar
Mootha, VK, Lindgren, CM, Eriksson, K-F, et al. (2003) PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genetics 34, 267273.Google Scholar
Oakes, N, Kjellstedt, A Thalén, P. Wettesten, M, Löfgren, L & Ljung, B (2002) Tissue-specific effects of AZ 242, a novel PPARa/g agonist, on glucose and fatty acid metabolism in obese Zucker rats: an in vivo simultaneous multi-tracer assessment. Diabetes 51, Suppl. 2, A110.Google Scholar
Patti, ME, Atul, JB, Crunkhorn, S, et al. (2003) Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proceedings of the National Academy of Sciences USA 100, 84668471.Google Scholar
Petersen, KF, Befroy, D, Dufour, S, Dziura, J, Ariyan, C, Rothman, DL, DiPietro, L, Cline, GW & Shulman, GI (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300, 11401142.Google Scholar
Picard, F, Naïmi, N, Richard, D & Deshaies, Y (1999) Response of adipose tissue lipoprotein lipase to the cephalic phase of insulin secretion. Diabetes 48, 452459.CrossRefGoogle Scholar
Polyzogopoulou, EV, Kalfarentzos, F, Vagenakis, AG & Alexandrides, TK (2003) Restoration of euglycemia and normal acute insulin response to glucose in obese subjects with type 2 diabetes following bariatric surgery. Diabetes 52, 10981103.CrossRefGoogle ScholarPubMed
Summers, LK, 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, 679683.CrossRefGoogle ScholarPubMed
Tiraby, C, Tavernier, G, Lefort, C, Larrouy, D, Bouillaud, F, Ricquier, D & Langin, D (2003) Acquirement of brown fat cell features by human white adipocytes. Journal of Biological Chemistry 278, 3337033376.Google Scholar
Wu, H, Naya, FJ, McKinsey, TA, Meercer, B, Shelton, JM, Chin, ER, Simard, AR, Michel, RN, Bassel-Duby, R, Olson, EN & Williams, RS (2000) MEF2 responds to multiple calcium-regulated signals in the control of skeletal muscle fiber type. EMBO Journal 19, 19631973.Google Scholar
Wu, Z, Puigserver, P, Andersson, U, Zhang, C-Y, Adelmant, G, Mootha, V, Troy, A, Cinti, S, Lowell, B, Scarpulla, RC & Spiegelman, B (1999) Mechanisms controlling mitochondrial biogenesis and respiration through thermogenic coactivator PGC-1. Cell 98, 115124.CrossRefGoogle ScholarPubMed
Yoon, JC, Puigserver, P, Chen, G, Donovan, J, Wu, Z, Rhee, J, Adelmant, G, Stafford, J, Kahn, CR, Granner, DK, Newgard, CB & Speigelman, BM (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1a. Nature 413, 131138.CrossRefGoogle Scholar