Deborah M. Muoio explains how her laboratory has employed a targeted metabolomics approach to survey several two-state models of insulin sensitivity.
|Intramuscular lipid droplet surrounded by interfibrillar mitochondria.
In metabolic diseases such obesity and diabetes, skeletal muscle fails to respond appropriately to insulin, resulting in impaired glucose disposal after a meal. The onset of this “insulin-resistant” condition is associated intimately with generalized increases in adiposity as well as ectopic lipid deposition within skeletal muscle (1). However, a now famous exception to this rule emerged from studies in muscles of highly trained athletes, which have more lipid droplets but remain exquisitely insulin-sensitive (2). These paradoxical findings have fascinated and puzzled scientists for many years, and the fundamental questions of if and how intramuscular lipid droplets contribute to insulin resistance remain unanswered.
A major quest has been to identify specific lipid molecules that universally discriminate insulin responsive versus resistant states. To this end, our laboratory has employed a targeted metabolomics approach to survey several two-state models of insulin sensitivity. Results of these analyses piqued our interest in a class of molecules known as acylcarnitines. These metabolites are byproducts of substrate degradation, formed from their respective acyl-CoA intermediates by a family of carnitine acyltransferases that reside principally in mitochondria. Insulin-resistant states were accompanied by muscle accumulation of lipid-derived acylcarnitines (byproducts of incomplete β-oxidation) and a corresponding diminution in free carnitine levels (3-5). Conversely, exercise training enhanced mitochondrial oxidative capacity but lowered acylcarnitine accumulation in obese mice (3). Our interpretation of these results was informed by metabolic assessments using several complementary methods (3, 4). The outcomes supported a negative association between incomplete fat oxidation and glucose tolerance (3-5) and led us to ask whether excessive mitochondrial lipid catabolism contributes to insulin resistance (6).
This question was addressed using mice that were engineered to have reduced-fat oxidation via deletion of malonyl-CoA decarboxylase; an enzyme that relieves the inhibitory action of malonyl-CoA on the initial step in β-oxidation. The mcd-null mice had reduced intramuscular acylcarnitine levels, increased glucose oxidation and preserved glucose tolerance when fed a high fat diet, despite high IMTG levels (4). The findings implied that intramuscular lipids in obese/inactive mice are less insulin-desensitizing when fat transport into mitochondria is restricted. Likewise, we found that a surplus of local triacylglycerol in obese compared with lean Zucker rats promotes β-oxidation and dissuades glucose use during muscle contraction (7). A similar glycogen sparing effect of IMTG has been observed in endurance athletes. Also intriguing are recent reports suggesting that intracellular lipid droplets play a specific and essential role in activating transcription factors that promote β-oxidation (8, 9). In aggregate, these studies support the possibility that intramuscular lipid droplets encourage a shift in metabolic currency, both by providing a plentiful source of fatty-acid substrate and by metabolic reprogramming at the genomic level. Further studies are necessary to determine whether persistent mitochondrial catabolism of IMTG-derived fatty acids contributes to systemic glucose intolerance in the context of overnutrition and to better understand how synthesis and turnover of this specific lipid pool is regulated in physically active muscles.
1. Muoio, D. M. (2010) Intramuscular Triacylglycerol and Insulin Resistance: Guilty as Charged or Wrongly Accused? Biochim. Biophys. Acta 1801, 281 – 288.
2. Dube, J. J., et al. (2008) Exercise-induced Alterations in Intramyocellular Lipids and Insulin Resistance: The Athlete’s Paradox Revisited. Am. J. Physiol. Endocrinol. Metab. 294, E882 – E888.
3. Koves, T. R., et al. (2005). Peroxisome Proliferator-activated Receptor-gamma Co-activator 1alpha-mediated Metabolic Remodeling of Skeletal Myocytes Mimics Exercise Training and Reverses Lipid-induced Mitochondrial Inefficiency. J. Biol. Chem. 280, 33588 – 33598.
4. Koves, T. R., et al. (2008) Mitochondrial Overload and Incomplete Fatty Acid Oxidation Contribute to Skeletal Muscle Insulin Resistance. Cell. Metab. 7, 45 – 56.
5. Noland, R. C., et al. (2009) Carnitine Insufficiency Caused by Aging and Overnutrition Compromises Mitochondrial Performance and Metabolic Control. J. Biol. Chem. 284, 22840 – 22852.
6. Randle, P. J. (1998) Regulatory Interactions Between Lipids and Carbohydrates: The Glucose Fatty Acid Cycle After 35 Years. Diabetes Metab. Rev. 14, 263 – 283.
7. Thyfault, J. P., et al. (2010) Metabolic Profiling of Muscle Contraction in Lean Compared to Obese Rodents. Am. J. Physiol. Regul. Integr. Comp. Physiol. Epub ahead of print.
8. Zechner, R., et al. (2009) Adipose Triglyceride Lipase and the Lipolytic Catabolism of Cellular Fat Stores. J. Lipid Res. 50, 3 – 21.
9. Sapiro, J. M., et al. (2009) Hepatic Triacylglycerol Hydrolysis Regulates Peroxisome Proliferator-activated Receptor Alpha Activity. J. Lipid Res. 50, 1621 – 1629.
Deborah M. Muoio (email@example.com) is an associate professor of medicine, pharmacology and cancer biology at the Duke University Sarah W. Stedman Nutrition and Metabolism Center.