International Journal of Obesity (2004) 28, S66–S71 & 2004 Nature Publishing Group All rights reserved 0307-0565/04 $30.00 www.nature.com/ijo PAPER Lipotoxicity: the obese and endurance-trained paradox AP Russell1* 1Clinique romande de re´adaptation SUVA Care, Sion, Switzerland The potential lipotoxic effect of intramyocellular triglyceride (IMTG) accumulation has been suggested to be a major component in the development of insulin resistance. Increased levels of IMTGs correlate with insulin resistance in both obese and diabetic patients, but this relationship does not exist in endurance trained (ETr) subjects. This may be, in part, related to differences in the gene expression and activities of key enzymes involved in fatty acid transport and oxidation as well as in the perodixation status of the IMTGs in obese/diabetic patients as compared with ETr subjects. Disruptions in fat and lipid homeostasis in skeletal muscle have been shown to activate protein kinase C (PKC), which acts on several downstream signalling pathways, including the insulin and the IkB kinase (IKK)/NFkB signalling pathways. Additionally, an increased peroxidation of IMTGs may reduce insulin sensitivity by increasing TNFa, which is known to increase the expression of suppressor of cytokine signalling proteins (SOCS). A common characteristic observed when activating both PKC and TNFa/SOCS3 is the inhibition of tyrosine phosphorylation of IRS-1 and subsequently an inhibition of its activation of downstream signalling molecules. These may be important players in the development of insulin resistance and understanding their activation and expression in both obese and ETr humans should assist in understanding how and why IMTGs become lipotoxic. International Journal of Obesity (2004) 28, S66–S71. doi:10.1038/sj.ijo.0802859 Keywords: intramyocellular triglycerides; PKC; insulin resistance; signalling pathways Introduction Mechanisms of IMTG accumulation Tissues other than adipose tissue, which have an increased IMTGs are situated in the cytoplasm of skeletal muscle and accumulation of lipids, often exhibit cellular dysfunction. can be seen as small droplets near the mitochondria. 4 In This is referred to as lipotoxicity and has been targeted as a obesity, the accumulation of IMTG may be a response to an factor contributing to insulin resistance in obese and increased uptake of plasma fatty acids and/or from a reduced diabetic subjects. Skeletal muscle is a site of regional fat oxidation of fatty acids by the mitochondria. Important rate distribution and has recently been the focus of numerous limiting steps in fatty acid oxidation include the transport of investigations due to the strong association between the fatty acids to the sarcoplasm, followed by the conversion of level of intramyocellular triglycerides (IMTGs) accumulation long-chain fatty acids to long-chain acyl-CoA. Fatty acid- and insulin resistance in obese, Type 2 diabetics and healthy binding protein (FABP) transports fatty acids from the subjects (for reviews, see Goodpaster1 and Schaffer2). How- circulation to the sarcoplasm, while carnitine palmitoyl ever, this association is not found in endurance trained (ETr) transferase (CPT) I and II translocate the long-chain acyl- subjects.3 This article examines (1) the mechanisms of IMTG CoA to the mitochondria. In obese humans, the content of accumulation, (2) the association between insulin resistance FABP is normal, while the activity of CPTI is reduced.5 and IMTG content, (3) the potential pathways linking IMTGs Additionally, in obese humans, a reduced CPTI activity is with insulin resistance, (4) the effects of exercise on IMTGs paralleled by reductions in enzymes of the Krebs cycle, and insulin resistance. Where possible, comparisons will be electron transport chain and b-oxidation, such as citrate made between the diametrically opposed conditions of synthase, cytochrome c and hydroxyacyl dehydrogenase, obesity and endurance training in humans. respectively.5 In obese subjects, as compared to lean subjects, it has been shown that under fasting conditions, a condition promoting fat oxidation and suppressing glucose oxidation, fatty acid uptakes across the leg tissues are similar, despite an *Correspondence: Dr AP Russell, Clinique Romande de Re´adaptation 6 SUVA Care, Av. Gd-Champsec 90, 1951 Sion, Switzerland. increased respiratory quotient and a reduced fat oxidation. E-mail: [email protected] Additionally, it was observed that during insulin infusion, an Lipotoxicity: the obese and Etr-trained paradox AP Russell S67 intervention promoting the oxidation of glucose and the Association between insulin resistance and IMTG suppression of lipolysis, fat uptake was similar in both lean and content obese subjects. However, fat oxidation by the leg tissues was The elevated levels of FFAs in obese subjects have been suppressed in lean but not in obese subjects.6 These results suggested to be a major link between obesity and insulin suggest that IMTG accumulation in the skeletal muscle of resistance (for a review, see Boden26). However, acute obese subjects is derived more from a reduced capacity for fat changes in plasma FFA concentrations do not immediately oxidation, and the inflexibility of skeletal muscle to suffi- alter insulin sensitivity and the effect is generally seen after ciently alter substrate metabolism, than from fatty acid uptake. 2–4 h.27,28 This time delay suggests that the effect of FFA on ETr is a condition also resulting in an accumulation of insulin resistance is not direct. It has been suggested that the IMTGs;7–9 however, unlike obesity it promotes both an effect of increased FFA on insulin resistance may come from increase in fatty acid transport and oxidation.10,11 Addition- their storage as IMTGs.28 Short-term elevation of FFAs, via ally, ETr, unlike obesity, also results in an increase in CPT-I, the infusion of a lipid emulsion under hyperinsulinemic citrate synthase and cytochrome c oxidase gene expression conditions, results in an elevation of the IMTG pool.29 and their respective enzyme activities.12–17 Therefore, the Furthermore, an increase in IMTGs has been shown in mechanisms regulating IMTG storage in ETr subjects appear insulin-resistant obese and Type 2 diabetics, when compared to differ to those from obese subjects. Endurance exercise has with lean subjects.3,9 Goodpaster et al3 found that the IMTG been shown to use both carbohydrate and lipids as a fuel content, measured using a routine Oil red oil stain, source. Carbohydrates, stored in the skeletal muscle and correlated with insulin sensitivity in lean, obese and type 2 liver, are hydrolysed to glucose and transported via the diabetic subjects. Perseghin et al30 reported that IMTG, circulation to the contracting muscle. Lipids provide a fuel quantified using magnetic resonance spectroscopy (MRS), source in the form of free fatty acids, derived from the in offspring of Type 2 diabetic patients correlated with lipolysis of adipose tissue. Additionally, the IMTG and lipid insulin resistance. Furthermore, it has been shown that stores located in skeletal muscle may also provide an whole-body insulin-stimulated glucose uptake was lower important energy source in the form of hydrolysed free fatty (3.070.4 vs 5.1 þ 0.5 mg kgÀ1 minÀ1) in a group of subjects acids. It has been demonstrated that IMTGs are continually with high IMTGs as compared to subjects with a low content turned over at rest and during exercise.18 Indeed several of IMTGs.31 Combined, these data support the notion that studies using 1H-MRS have shown that IMTGs are reduced by increased IMTG levels participate in the reduction of insulin approximately 20–40% during low-intensity exercise per- sensitivity. However, it is important to note that the link formed at 50–70% of VO2max for 80–180 min (for a review, between increased IMTG and insulin resistance is not see Watt et al19). A major player in the hydrolysis of IMTG is observed in all situations. For example, ETr also results in the neutral lipase, hormones-sensitive lipase (HSL). Correla- an accumulation of IMTGs, but unlike obesity, it is paralleled tions have been shown between HSL content and IMTG with an improvement in insulin sensitivity.32,33 The content storage and the oxidative capacity of the skeletal muscle of IMTG also varies between skeletal muscle fibre types and is types.20 HSL activity is increased two-fold in humans in positively related with the oxidative capacity of the fibres. In response to moderate–low-intensity exercise.21 HSL protein both obese and lean subjects, it has been shown that the expression is greater in oxidative as compared to glycolytic IMTG content is the greatest in the oxidative type I and the muscle fibres.22,23 Taken together, these results show that lowest in the glycolytic type II muscle fibres.34 Interestingly, HSL is found in skeletal muscle and suggest a role for HSL in it is the oxidative type I fibres which are the most insulin the mobilisation of IMTG stores by muscle contraction. sensitive.35 When comparing the divergent conditions of Whether a difference exists in the content and activity of obesity and ETr, an apparent inconsistency exists in the HSL in the skeletal muscle of obese subjects as compared to relationship between IMTG and insulin sensitivity. It has lean and/or ETr subjects is presently unknown. If results been suggested by Goodpaster et al3 that this should not be obtained from adipose and pancrease tissue are any indica- seen as a contradiction, but more as an indication that the tion, skeletal muscle HSL activity may be an important relationship between IMTG and insulin resistance is asso- player in the development of insulin resistance. Recently, a ciated with the fatty acid oxidative capacity of the muscle. truncated HSL protein has been found in the adipose tissue This suggests that IMTG may not directly affect insulin of obese subjects.24 The shortened HSL protein had a 20% resistance but instead provide a source for other toxic lipid lower activity than the longer protein.