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Department of Endocrinology and Metabolism (J.L.-S., C.C., M.M.), Section of Endocrinology, Ospedale di Cisanello, University of Pisa, Pisa 56126, Italy; Institut National de la Santé et de la Recherche Médicale U-636 (P.A.G.), Centre de Biochimie, Parc Valrose, Nice 06108, France; and Departament de Bioquímica i Biologia Molecular (J.L.-S., J.M.A.), Universitat de Barcelona, Barcelona 08071, Spain
Correspondence: Address all correspondence and requests for reprints to: Josep M. Argilés, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona 08071, Spain. E-mail: argiles{at}porthos.bio.ub.es
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Abstract |
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 Top Abstract I. IntroductionII. Roles of Fatty...III. Adipokines and Myokines:...IV. Skeletal Muscle Alterations...V. Exercise: Prevention and...VI. PPAR{delta} as an...VII. Conclusion and PerspectivesReferences |
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in skeletal muscle functions as well as the secretory capabilities of muscle, now considered as an endocrine tissue, have changed the general point of view on lipid homeostasis, opening new and promising doors for the treatment of lipid disorders.
as an Emerging Target for the Metabolic Syndrome |
I. Introduction |
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TopAbstractI. IntroductionII. Roles of Fatty...III. Adipokines and Myokines:...IV. Skeletal Muscle Alterations...V. Exercise: Prevention and...VI. PPAR{delta} as an...VII. Conclusion and PerspectivesReferences |
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So far, pharmacological and even surgical treatments of obesity have produced relatively low success (5, 6), whereas the treatment of type 2 diabetes has only improved significantly in recent years with the introduction of thiazolidinediones (TZDs). Some other clinical compounds used for the treatment of diabetes include metformin, a biguanide that seems to act primarily by decreasing hepatic glucose production; 
-glucosidase inhibitors, which inhibit intestinal oligosaccharide absorption; insulin secretagogues; and insulin (7). Interestingly, despite the fact that skeletal muscle is considered to be the main tissue involved in insulin resistance and most affected by sedentarism, it rarely represents a direct target for these drugs. In addition, exercise has also shown beneficial effects on insulin resistance; therefore, it would seem appropriate to develop strategies to specifically target skeletal muscle lipid metabolism, thus mimicking what happens in healthy individuals during exercise. This would theoretically help in the treatment of both diabetes and obesity, bypassing at the same time the problems associated with the difficulties of applying exercise and weight loss therapies to treat these metabolic disturbances once they have appeared. This will be discussed further in this review. Treatments to date have not properly addressed one of the main components, if not the first, of these illnesses, which is sedentarism, and could explain why it is so difficult to correct them. Because changing our modern lifestyle seems very unlikely in the short term, pharmacological treatments that can yield equivalent results are of great interest, and knowledge of the molecular basis of muscle lipid metabolism is required to accomplish that.
It is worth mentioning that skeletal muscle is an optimal target for lipid disturbances for different reasons. First, it is a tissue that represents a very high percentage of total body mass, between 40% and 45%, and has a very active lipid metabolism, notably catabolism, which can also be substantially increased in physiological situations, such as aerobic exercise, without any side effects. Second, it seems to be the tissue most related to insulin resistance, as demonstrated by the facts that muscle triglyceride content is one of the best predictors of insulin sensitivity (8, 9, 10, 11) and that it accounts for a very high percentage of glucose uptake during an insulin clamp (12). Third, it has been shown that the muscle of obese and diabetic patients presents important alterations concerning the composition of fiber types and oxidative metabolism (discussed in later sections). Lastly, and unlike the two tissues most often targeted, liver and adipose, it has an almost unidirectional flow of fatty acids, because all the fatty acids taken up by this tissue have to be oxidized because they can not be further re-exported. Taking all these factors together, as well as the beneficial effects of exercise, it seems clear that future treatments of lipid disorders must take this tissue into serious consideration. Although the heart could also be a target for insulin resistance, the quantitative importance of this organ is rather small, as compared with skeletal muscle. In addition, severe side effects could arise with a pharmacological treatment addressed to the cardiac muscle.
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II. Roles of Fatty Acids and Fatty Acid Nuclear Receptors [Peroxisome Proliferator-Activated Receptors (PPARs)] |
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TopAbstractI. IntroductionII. Roles of Fatty...III. Adipokines and Myokines:...IV. Skeletal Muscle Alterations...V. Exercise: Prevention and...VI. PPAR{delta} as an...VII. Conclusion and PerspectivesReferences |
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PPARs belong to the nuclear receptor superfamily, molecules activated by small, lipophilic compounds. They bind to specific regions of the promoters of many genes modulating their expression (13). Interestingly, among these genes we find many related to lipid metabolism, including those involved in fatty acid transport and clearance in blood (apolipoproteins and lipoprotein lipase), fatty acid transport through plasma membrane [fatty acid translocases (FAT)/CD36 and fatty acid transport protein], cytoplasmic fatty acid binding and activation [fatty acid-binding proteins, acyl-coenzyme A (CoA) binding protein, acyl-CoA synthetase], mitochondrial transport (carnitine palmitoyl transferase), fatty acid oxidation (acyl-CoA oxidase), lipogenesis (acetyl-CoA carboxylase, fatty acid synthase, ATP-citrate lyase), mitochondrial uncoupling [uncoupling proteins (UCP)-1, UCP-2, and UCP-3], some transcription factors also involved in lipid metabolism control (sterol-regulatory element-binding protein 1), in addition to other genes related to glucose metabolism (1, 14, 15).
There are three known isoforms of PPARs: , 
, and ß/. The first two have been well characterized both by genetic models and by the use of synthetic specific ligands, such as the fibrates and TZDs, which have been applied for the treatment of lipid disorders. By contrast, the -isoform has only been studied in depth in the last few years, given the initial absence of available specific ligands and suitable genetic models. Figure 1
summarizes the main metabolic roles of the three PPAR isoforms and the metabolic paths modulated by treatment with their agonists.
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is expressed mainly in liver, brown adipose tissue, and heart. It seems to be activated directly by fatty acids, both saturated and unsaturated, and it mainly controls fatty acid oxidation, both mitochondrial and peroxisomal ß-oxidation, and peroxisomal 
-oxidation. Numerous studies have been performed using the knockout model, which has demonstrated its important functions, in addition to the results obtained with the use of specific agonists (see Ref. 1 for reviews). However, there is still some debate about its possible role in tissues such as adipose and muscle, although an unexpected role in regulating feeding behavior has recently been postulated (16) as well as a role in controlling amino acid metabolism (17).
A plethora of reports on PPAR has been published in recent years (see Refs. 13 and 18, 19, 20, 21, 22 for extensive reviews on this isoform). The -2 isoform has been the best characterized of the two alternative splicing forms, given its important role on adipogenesis. Among the unresolved points about this isoform, to date the endogenous ligand of PPAR-2 has not yet been identified. It has been considered for many years that 15-deoxy-
12,14-prostaglandin J2 could be the main endogenous ligand, but many studies have shown PPAR-independent effects of this molecule (23, 24). In addition, its role in pathological situations in which PPAR is involved, such as obesity, or even in adipocyte differentiation, seems doubtful (25).
TZDs have been widely used in recent years to treat insulin resistance and type 2 diabetes, with relatively high success, either alone or in combination with other drugs such as metformin (26, 27). However, there are still many questions about these compounds that should be addressed in the near future. First, it is not clear whether their effects are PPAR dependent or independent, including some of their properties as insulin sensitizers, as shown by several recent reports (21, 28, 29, 30, 31, 32, 33). Another interesting point that remains to be solved is to identify the tissue actually targeted by these molecules in vivo. It would seem to be adipose tissue, given the high expression levels of PPAR in this tissue, but it has been demonstrated, in animal models, that absence of adipose mass does not abolish the antidiabetic effects of TZDs (34), thus suggesting a main role for skeletal muscle. On the other hand, a study on muscle-specific PPAR-deficient animals showed that the antidiabetic effects of TZDs are independent of the -isoform present in muscle (35). A similar approach was used by other authors (36) with different results: the animals were somewhat insulin resistant, and TZD did not show effects on insulin sensitization in skeletal muscle, although older animals were used. Future studies are required to clarify this apparent paradox and to explain possible compensatory roles or alterations in adipokine secretion in these two models, as well as to clarify the role of liver in humans, which could differ from what is observed in rodent models and play a compensatory role. To add more confusion, partial deficiency of PPAR isoform protects from obesity and insulin resistance associated with a high-fat diet (37), thus suggesting that the degree of activation of PPAR is not linearly correlated with the degree of insulin sensitivity (38, 39). Despite all this, the presence of adipose tissue depots in skeletal muscle tissue, particularly in obese subjects, may allow for a possible explanation of the effects of TZDs in skeletal muscle.
Concerning the clinical use of TZDs, we are still far from knowing the long-term effects of treatment with these compounds. In has been reported in the literature that TZD treatment induces an accumulation of fat mass, in general accepted to be mainly as sc fat. Even if this adipose depot is less important for insulin resistance than visceral fat, it seems a paradox to treat lipid disorders by increasing fat mass, and the final success of these molecules is still to be evaluated after long-term treatments (see Ref. 15 for review). In addition, it is unclear whether the activation of the -1 isoform in other tissues in humans could be accompanied by adverse effects. It is well established that TZDs induce expression of adipose-specific genes in liver in animal models (40) and that overexpression of the -1 isoform in liver has similar effects (41). For this reason, some authors have, in fact, suggested the use of PPAR antagonists, because they have antidiabetic properties (42, 43). Other compounds such as dual - and -agonists, such as ragaglitazar, O-arylmandelic acids, and KRP-297, are under research with the aim of reducing the adipogenic effects of TZDs, by simultaneously up-regulating fatty acid oxidation through PPAR effects (44, 45, 46).
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III. Adipokines and Myokines: the Adipose-Muscle Axis in Obesity and Diabetes |
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TopAbstractI. IntroductionII. Roles of Fatty...III. Adipokines and Myokines:...IV. Skeletal Muscle Alterations...V. Exercise: Prevention and...VI. PPAR{delta} as an...VII. Conclusion and PerspectivesReferences |
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, resistin, acylation-stimulating protein, adiponectin, adipsin, and some interleukins such as IL-1 and IL-6, but in fact the list is much more extensive (see Ref. 48 for review), including the recently described haptoglobin (49). The role of these adipose-secreted molecules has been studied by many authors during the last years, as well as their altered secretion in situations of metabolic disturbances. Here we briefly describe a few of them to illustrate their role in lipid metabolism and insulin resistance states. The role of leptin has been characterized by numerous studies since its discovery only a decade ago. It is a key molecule that controls body weight and lipid metabolism, as evidenced by the leptin-deficient mice (ob/ob mice) and by animal models presenting mutations of the leptin receptor (Zucker fa/fa rat and db/db diabetic obese mice) (50, 51). Leptin regulates food intake behavior, as well as energy expenditure, glucose homeostasis, and insulin action by acting both centrally and peripherally, but it has also been implicated in many other processes, such as immune response, inflammation, and hematopoiesis (52). Leptin exerts direct effects on adipose, liver, and skeletal muscle (51). A likely physiological role proposed for this adipokine is to protect adipocytes from steatosis and lipotoxicity by preventing the up-regulation of lipogenesis and by increasing fatty acid oxidation after an excess of caloric intake (53, 54). Notably, the situation in obesity is quite complex, because there appears to be leptin resistance, which can explain why the induction of muscle fatty acid oxidation by leptin is impaired in this situation (55).
TNF is a cytokine expressed by adipocytes, and it plays a crucial role in the development of lipid disorders. TNF is a lipolytic agent that regulates the expression of many lipid metabolism genes in the adipocyte (56). It also reduces insulin receptor phosphorylation in many cell types (56, 57, 58). Genetic models of TNF mutations are quite complex: TNF knockout mice are normal, and develop high-fat diet-induced obesity as wild type do, but are more insulin sensitive; TNF receptor (TNFRs) knockout mice also develop obesity similar to wild type animals, but with an improved insulin sensitivity. It has also been characterized that TNFR1, also called p55, is the receptor involved in this action of TNF. Unexpectedly, TNFR1 knockout animals present higher glucose transporter 4 (GLUT4) levels in muscle when developing diet-induced obesity than lean animals, and this highlights some of the insulin-resistant properties of this cytokine [reviewed by Hotamisligil (57)]. It has also been described that TNF gene expression is up-regulated in adipocytes in human obesity, as well as TNFR2, but not TNFR1, although there are contradictory reports [reviewed by Warne (59)]. In fact, TNF seems more correlated with total fat content than body mass index; therefore, a lot of care must be taken when considering human studies, in addition to the fact that TNF overexpression seems to appear in extreme forms of obesity, but not at early stages (59). Without any doubt, additional studies are required to unveil the actual role of TNF in both adipocyte metabolism and insulin resistance.
Adiponectin is another adipokine of key importance in understanding lipid disorders. It is a cytokine with clear effects on muscle cells, where it induces fatty acid oxidation (60). Adiponectin knockout mice develop diet-induced insulin resistance (37, 61), in parallel with reduced fatty acid transport protein 1 levels in muscle. The expression of adiponectin is reduced in animal models of insulin resistance, both obese and lipodystrophic, and it seems to directly affect insulin sensitivity by regulating muscle and liver triglyceride content (62, 63, 64). In addition, adiponectin induces the different UCPs in brown (UCP-1) and white adipose tissues (UCP-2), and skeletal muscle (UCP-3) (65). In humans, adiponectin levels are also reduced in insulin-resistant (66) and obese individuals (67, 68), whereas weight loss increases adiponectin levels (67, 68). Interestingly, adiponectin has also been implicated in insulin resistance associated with HIV lipodystrophy (69). Finally, its expression has been reported to be down-regulated, at least in vitro, by IL-6 and TNF (70), molecules highly expressed in adipose tissue during obesity and insulin resistance.
B. Myokines
To the same extent as adipose tissue, skeletal muscle is the source of many metabolic signals not only with autocrine effects, but also with direct and specific effects in other tissues such as adipose tissue and liver. For this reason, skeletal muscle must be equally considered as an endocrine tissue, as has been recently suggested (48). In this sense, we can use the name "myokines" for the muscle-secreted molecules, which include at least myostatin, TNF, IL-6, IL-15, and IGF-I, but possibly also "genuine" adipokines such as leptin, adiponectin, and plasminogen activator inhibitor-1 (PAI-1), because their expression has been demonstrated in particular conditions in muscle cells. However, the list of myokines may well increase in the coming years (see Ref. 48 for review).
From the few studies already published dealing with muscle-produced molecules, it is important to mention those related to IL-6. This cytokine was previously described as a proinflammatory molecule, and in fact that seems true when it is produced, or overproduced, by adipose tissue, contributing in a decisive way to insulin resistance (71). However, IL-6 is highly expressed by myocytes during exercise (72, 73), and its role seems to be rather antiinflammatory in such physiological situations (74). IL-6 is a lipolytic agent in adipose tissue, while at the same time stimulating myoblast proliferation (72), thus representing a good candidate to explain many of the beneficial effects of exercise. In addition, during exercise, IL-6 stimulates the appearance in the circulation of other antiinflammatory cytokines such as IL-1ra and IL-10 and inhibits the production of TNF, a proinflammatory cytokine (75).
Although the above-described results concerning IL-6 produced in myocytes or adipocytes may seem contradictory, it can be speculated that the cytokine has an important role, together with TNF, in controlling adipose mass in normal weight conditions; therefore, its autocrine/paracrine production would contribute to maintain adipose mass under control due to its lipolytic action (72, 73). In skeletal muscle, however, IL-6 production in a TNF-independent pathway would essentially be associated with exercise, acting in an endocrine manner, and participating in the regulation of adipose tissue release of fatty acids for muscle oxidation by activating lipolysis.
Another interesting molecule is IL-15, also involved in myoblast differentiation (76), but with clear in vivo effects on adipose tissue, where it induces a reduction of mass, lipogenic activity, and lipoprotein lipase activity (77). IL-15 receptors have been shown to be expressed differentially in adipose tissue from obese and normal animals (78). A recent paper has shown a regulation of IL-15 expression in human skeletal muscle with exercise (79). Given the fact that IL-15 is highly expressed in skeletal muscle, its role in the regulation of muscle and adipose fatty acid metabolism may contribute to a better understanding of the metabolic basis of obesity and insulin resistance.
Myostatin, a cytokine of the TGF-ß superfamily, is a molecule expressed by muscle cells that negatively regulates muscle growth. Myostatin knockout mice display increased muscle mass due to increased myogenesis and an important reduction in adipogenesis (80, 81). In addition, myostatin deletion in agouti yellow and obese ob/ob mice partially attenuates their obese and diabetic phenotypes (81). In a related model of p27, knockout mice, a defect in myostatin synthesis appears, generating increased muscle mass, while also important disturbances in adipogenesis not reflected in adipose mass changes, but with increased adipogenesis and apoptosis of fat cells (82). Possible direct effects of myostatin on preadipose cells have been reported, with reduction in the expression of markers of adipose differentiation such as PPAR, and inhibition of differentiation of preadipocytes (83). Notably, bovine models of excess musculature, known by the name of double-muscled cattle, present reduced levels of myostatin and show also a decrease in fat content (84).
The fact that both adipose tissue and skeletal muscle are capable of secreting molecules that can affect each other’s metabolism opens new interesting questions. It is possible that there is a metabolic cross-talk finely regulated, in a way that alterations in one tissue can affect the other through these mediators (48). In fact, it is easy to understand that overactivation of one tissue can promote atrophy or diminished activity in the other. This can be seen, for example, in obesity, where increases in fat mass are usually associated with a relative decrease in lean mass (85, 86) and muscle fiber type composition (87, 88, 89), and also in muscle-specific knockout of the insulin receptor (90). Conversely, exercise training is normally associated with reductions in fat mass, and hence its therapeutic value against obesity. In addition, some animal models of muscle hypertrophy also show reduced adiposity, such as the above-mentioned myostatin knockout mice (81) and double-muscled cattle (84), or even ski-oncogene-overexpressing animals (91, 92). Which molecules are actually responsible for this mutual cross-talk is still an unanswered question; therefore, future new experiments and approaches dealing with both adipokines and myokines are needed to solve this point. Indeed, it has been recently suggested that the expression of a given cytokine can be differentially regulated in adipose and skeletal muscle, as is the case for IL-6 and TNF (93), thus explaining, in part, some of their regulatory properties. It seems important to deeply characterize this cross-talk not only to treat metabolic disturbances, such as obesity and diabetes, but also other pathological situations where the system seems altered, such as cancer cachexia, muscle dystrophy, or sarcopenia.
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IV. Skeletal Muscle Alterations in Lipid Metabolism Disturbances |
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TopAbstractI. IntroductionII. Roles of Fatty...III. Adipokines and Myokines:...IV. Skeletal Muscle Alterations...V. Exercise: Prevention and...VI. PPAR{delta} as an...VII. Conclusion and PerspectivesReferences |
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Muscles of diabetic and obese individuals have important metabolic alterations in relation to lipid partitioning. First, there is a clear reduction in lipid oxidative performance (95, 97, 98) and impaired bioenergetic capacity of mitochondria (95). There seems to be also an increased fatty acid uptake rate (99) associated with higher plasma membrane content of FAT/CD36 (100) and acyl-CoA binding protein (101). The increase in triglyceride synthesis rate, together with the referred decreased oxidative capability, could then explain the accumulation of triglycerides in muscle.
A decrease in the size of some muscles in both diabetic db/db mice and young obese diabetic Zucker rats (86) has been reported, although the situation in humans is not so clear. However, important alterations in fiber type composition have been described in both animals and humans. An increase in the percentage of glycolytic type IIb fibers, with a concomitant decrease in the percentage of the more oxidative type I fibers, have been reported both in obesity and insulin resistance (87, 88, 89, 102, 103, 104). In addition, short-term weight loss in humans seems unable to normalize fiber type composition to that of normal individuals, being the improvement on muscle insulin sensitivity more related to changes in maximal oxidative capability, measured as succinate dehydrogenase activity, and capillarization (105). Another important alteration found in skeletal muscle of diabetic individuals is the relative content of the insulin-sensitive GLUT4. There appears to be a significant decrease of this transporter specifically in slow-twitch, type I oxidative fibers (106), together with an increase in FAT/CD36 in plasma membrane (100), indicating a change in substrate preference of the muscle tissue. The combined reduction in percentage of oxidative fibers and the alterations in GLUT4 and FAT/CD36 trafficking may account for most of the reduction in muscle insulin sensitivity (100). In this sense, a therapeutic approach reversing the fiber type changes and triglyceride content of muscle may represent a reasonable approach to revert the metabolic alterations observed in insulin resistance, as we will discuss in the next sections.
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V. Exercise: Prevention and Therapeutic Value |
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TopAbstractI. IntroductionII. Roles of Fatty...III. Adipokines and Myokines:...IV. Skeletal Muscle Alterations...V. Exercise: Prevention and...VI. PPAR{delta} as an...VII. Conclusion and PerspectivesReferences |
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It is generally accepted that most of the improvements achieved by exercise have skeletal muscle as the main tissue involved, simply because of evident topological reasons, because this is the tissue that actually participates in the exercise. In fact, molecular evidence at different levels seems to confirm this point of view. First, exercise can affect muscle fiber type composition, clearly in normal (neither diabetic nor obese) animals, with a shift to a more oxidative phenotype (111). In humans the results are more complex, although a similar trend concerning fiber type changes has been reported by many researchers (112, 113, 114, 115) in addition to other changes such as increased capillarization (116, 117) and reduction in fiber cross-sectional area (112, 116).
Second, exercise can normalize insulin-stimulated glucose uptake through increased GLUT4 expression (118, 119, 120) and mobilization to plasma membrane (121). More controversial are the effects on insulin receptor signaling: some authors report that exercise normalizes some downstream processes (118, 122, 123), whereas others do not (124).
Third, some effects of exercise have been demonstrated on adipose tissue. Exercise protects from the development of fat cell hypertrophy and insulin resistance (125), while down-regulating fatty acid synthase activity (126). Most remarkably, exercise can affect the TNF system in glucose-intolerant humans by decreasing plasma TNF and soluble TNFR2, but not soluble TNFR1 (127). However, it remains to be clarified whether muscle also participates in the observed decrease in TNF and TNFRs, because both are also overexpressed in this tissue in insulin-resistant individuals (128); therefore, muscle contraction could have an autocrine effect through yet undisclosed mediators, but possibly related to mitochondrial oxidative products or myokine expression.
Another important aspect of exercise is its modulation of secreted signals at both adipose and skeletal muscle tissues. Results on adipokines seem rather discrete, as exercise apparently does not modify adiponectin production (129, 130, 131, 132) even after 40% reduction in fat mass, whereas leptin levels are decreased (131) or not modified (132) in humans. By contrast, TNF seems to be up-regulated, at least in adipocytes of normal (133) and insulin-resistant rats (134), a situation that could be explained by an increased lipolysis to sustain muscle energetic demand elicited by myokines. By contrast, myokine secretion is altered, with myostatin being decreased (135), whereas IL-15 and IL-6 are increased (72, 74, 79). Contradictory results are reported concerning TNF secretion during exercise (72, 136). However, given the heterogeneity of models used, a revision of all these results is needed to confirm a role of exercise—notably chronic, low-intensity exercise—on expression of signal molecules by these two tissues.
Lastly, it is important to mention that exercise has positive effects on inflammation, as mentioned before, due to alterations in the IL-6/TNF system in skeletal muscle (72, 74, 75) and on cellular immune function in natural killer cells and splenic lymphocytes of obese animals (137) as well as on atherosclerosis (138).
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VI. PPAR as an Emerging Target for the Metabolic Syndrome
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TopAbstractI. IntroductionII. Roles of Fatty...III. Adipokines and Myokines:...IV. Skeletal Muscle Alterations...V. Exercise: Prevention and...VI. PPAR{delta} as an...VII. Conclusion and PerspectivesReferences |
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is the least studied of the three known PPAR isoforms, because, until recently, there were no specific agonists commercially available, and its ubiquitous expression makes more complex the use and interpretation of genetic animal models. However, several recent studies have unveiled some important functions related to placentation (139), colon cancer (140), keratinocyte proliferation and response to inflammation (141, 142), preadipocyte differentiation (143, 144, 145, 146), macrophage metabolism (147, 148), and intestinal lipid uptake (149), among others (see Fig. 2 and Ref. 150 for review). More interestingly, some reports have shown important metabolic functions related to lipid metabolism in skeletal muscle, where it seems to be the main isoform expressed (151, 152).
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has been suggested to play an alternative role to PPAR concerning fatty acid oxidation in muscle. PPAR knockout animals present small abnormalities concerning fatty acid metabolism in skeletal muscle, in clear contrast to what is seen in liver and heart, and notably even after a lipid metabolism challenge such as fasting or exercise (152). It has been reported that, in cultured myocytes, PPAR agonists induce fatty acid oxidation and expression of some genes related to this pathway, such as pyruvate dehydrogenase kinase-4 and UCP-3 (152).
In a study of muscle-specific overexpression of PPAR, it has been demonstrated that this isoform is highly involved in muscle remodeling, and likely also in the adaptive response to exercise (150). Indeed, skeletal muscle of these animals resembles that of exercise-trained ones (111), with higher percentage of aerobic fibers and higher oxidative enzymatic capabilities, while at the same time presenting reduced fat depots due to reduced size of the adipocytes. In fact, moderate exercise training increases PPAR levels in muscle of wild-type animals (150), pointing to a central role for this nuclear receptor in such an adaptive response. In addition, PPAR seems to be also nutritionally regulated in skeletal muscle, interestingly by fatty acids (153). These results have been confirmed by those of Wang et al. (154), showing an increase in the running ability of mice overexpressing PPAR in muscle, accompanied by a switch to a more oxidative muscle, and an increased resistance to diet-induced obesity.
The link between IL-6 and PPAR in skeletal muscle is particularly interesting and relevant, because exercise induces both an increase in PPAR expression (150) and an increase in IL-6 release (75). This supports the view that IL-6 release favors fatty acid oxidation in skeletal muscle during exercise. Interestingly, the fact that PPAR is also linked with skeletal muscle red fiber differentiation (150) may indicate a role of IL-6 during chronic exercise in changing muscle fiber composition toward a more oxidative, higher insulin-sensitive pattern, although the molecular basis of this remains unresolved.
PPAR overexpression in adipose tissue has also shown promising results. In such a model, increased fatty acid oxidation and energy dissipation have been observed, probably through the expression of UCP-1, a marker of transdifferentiation of white adipocytes into brown fat-like cells (155). More interestingly, adipose-restricted PPAR overexpression leads to reduction of adiposity in genetic models of obesity. In fact, the same authors demonstrated that there is an increased oxidative capability in incubated adipocytes and myocytes in response to the agonists, the activity of muscle cells being about 10 times higher, which points to the fact that skeletal muscle could be the main tissue responsible for the observed increase in lipid oxidation after PPAR agonist treatment. In any case, the presence of higher thermogenic capability due to altered white fat metabolism is a promising result regarding treatment of obesity.
Finally, all these above-mentioned papers on PPAR function seem to confirm a central role for skeletal muscle in the positive effects observed after treatment of obese or diabetic animals with potent, specific PPAR ligands. In this sense, treatment of db/db mice with a PPAR agonist induces a dramatic change in lipoprotein profile, notably increasing high-density lipoprotein cholesterol levels without changes in very low-density lipoprotein or low-density lipoprotein (LDL) fractions, and reduction in lipoprotein lipase activity (156). In addition, treatment of insulin-resistant rhesus monkeys with a different PPAR agonist promotes a less atherogenic lipoprotein profile, with increased high-density lipoprotein cholesterol and reduction in the LDL cholesterol and triglyceridemia and almost normalizing insulin levels and sensitivity (157). Some other authors suggested that skeletal muscle could be the main tissue responsible for such alterations (158, 159), and indeed it has been demonstrated that exercise promotes similar responses concerning triglyceride and lipoprotein profiles (107, 108, 160). Overall, these results point to a likely interest in PPAR agonists or PPAR activation as a new therapeutic approach for both obesity and the metabolic syndrome.
Concerning cardiac effects of PPAR agonist treatment, little information is available, but cardiomyocyte-restricted PPAR deletion in mice has shown a central role for this PPAR isoform in the control of fatty acid oxidation and normal cardiac function, suggesting it may represent a good target for treating lipotoxic cardiomyopathy associated with obesity (161).
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VII. Conclusion and Perspectives |
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TopAbstractI. IntroductionII. Roles of Fatty...III. Adipokines and Myokines:...IV. Skeletal Muscle Alterations...V. Exercise: Prevention and...VI. PPAR{delta} as an...VII. Conclusion and PerspectivesReferences |
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Much evidence suggests the presence of an important metabolic cross-talk between adipose tissue and skeletal muscle, the two main tissues related to total body mass, peripheral insulin sensitivity, and fatty acid metabolism. The "adipocentric" point of view generated in the last decade tries to explain this interrelationship by a unidirectional flow of messengers from the "endocrine" adipose tissue to a rather "passive" muscle, but this explanation seems inadequate to explain such a complex situation. However, it has been demonstrated that skeletal muscle is indeed another endocrine tissue, capable of expressing a wide range of molecules with similar endocrine actions to the adipokines. The metabolic cross-talk between these two tissues must be reevaluated, taking into consideration the two-tissue system of messengers (Fig. 3). In addition, the central role demonstrated for PPAR in muscle lipid metabolism can open new therapeutic strategies for the treatment of obesity and type 2 diabetes, either by the direct use of PPAR agonists, as already demonstrated in animal models, or through drugs related to its downstream effects, in a way that mimics what is happening during exercise in healthy subjects. However, much work is needed to characterize PPAR endogenous ligands—in a similar fashion to what happens with PPAR—and, most notably, to better define the roles and modulations of the nuclear receptor in physiological and pathological situations. In fact, much experimental evidence suggests that many of the positive effects of TZDs are not directly related to PPAR activation; therefore, a new general vision of their mode of action is required to understand the points that should be modified to improve the treatment of the pathologies they are intended for, including inflammation and cardiovascular disease. After a decade devoted to intensive study of adipose tissue and PPAR, skeletal muscle and PPAR are ready to claim their part.
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Footnotes |
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The authors have nothing to declare.
First Published Online March 23, 2006
Abbreviations: CoA, Coenzyme A; FAT, fatty acid translocase; GLUT 4, glucose transporter 4; LDL, low-density lipoprotein; PPAR, peroxisome proliferator-activated receptor; TNFR, TNF receptor; TZD, thiazolidinedione; UCP, uncoupling protein.
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TopAbstractI. IntroductionII. Roles of Fatty...III. Adipokines and Myokines:...IV. Skeletal Muscle Alterations...V. Exercise: Prevention and...VI. PPAR{delta} as an...VII. Conclusion and PerspectivesReferences |
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