Abstract
Over the past decades, obesity and its metabolic co-morbidities such as type 2 diabetes (T2D) developed to reach an endemic scale. However, the mechanisms leading to the development of T2D are still poorly understood. One main predictor for T2D seems to be lipid accumulation in “non-adipose” tissues, best known as ectopic lipid storage. A growing body of data suggests that these lipids may play a role in impairing insulin action in metabolic tissues, such as liver and skeletal muscle. This review aims to discuss recent literature linking ectopic lipid storage and insulin resistance, with emphasis on lipid deposition in skeletal muscle. The link between skeletal muscle lipid content and insulin sensitivity, as well as the mechanisms of lipid-induced insulin resistance and potential therapeutic strategies to alleviate lipotoxic lipid pressure in skeletal muscle will be discussed.
Introduction
Nowadays, obesity has become one of the most prevalent disease worldwide, leading to the development of metabolic and cardiovascular pathologies [1]. Obesity is currently the strongest risk factor known for type 2 diabetes (T2D). T2D is characterized by a fasting hyperglycemia that is due to an impaired action of insulin on insulin sensitive tissues (i.e. adipose tissue, liver and skeletal muscle), the so-called insulin resistance [2, 3]. In the last decades, at least two mutually not exclusive hypotheses have emerged linking obesity to insulin resistance as recently reviewed by Samuel and Shulman [4]. One prevailing hypothesis is lipotoxicity caused by lipid overflow out of adipose tissue and ectopic lipid storage in lean tissues. This situation typically occurs when excess dietary lipids cannot anymore be appropriately stored into adipose tissue. Thus an enhanced expansion of fat mass is thought to protect against metabolic disturbances and to convey a healthy obese profile [5]. As a consequence, excess lipid accumulation in pancreas causes beta cell dysfunction. Some data suggest that, in a context of hyperglycemia, fatty acids can induce beta-cell death by apoptosis, a process called glucolipotoxicity [6].
In liver, ectopic lipid accumulation is referred as nonalcoholic fatty liver disease (NAFLD). Increased hepatocellular lipid content correlates negatively with both whole body and hepatic insulin sensitivity, leading to impaired suppression of endogenous glucose production and decreased hepatic glycogen synthesis during euglycemic hyperinsulinemic clamp [7]. When T2D patients are subjected to a hypocaloric diet, a strong decrease of 85% of hepatic lipid content is observed, associated with a normalization of hepatic insulin sensitivity as well as decreased hyperglycemia and hepatic glucose production. Importantly, these changes occur without any modifications of skeletal muscle lipid content, suggesting that the reduction of hepatic lipids per se could improve insulin sensitivity [8].
Numerous studies have linked ectopic lipid accumulation in skeletal muscle and insulin resistance [9–13]. Skeletal muscle plays a major role in whole body glucose homeostasis, as it is responsible for 80% of glucose disposal in response to insulin in the postprandial phase [14, 15]. Thus, as this organ acts as a metabolic sink for glucose, it is easy to figure out that impaired insulin action in muscle will lead to whole body insulin resistance and further development of T2D.
The purpose of this review was to summarize current understanding of how lipids emerge in skeletal muscle and to what extent they can contribute to muscle and whole body insulin resistance.
Skeletal muscle ectopic lipids and insulin resistance
Lipids can be found under two different forms in skeletal muscle: adipose cells, located between muscle fibers (i.e. intramuscular adipose tissue), and lipid droplets inside muscle fibers (i.e. intramyocellular triglycerides) [16, 17] (Figure 1).
Model linking obesity, muscle lipids and insulin resistance.
This cartoon illustrates that in young and lean subjects, a physiological amount of lipids is present in skeletal muscle. These lipids are stored in intramuscular adipocytes located between muscle fibers and in intramyocellular lipid droplets (imLD) within muscle fibers. When obesity develops, and this is also observed with aging, these lipids are stored in excess in skeletal muscle, leading to lipotoxicity responsible for insulin and anabolic resistance.
Intramuscular adipose tissue
Intramuscular fat is made of adipose cells (i.e. adipocytes) located between muscle fibers and muscle groups. Different studies in rodents and humans report a positive correlation between intramuscular adipose tissue (IMAT) and insulin resistance [18–20], and even when body mass index (BMI) is accounted for, it remains a strong predictor of fasting glucose and insulin levels [21].
However, it is still unclear if these adipocytes emerge from resident adipogenic progenitors or from satellite cells in skeletal muscle [16, 22]. Recent data from our group suggest that resident adipogenic progenitors, with potential to differentiate into functional adipocytes in vitro, are present in human skeletal muscle. We suggest that the proximity of these adipocytes to muscle fibers may impair muscle insulin action in a paracrine manner, and thus impact on whole body insulin sensitivity. On the other hand, one could speculate that these adipogenic progenitors differentiate into mature adipocytes as an adaptive mechanism during periods of lipid overload, as a buffer system to prevent lipid accumulation within myofibers. Future studies should investigate if IMAT can cause muscle dysfunction.
Intramyocellular triglycerides
In muscle fibers, lipids are stored within lipid droplets (LD) as triacylglycerols (TAG). Intramyocellular triglycerides (IMTG) constitute an important energy fuel source during muscle contraction [23, 24]. Indeed, elegant studies from Jensen’s group demonstrated that plasma fatty acids are first esterified into IMTG pools before being oxidized, both at rest [25, 26] and during exercise [27]. They further demonstrated that during submaximal exercise IMTG turnover is high, without changes in the IMTG pool size. However, other studies report that 60%–100% of radiolabeled oleate or palmitate taken up in skeletal muscle was directly oxidized [24, 28]. Such discrepancies may be due to differences in experimental protocol and/or training status of the subjects, which really differs from one study to another [23].
Importantly, maximal fatty acid oxidation in skeletal muscle is observed at moderate exercise intensities between 45 and 65% of maximal oxygen uptake depending on the type of subjects [24].
However, increased IMTG content is also found in obese and T2D people [10], and studies in lean healthy individuals report IMTG content as a stronger predictor of muscle insulin resistance than circulating fatty acids [29]. However, these studies did not account for the sedentary or active status of the subjects. In sedentary individuals, a strong inverse relationship has been reported between IMTG content and insulin sensitivity, independently of body mass index [30]. However, this relationship has proven much more complex than initially thought. Indeed, Goodpaster and colleagues have demonstrated that the skeletal muscle of endurance-trained athletes is highly insulin sensitive despite having an elevated IMTG content [31]. This could be explained by a more efficient lipid handling in skeletal muscle of athletes, allowing an optimal coupling between lipid storage and utilization to avoid lipotoxic insults. Interestingly, a close physical association between LD and mitochondria has been reported in active versus sedentary subjects, as well as a higher turnover of the IMTG pool [32–36].
Lipotoxic lipids
In the last few years, several studies aimed to identify the molecular actors responsible for the impairment of insulin signaling in skeletal muscle. It is now well established that IMTG per se do not cause insulin resistance, and several evidence dissociate TAG content from insulin resistance in humans [37, 38]. These observations raised the question of which molecular triggers could link increased IMTG content and insulin resistance in T2D subjects. Several lipid species emerged as potential candidates and in particular diacylglycerols (DAG) and ceramides (CER) [39, 40]. Indeed, increased DAG and CER content in skeletal muscle has been associated with insulin resistance in rodents [41, 42] and humans [43, 44]. A study from Goodpaster and colleagues demonstrated that diet-induced weight loss and exercise improved insulin resistance while reducing muscle DAG and CER content [45]. However, controversies exist related to the role of these lipid metabolites in impairing muscle insulin signalling, as some studies describe no change in muscle DAG and CER content associated with insulin resistance [17, 46–48], although data are not consistent [17, 49]. Taken together, these studies reveal that it seems that subcellular localization and composition of DAG [50] and CER, as well as their stereospecificity play an important role in their ability to impede insulin action, and needs to be further investigated.
Diacylglycerols pools
In rats, intralipid/heparin induces a strong increase of plasma fatty acids, and starts to reduce insulin sensitivity 3h after the beginning of infusion concomitant with the accumulation of DAG, impaired insulin signalling and glucose uptake in skeletal muscle. Of importance, insulin resistance occurred without any changes in IMTG content [40, 51]. DAGs act as signalling molecules, and are allosteric activators of protein kinase C (PKC). It has been shown that DAG-induced activation of novel PKC isoforms, and particularly PKCθ and PKCε in skeletal muscle, induces serine phosphorylation of insulin receptor substrate 1 (IRS1), thereby inhibiting insulin signalling [40, 52, 53].
Ceramides pools
It is interesting to note that mice fed for 12 weeks with a high-fat diet are protected from glucose intolerance if they are treated with myriocin, an inhibitor of serine palmitoyl tranferase 1 which decreases skeletal muscle CER content [54]. However, the role of CER in insulin resistance appears restricted to saturated fat, as myriocin prevents skeletal muscle insulin resistance after infusion of palmitate but not oleate [55].
CER seems to activate atypical PKC isoforms such as PKCξ, and the protein phosphatase 2A (PP2A), leading, respectively, to the phosphorylation of Akt on a Thr34 residue decreasing its ability to bind to membrane PI3P and to the dephosphorylation of Ser473 activating residue, thus impairing insulin-induced activation of Akt, and subsequent translocation of GLUT4 vesicles to the plasma membrane [56, 57].
Molecular mechanisms leading to intramyocellular triglycerides accumulation
Defects in muscle fatty acids storage
IMTG emerge from circulating fatty acids, and their uptake inside muscle fibers is partly regulated by cluster of differenciation 36 (cd36) and fatty acid transport protein 1 (FATP1) transporters. Knock-out studies in mice have shown that CD36 [58, 59] and FATP1 [60] deletion protects mice from muscle lipid accumulation and muscle insulin resistance under high-fat diet. The first step of TAG synthesis is controlled by glycerol-3-phosphate acyltransferase (GPAT), which catalyzes the formation of lysophosphatidic acid from fatty acyl CoA and glycerol-3-phosphate. The final step of TAG synthesis is catalyzed by diacylglycerol acyltransferases 1 and 2 (DGAT1 and DGAT2), which acylate DAG into TAG. Muscle-specific DGAT1 [61] or DGAT2 [62] overexpression leads to an accumulation of TAG in skeletal muscle, concomitant with a decrease in DAG content. In addition, unilateral overexpression of DGAT1 in rat skeletal muscle increased TAG content and rescued muscle insulin sensitivity when animals were fed high-fat diet [63]. Recently, Sparks and coworkers showed that muscle homogenates and human primary myotubes from obese individuals with T2D exhibit a reduced ability to incorporate FA into TAG pools [64]. Altogether, these studies indicate that increased rates of esterification of FA into TAG pools could be beneficial for insulin sensitivity by lowering lipotoxic lipid pressure in skeletal muscle.
Dysregulation of lipid droplets homeostasis
Perilipins
LDs are dynamic organelles, composed of a neutral lipid core surrounded by a phospholipid monolayer [65–67]. The surface of LDs is coated by different membrane-associated proteins, and the major structural components of LDs belong to the family of perilipins. Five members of the perilipin family have been identified so far, with various tissue expression patterns. In skeletal muscle, the most represented isoforms are PLIN2, PLIN3, PLIN4 and PLIN5 [68]. By forming a “lipolytic barrier”, they also protect LDs against their hydrolysis by lipases. PLIN5 is highly expressed in oxidative tissues such as skeletal muscle, and PLIN5 knock-out mice display an accumulation of CER in muscle fibers and skeletal muscle insulin-resistance [69]. However, upon specific conditions, perilipins could also facilitate lipolysis. For instance, in adipose tissue, PLIN1 facilitates lipases access to LDs upon adrenergic stimulation of lipolysis [70–72]. In skeletal muscle, PLIN5 may play a role in fatty acids channeling to mitochondria, promoting by this way their oxidation upon stimulated conditions [73]. Indeed, independent studies from two different groups have demonstrated that PLIN5 also localizes to mitochondria, providing a physical linkage between LDs and mitochrondria [74, 75]. Further work is needed to clarify the physiological role of perilipins in skeletal muscle, with emphasis on the apparent discrepancy between resting and stimulated conditions.
Lipases
IMTG breakdown (i.e. lipolysis) is controlled by different enzymes, and their activity is finely regulated. The lipolytic machinery is highly expressed in red oxidative compared to white glycolytic muscle (Figure 2), and this is correlated with both IMTG content and oxidative capacity (unpublished data). The first step of IMTG breakdown is catalyzed by adipose triglyceride lipase (ATGL), which converts TAG into DAG. Then, hormone-sensitive lipase (HSL) converts DAG into MAG, and MAG are finally hydrolyzed by the monoacylglycerol lipase (MGL) [76]. At the end, lipolysis of one TAG molecule releases three fatty acid molecules and one glycerol molecule. Although HSL and MGL were the first lipases identified in skeletal muscle, and are both highly expressed, ATGL appears to be the first and rate limiting step of skeletal muscle lipolysis.
Lipolytic proteins are highly expressed in oxidative compared to glycolytic muscles.
Representative blot of protein expression of the major lipolytic proteins in glycolytic (EDL), mixed (TA) and oxidative (Sol) skeletal muscles. EDL, Extensor digitorum longus; TA, tibialis anterior; Sol, soleus; ATGL, adipose triglyceride lipase; HSL, hormone-sensitive lipase; G0S2, G0/G1 switch gene 2; PLIN5, perilipin 5.
Monoacylglycerol lipase
MGL was discovered in 1976 by Tornqvist and colleagues, isolated from rat adipose tissue, and shown to specifically hydrolyze MAG but not TAG and DAG [77, 78]. MGL-knockout mice exhibit an increased MAG content associated with a down-regulation of free fatty acid and glycerol release from white adipose tissue [79]. MGL deletion also protects from diet-induced insulin-resistance and its inhibition in diabetic mice improves glucose tolerance [79, 80]. However, the physiological role of MGL in skeletal muscle lipolysis has not been investigated so far.
Hormone-sensitive lipase and adipose triglyceride lipase
Recent studies from our group have shown that diabetic status is associated with changes of ATGL and HSL activity and expression level in humans [81]. An increase of ATGL and a decrease of HSL expression/activity in skeletal muscle of obese and T2D patients was observed when compared to lean healthy individuals [82]. ATGL activity is negatively associated with whole-body insulin sensitivity measured by a hyperinsulinemic-euglycemic clamp [81]. Furthermore, ATGL protein expression has been shown to be increased in obese and T2D patients [81]. On the other hand, HSL expression and activity is down-regulated in obese insulin resistant subjects [82]. Of interest, this could be a primary defect acquired in obesity that persists in cultured human primary myotubes from obese type 2 diabetic individuals [83].
HSL was first identified in 1964 as a lipase sensitive to catecholamines in adipose tissue [84]. HSL presents TAG and DAG hydrolase activities, but displays a 10-times higher affinity for DAG rather than for TAG [76]. Confocal imaging studies have shown that HSL translocates to LDs in skeletal muscle upon stimulation by epinephrine or in response to contraction [85]. HSL-knockout mice accumulate DAG, but not TAG, in white adipose tissue and skeletal muscle, strengthening its role as a DAG hydrolase in vivo [86]. The observation that HSL-knockout mice do not accumulate TAG in skeletal muscle led to the conclusion that another enzyme is responsible for TAG-specific hydrolysis in skeletal muscle.
ATGL is highly expressed in skeletal muscle and white adipose tissue [87, 88], and ATGL mutations in humans lead to neutral lipid storage disease with myopathy [89]. Genetic modulations of ATGL expression in rodents helped to unravel its physiological role in vivo. Importantly, ATGL knockout mice display a massive TAG accumulation in cardiac and skeletal muscles [88]. In contrast, ATGL overexpression in human primary myotubes strongly decreases TAG content, while FA release and oxidation are increased [81]. More recent studies confirmed the important role of ATGL in skeletal muscle through muscle-specific modulations of its expression in mice [90, 91]. Collectively, these findings strengthen the role of ATGL as a TAG-specific hydrolase in skeletal muscle.
Mouse and cell models were helpful to define a causal relationship to strengthen the correlative findings linking ATGL to insulin resistance in human studies. Thus, ATGL knockout mice display a strong accumulation of TAG in skeletal muscle [88], as stated above, and are protected against high-fat diet induced insulin-resistance [92]. ATGL overexpression in human primary myotubes blunted insulin signalling and action. This phenotype was rescued when HSL was simultaneously overexpressed with ATGL, thus highlighting an important role for the balance between ATGL and HSL activity to maintain insulin sensitivity [81].
Enzymatic co-factors
ATGL activity is regulated by an enzymatic coactivator called comparative gene identification 58 (CGI58), which has also been shown to enhance TAG hydrolase activity in skeletal muscle [39]. CGI58 mutations in humans lead to the development of the Chanarin-Dorfman syndrome, associated with a severe myopathy [93]. CGI58 overexpression in human primary myotubes reduces TAG content and induces FA release and oxidation, whereas its downregulation leads to TAG accumulation and reduces lipolysis [39]. It was demonstrated more recently that ATGL activity is also inhibited by G0/G1 switch gene 2 (G0S2) in adipocytes [94, 95]. Unpublished data from our group suggest that G0S2 also inhibits ATGL activity in human and mouse skeletal muscle, and further studies are necessary to better characterize its functional role.
Concluding remarks
Even if skeletal muscle lipids are undoubtedly linked to insulin resistance, which lipid species are responsible for the impairment of insulin signaling and action is still a matter of ongoing debate. Unlike what was originally proposed, IMTG per se do not seem to induce insulin resistance, and IMTG content is a predictor for T2D development only in sedentary individuals. In highly trained individuals, IMTG content is increased to match the energy demand of the exercising muscle, thus disconnecting IMTG from insulin resistance. In this case, muscle oxidative capacity seems to be a better predictor of insulin resistance than lipid content. This is explained by the fact that a mismatch between skeletal muscle lipolysis and oxidative capacity leads to the accumulation of lipotoxic species, such as DAG and CER, impairing insulin action. Of importance, other molecular mechanisms besides lipotoxicity might contribute to insulin resistance in metabolic diseases as reviewed extensively [4]. For instance, saturated fat and/or endotoxin-mediated inflammation could also trigger insulin resistance in liver and skeletal muscle [96, 97]. Endoplasmic reticulum and oxidative stress may also play a role in some organs while their direct role in mediating insulin resistance in skeletal muscle is still debated [98]. Although no direct evidence of apoptosis are visible in mouse skeletal muscle in response to lipid infusion and chronic high fat feeding [4], ceramides can induce apoptosis by activating caspase 3 in a number of cell type such as beta cells [99]. Thus all these mechanisms are not mutually exclusive in mediating skeletal muscle insulin resistance and could be interconnected. Although it is now widely accepted that DAG and CER are key mediators of insulin resistance in skeletal muscle, the molecular mechanisms by which these lipotoxic lipids emerge in skeletal muscle remain unclear and need further investigation.
Expert opinion
During the last two decades the field has evolved with the concept that ectopic lipid storage in skeletal muscle can cause insulin resistance. It is now clear from a number of studies that not all lipids are alike and have the potential to inhibit insulin signaling and action. Thus non esterified fatty acids incoming to the muscle are neutralized within LD as IMTG. One current view, supported by in vitro data in human primary myotubes and in vivo work in transgenic mice, proposes that disturbances in LD dynamics could facilitates the emergence of toxic lipids, i.e. lipotoxicity, and insulin resistance. This includes alterations in lipases expression/activity and in LD proteins such as perilipins like PLIN2 and PLIN5. Because studies describing the link between muscle PLIN expression and insulin resistance are mostly correlative, future studies should examine the underlying molecular mechanisms in vitro as well as in vivo in mice with muscle-specific manipulations of PLIN in particular, and LD proteins in general. This area of research may help identify novel players in insulin resistance and design drug therapies to combat this strong risk factor of T2D in obese individuals.
Outlook
LD is now recognized as a complex organelle with a specific proteome. Understanding if and how the LD proteome influences its dynamic and potential FA flux in and out the LD is a key challenge for the next decade. It is predictable that novel specific LD proteins will be identified in skeletal muscle and may behaves as potential druggable targets to combat insulin resistance.
Although a number of clinical studies now underscore the potential importance of IMAT in metabolic diseases and aging, little is known on this ectopic fat depot and the biology of intramuscular adipocytes. It will be important in the near furture to investigate if IMAT is causally related to muscle dysfunction and how this depot emerges in the context of metabolic diseases and aging.
Highlights
Intramuscular lipids are stored either as adipocytes between muscle fibers or as LD within muscle fibers
Skeletal muscle lipid content is a stronger predictor of insulin resistance than circulating fatty acids in sedentary individuals
The pathophysiological role of adipocytes located in skeletal muscle remains to be elucidated
DAG and CER impair insulin signaling by activating PKC and PP2A
Elevated ATGL activity in skeletal muscle contributes to lipotoxicity and insulin resistance
HSL expression is reduced in skeletal muscle and primary myotubes from obese and T2D subjects
Disturbances in LD dynamics and/or LD protein expression influences lipotoxicity and insulin sensitivity
PLIN5 protein expression in skeletal muscle is a determinant of insulin sensitivity
Acknowledgments
The authors are grateful to Dr. François Crampes for outstanding discussion and critical reading of the manuscript. Some of the work that is discussed here was supported by grants from the National Research Agency ANR-09-JCJC-0019-01 and ANR-12-JSV1-0010-01, and from the Société Francophone du Diabète.
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