Skeletal Muscle Lipotoxicity in Insulin Resistance and Type 2 Diabetes: a Causal Mechanism Or an Innocent Bystander?

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C Brøns and L G Grunnet Dysfunctional adipose tissue 176:2 R67–R78 Review and T2D

MECHANISMSPROOF IN ENDOCRINOLOGY ONLY Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes: a causal mechanism or an innocent bystander?

Charlotte Brøns and Louise Groth Grunnet Correspondence should be addressed Department of Endocrinology (Diabetes and Metabolism), Rigshospitalet, Copenhagen, Denmark to C Brøns Email [email protected]

Abstract

Dysfunctional adipose tissue is associated with an increased risk of developing type 2 diabetes (T2D). One characteristic of a dysfunctional adipose tissue is the reduced expandability of the subcutaneous adipose tissue leading to ectopic storage of fat in organs and/or tissues involved in the pathogenesis of T2D that can cause lipotoxicity. Accumulation of lipids in the skeletal muscle is associated with insulin resistance, but the majority of previous studies do not prove any causality. Most studies agree that it is not the intramuscular lipids per se that causes insulin resistance, but rather lipid intermediates such as diacylglycerols, fatty acyl-CoAs and ceramides and that it is the localization, composition and turnover of these intermediates that play an important role in the development of insulin resistance and T2D. Adipose tissue is a more active tissue than previously thought, and future research should thus aim at examining the exact role of lipid composition, cellular localization and the dynamics of lipid turnover on the development of insulin resistance. In addition, ectopic storage of fat has differential impact on various organs in different phenotypes at risk of developing T2D; thus, understanding how adipogenesis is regulated, the interference

European Journal European of Endocrinology with metabolic outcomes and what determines the capacity of adipose tissue expandability in distinct population groups is necessary. This study is a review of the current literature on the adipose tissue expandability hypothesis and how the following ectopic lipid accumulation as a consequence of a limited adipose tissue expandability may be associated with insulin resistance in muscle and liver. European Journal of Endocrinology (2017) 176, R67–R78

Introduction

Obesity is a major global health problem with often accompany obesity. T2D pathophysiology is increasing prevalence (1). Multiple metabolic disorders associated with an increased fat mass (2), and insulin and diseases including insulin resistance and T2D most resistance correlates with obesity even within the

Invited Author’s profile Charlotte Brøns PhD, is currently head of the Department of Diabetes and Metabolism at Rigshospitalet, and adjunct Associate Professor at the University of Copenhagen, Denmark. Her scientific expertise lies within the field of metabolism and integrative physiology with an extensive focus on the physiologic and molecular mechanisms underlying the etiology and pathophysiology of type 2 diabetes primarily in individuals exposed to intrauterine over- (gestational diabetes) and under-nutrition (low birth weight).

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normal range (3, 4). The adipose tissue plays an Adipose tissue expandability important role in regulatingPROOF energy balance via lipid ONLY storage and secretion and by being an active endocrine The underlying molecular mechanisms explaining the organ secreting adipokines that influence systemic link between obesity and T2D are not understood in metabolism (5). depth. One hypothesis is the ‘adipose tissue expandability’ It is well known that obesity is associated with hypothesis, proposing that it is the limited capacity or increased plasma levels of free fatty acids (FFA) due dysregulation of the adipose tissue expansion, rather than to increased lipolysis and thus FFA release from obesity per se which explains the link between a positive the adipose tissue and/or due to a reduced FFA energy balance and T2D (11). All human individuals clearance rate. Elevated plasma FFA levels inhibit the possess a maximum capacity for adipose expansion antilipolytic effect of insulin resulting in a further that is determined by both genetic and environmental increased release of FFA into the circulation. However, factors. Once the adipose tissue expansion limit has been the relationship between circulating FFA and insulin reached, adipose tissue ceases to store energy efficiently resistance is being debated. Studies have both provided and lipids begin to accumulate in other tissues (Fig. 1). evidence of insulin resistance and T2D in the presence Ectopic lipid accumulation in non-adipocyte cells causes of normal circulating levels of FFA (6) as well as lipotoxic insults including insulin resistance, apoptosis elevated FFA levels without concomitant insulin and inflammation 12( ). resistance, thus questioning the causal role of FFA in There are two models of adipogenesis. One model is T2D pathophysiology (7). from the pluripotent mesenchymal stem cell line that has Insulin resistance is a hallmark feature of T2D not undergone commitment to the adipocyte lineage. preceding the onset of overt disease by decades. Upon stimulation, the pluripotent stem cells can be Since the studies by Sir Philip Randle documenting committed to a number of different lineages including substrate competition between fat and glucose adipocytes, but once committed, the preadipocytes can oxidation, the ‘glucose fatty acid cycle’ also known as only differentiate into adipocytes. The commitment of the ‘Randle Cycle’ has been a central concept explaining stem cells into the preadipocyte lineage and differentiation the development of insulin resistance (8). Although of preadipocytes to adipocytes take place throughout life. many studies have confirmed the mechanisms of The other model is from the preadipocyte cell lines that the ‘Randle Cycle’, new mechanisms of glucose and have been committed to the adipocyte lineage. When fatty acids utilization have subsequently been discovered stimulated, the preadipocytes undergo multiple rounds of European Journal European of Endocrinology suggesting various additional, parallel or corresponding mitosis and then differentiate into adipocytes (13). The mechanisms by which fatty acids adversely affect two models together refer to hyperplasia of the adipose muscle insulin action and glucose uptake. Potentially tissue, whereas enlargement of adipocytes volume refers to deleterious lipid intermediates such as diacylglycerol hypertrophy (Fig. 2). Together, the two abovementioned (DAG) and ceramides accumulating within the processes are responsible for the increase in adiposity due tissue have been associated with the development of to excessive energy intake accompanied by low energy muscle insulin resistance (9). Also, increased adipose expenditure, and it is the transcription factor PPARγ tissue mass is related to an increased production of pro- (peroxisome-proliferator-activated receptor γ), which is inflammatory cytokines and endoplasmic reticulum the main regulator of differentiation of the preadipocytes stress which, together with elevated circulating intro mature adipocytes (14). Manipulation with PPARγ FFAs, are involved in the development of insulin suggests that treatment with PPARγ agonists results in resistance (10). increased fat mass expansion, whereas the inactivation of In the present review, we will discuss how the PPARγ decreases fat mass expansion (15). ectopic lipid accumulation may occur by the adipose When recruitment of new fat cells fails because of tissue expandability hypothesis and the impact of these impaired differentiation, it will eventually lead to a lipids on insulin resistance and mitochondrial function. decreased capacity of the adipose tissue to accumulate Furthermore, we will exemplify the link between excess lipids. Adipocytes that are filled to capacity are lipotoxicity and insulin resistance in individuals extremely insulin resistant and therefore less efficient as exposed to intrauterine growth retardation because metabolic buffers (16, 17), and it has been shown that these subjects have a prediabetic phenotype already at adipocyte hypertrophy is a key phenotype of non-obese a young age. T2D patients (18). Increased adipocyte size is also shown

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Figure 1 The proposed hypothesis for limited adipose tissue expandability. When the body is in a positive energy balance, the adipose tissue will expand to handle the excess energy. If the adipose tissue is not capable of expanding sufficiently, there will be a spillover of FFA to non-adipose tissue leading to harmful effects in liver, muscle and pancreas.

in obese, prediabetic and T2D subjects (19, 20, 21, 22) been demonstrated that lipodystrophy in both animal and is associated with insulin resistance independently and humans results in severe insulin resistance and T2D of BMI (23, 24). Also, patients with T2D have fewer total (26, 27). Furthermore, there are several similarities between subcutaneous adipocytes compared with BMI-matched the biochemical and clinical profiles of these two groups obese subjects (25). of individuals including dyslipidemia and hepatic steatosis. Paradoxically, the metabolic consequences of having The physiological importance of adipose tissue too much fat are surprisingly similar to those of having expandability has been demonstrated in multiple studies. an abnormal lack of fat i.e. lipodystrophy, and it has For example, evidence from animal models has shown that severe insulin resistance was present in an obese mouse model with a limited capacity of adipose tissue expandability (14). On the contrary, a transgenic mouse model of morbid obesity was associated with significantly greater amounts of adipose tissue – mainly non-visceral depots, reduced triglyceride levels in liver and muscle

European Journal European of Endocrinology and an improved metabolic profile 28( ). A polymorphism of the lipid sensor G-protein-coupled receptor 120 (GPR120) has been associated with a reduced capacity to proliferate subcutaneous tissue in response to a high-fat diet, subsequently resulting in ectopic accumulation of fat in liver and muscle (29). A recent study showed that regulation of lipid storage-related genes (DGAT2, SREBP1c and CIDEA) was defective in the subcutaneous adipose tissue of subjects exhibiting the largest fat accumulation in the visceral adipose tissue of non-obese subjects when overfed for 56 days, supporting the adipose tissue expandability theory (30). Apart from adipogenesis and lipogenesis, appropriate plasticity ensured by remodeling of the extracellular matrix and the vasculature are required for the maintenance of adipose tissue expandability (31). Figure 2 A suboptimal early-life environment due to poor Models of adipose tissue enlargement. Obesity is an nutrition and/or stress during pregnancy can influence enlargement of adipose tissue to store energy surplus, and the phenotype of the offspring (32), and low birthweight the adipose tissue grows by two mechanisms namely is consistently associated with increased risk of T2D hyperplasia (increase in cell number) and hypertrophy (33, 34). Young, healthy men born with a low birthweight (increase in cell size). have significant changes in body fat content and

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distribution, increased rate of lipolysis and impaired expression and protein synthesis in these cells, which preadipocyte maturationPROOF (35, 36), which may contribute was shownONLY to be associated with a significantly increased to the development of whole-body as well as adipose degree of DNA methylation of the leptin promoter in tissue and hepatic insulin resistance later in life. De Zegher the preadipocytes from SGA subjects (36). This provides et al. found that fetal growth restriction was associated evidence of a prime role for immature adipose tissue stem with increased circulating levels of preadipocyte factor 1 cell function in developmental programming of T2D (Pref-1), which inhibits adipocyte differentiation (37). possibly mediated by early defects in the adipose tissue These data suggest that Pref-1 may be a mediator of reduced and a reduced expandability resulting in ectopic lipid adipocyte differentiation in growth-restrained fetuses, storage, lipotoxicity and insulin resistance (Fig. 3). and thus of a reduction in life-long lipid storage capacity During pregnancy, the adipose tissue must expand and thereby of adult vulnerability to metabolic disease, rapidly not only to meet the needs of the growing fetus once lipid storage becomes an issue. Following this line of but also to support the future needs of the offspring thinking, Sebastiani et al. showed that SGA children have through lactation. Rojas-Rodriguez et al. showed that more hepatic fat than matched appropriate for gestational women with gestational diabetes had greater adipocyte age (AGA) children (38). Supporting the adipose tissue size and decreased capillary density in the omental fat expandability hypothesis as a reason for lipotoxicity, compared with women with a normal glucose tolerance the authors propose that a postnatal reduction of test during pregnancy, indicating an impaired adipose subcutaneous adipogenesis, followed by hyperexpansion tissue expandability in gestational diabetes (40). In and subsequent overfilling of subcutaneous adipocytes addition, it was recently shown that the progenitor density due to post-natal catch-up growth, may be among the (and thus the source of new adipocytes) was lower and mechanisms predisposing SGA children to excessive lipid accompanied by limited expansion of adipocyte number storage in other organs, including in the liver (38). when challenged with a high-fat diet in a 3-month-old We have shown, in a study of human subjects and rat offspring of maternal obese dams compared with that rats exposed to suboptimal nutrition during fetal life, that in the offspring of control dams. This was associated increased in vivo expression of miR-483-3p, programmed with lower DNA methylation of the zinc finger protein by early-life nutrition, limits the storage of lipids in 423 (involved in adipogenesis) in the epididymal fat adipose tissue via translational repression of the growth in the offspring of obese dams (41), suggesting a focus differentiation factor-3 (GDF3) (39). Dysregulation on epigenetic changes in adipocyte progenitors when of miR-483-3p expression could possibly affect the looking for possible mechanisms in fetal programming of European Journal European of Endocrinology whole body physiology by constraining adipose tissue an obesogenic maternal environment. expandability and therefore lipid storage, promoting Altogether, the importance of normal adipose tissue ectopic triglyceride storage and lipotoxicity in other tissues development, and that disturbances of adipose tissue and thus increasing susceptibility to metabolic disease. function can result in features of T2D is well documented, Furthermore, SGA subjects have immature preadipocyte supporting the adipose tissue expandability hypothesis. stem cells as reflected by impaired leptin mRNA The importance of the adipose tissue and especially the

Figure 3 Metabolic consequences of an immature preadipocyte. Decreased expression of the differentiation markers such as FABP4, PPARγ and GLUT4 mRNA suggested impaired human adipocyte maturation. In addition, reduced leptin mRNA expression and a reduced leptin release from these preadipocytes suggest diminished endocrine function that may lead to a decreased ability to store lipids in the adipose tissue and eventually insulin resistance (adapted from (36)).

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dynamics of adipose tissue turnover have furthermore of glucose transport in the high-fat-feeding model of been illustrated by ArnerPROOF et al. They showed that the insulin ONLY resistance (49, 50). lipid removal rate was positively associated with the capacity of adipocytes to break down triglycerides and Intramyocellular lipids inversely associated with insulin resistance in human subjects independent of the degree of obesity (42). Accumulation of toxic lipids species as intramyocellular Nevertheless, knowledge on programming of adipose lipid (IMCL) may occur as a result of increased fatty acids tissue expandability in humans is still limited. uptake due to sustained lipid overload and/or as a result of a reduced rate of fatty acids oxidation (51) and might be a primary factor in the development of insulin resistance Lipotoxicity and insulin action in (52, 53). IMCL is the common denominator for any form skeletal muscle of lipid species that is located within the myocyte and stored in lipid droplets, mostly in the form of triglyceride Lipid overload (TG) but in some cases, as lipid intermediates such as long- Infusion of lipids in various doses has been used in chain fatty acyl-CoAs, DAG and ceramides. It is well known many studies to imitate the state of lipid oversupply as that IMCLs have a physiological function as an important can be seen in obesity and T2D. In healthy individuals, energy source that drives muscle fat oxidation, and data acute elevation of plasma FFA by lipid infusion produces from early studies suggested that IMCL could be used as acute insulin resistance of the skeletal muscle tissue (43). a source of fuel during exercise as muscle TG was found It has been demonstrated that increased levels of plasma to be depleted after prolonged exercise (54), and during FFAs induce insulin resistance by initial inhibition of exercise, large amounts of circulating FFAs are directed glucose transport/phosphorylation and thereby by the into muscle cells for energy (54). Studies have shown impairment of the proximal insulin signaling pathway, a strong association between high IMCL content and followed by a reduction in both the rate of muscle skeletal muscle insulin resistance in obese subjects (55), glycogen synthesis and glucose oxidation (44, 45). in lean non-diabetic offspring of T2D subjects (56) and in However, the molecular mechanisms underlying this T2D subjects (53). Furthermore, a study has shown that, impairment is presently not fully understood, and data a diet high in fat and intravenous lipid infusion increase are somewhat contradicting. For example, Belfort et al. the amount of IMCL and simultaneously decrease insulin showed that an increase in plasma FFA caused a dose- sensitivity (20). The association between IMCL and insulin European Journal European of Endocrinology dependent inhibition of insulin-stimulated glucose resistance is further supported by studies showing decreased disposal and insulin signaling in skeletal muscle of lean, IMCL concentrations and corresponding improved insulin healthy individuals. The inhibitory effect of plasma sensitivity in response to weight loss (20, 21). It has been FFA was already significant after a modest increase in shown that under conditions of lipid oversupply the plasma FFA and developed at concentrations within the content of signaling molecules (intermediates), including physiological range (46). Kruszynska et al. have reported long-chain acetyl CoA, DAG and ceramides is increased similar results on insulin signaling (47). In contrast, in skeletal muscle, which can activate protein kinase when lipids are infused to already insulin-resistant obese C (PKC), resulting in a serine phosphorylation of the individuals, physiological elevation of plasma FFA levels insulin receptor substrate-1 (IRS-1), impairing its ability resulted in lipid-induced metabolic changes, which could to associate with the insulin receptor and interfering with not be explained by reduced proximal insulin signaling in PI3K activation and insulin signaling (57). skeletal muscle (48). Lipid infusion studies can obviously However, the causal relationship between skeletal induce responses different from what would have been muscle lipotoxicity in insulin resistance and T2D has observed if a dietary intervention was applied because been challenged, suggesting that accumulation of IMCL ingestion of food evidently affects different hormones and per se is not the direct cause of the development of insulin pathways, which are not activated during lipid infusion. resistance, but merely a marker for the presence of lipid Thus, lipid infusion studies may be artificial and needs to intermediates within the cell interfering with insulin be interpreted with that in mind. signaling (58, 59). Indeed, there are data to support a Studies on the effects of high-fat feeding on insulin key role of both DAG and ceramide content in the signaling in human subjects are lacking; however, rat pathogenesis of lipid-induced muscle insulin resistance studies have reported defective insulin-induced activation in obese and T2D individuals (60, 61, 62). This notion

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was also confirmed by Bergmanet al. who showed that resistance remains controversial indicating that the both the cellular localizationPROOF and composition of DAG relationship ONLY is more complex than first anticipated. influence the relationship with insulin sensitivity, and their data suggested that only saturated DAGs in skeletal muscle membranes were related to insulin Lipid accumulation in skeletal muscle resistance in obese and T2D subjects (63). Even though vs liver there is strong evidence to support a role of DAG and ceramides in the development of insulin resistance, Ectopic lipid accumulation in the liver, named recent studies also question the casual influence of nonalcoholic fatty liver disease (NAFLD) affects up to 30% these lipid intermediates that may among other factors of the general population and is thus the most common depend on their intracellular distribution. Recently, it liver disease (74). NAFLD is characterized by steatosis, was shown that especially the membrane and cytosolic which is caused by hepatic triglyceride accumulation C18:2 DAGs were associated with both acute lipid- possibly serving as a protective mechanism against induced and chronic insulin resistance in humans (64). lipotoxicity (75). Insulin resistance and excessive fatty However, some studies found no association between acid influx into the liver are the major driving forces ceramides and insulin resistance (65) or between DAGs for hepatic steatosis, and NAFLD is considered to be the and insulin resistance (66) indicating that the exact role hepatic component of the metabolic syndrome (76). of both these lipid intermediates is still debated. The There are studies suggesting that hepatic insulin phenomenon named the athlete’s paradox has revealed resistance may precede skeletal muscle insulin resistance, that athletes who possess a high oxidative capacity and and it is therefore suggested that early ectopic lipid enhanced insulin sensitivity also have higher skeletal accumulation in the liver and concurrent hepatic muscle IMCL content (67), and do likewise challenge insulin resistance are major contributing factors in the causality between increased muscle IMCL content the development of T2D. In elderly twins, total muscle per se and insulin resistance. Acute exercise, endurance triglyceride content was not associated with peripheral training as well as moderate aerobic exercise training insulin sensitivity but was associated only with hepatic increase the rate of IMCL synthesis (68, 69), suggesting insulin resistance, proposing that the muscle triglyceride that lipid accumulation in itself is not sufficient to content may reflect the general ectopic accumulation of explain the lipid-induced muscle insulin resistance. triglycerides including fat in the liver, that unfortunately Perilipin 5 (PLIN5) affects the size of the lipid droplets was not measured in the study (77). This theory is further European Journal European of Endocrinology and has been suggested as a unifying factor in conditions supported by a study showing that liver fat content in which insulin sensitivity is maintained despite measured by 1H magnetic resonance spectroscopy was the presence of high levels of IMCL. A very recent negatively correlated with insulin sensitivity in overweight study proposes that PLIN5 is driving the association men (78). Mice exhibiting a genetic inactivation of between promotion of the capacity to store lipids as adipose triglyceride lipase disproved the hypothesis that IMCL and amelioration of fasting-induced insulin triglyceride accumulation per se causes lipotoxicity and resistance (70). In addition, it has been demonstrated insulin resistance as these mice have both increased that IMCL turnover is high during submaximal exercise insulin sensitivity and glucose tolerance despite increased without causing changes in the total IMCL pool (71), triglyceride levels in muscle and liver (79). However, these whereas in healthy males, a single session of aerobic genetic manipulated mice models are not physiological exercise decreases IMCL levels, indicating that ectopic and therefore the results should be interpreted with lipids are flexible lipid depots 72( ). The IMCL could caution. Dufour et al. showed that the healthy young lean therefore be considered a reservoir for fatty acids that individuals born with a low birth weight, and therefore can be used for readily available substrate delivery, for at increased risk of developing T2D compared with the example during exercise (54), and the harmful effects of background population, exhibited both hepatic and IMCL may be limited when accompanied by an increased muscle insulin resistance independent of ectopic lipid oxidative capacity (73). accumulation in these organs (80). In addition, when Altogether, these studies suggests that the extent to young men are overfed for 5 days with a high-fat diet, which increased availability of plasma FFA levels and their liver becomes insulin resistant, whereas peripheral intracellular fat accumulation in itself impairs insulin tissues as mainly reflected by the muscles do not become signaling transduction and thereby causes muscle insulin insulin resistant (81), thus providing new evidence to

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imply that increased hepatic lipid infiltration possibly in fat and calories have been linked to mitochondrial occurs early in the pathogenesisPROOF of insulin resistance. dysfunction ONLY (89, 90), we investigated the potential effect Altogether, the role of ectopic fat in the development of 5-day high-fat overfeeding. We found that in vivo of insulin resistance and T2D points toward a central role mitochondrial function was not affected by overfeeding of the liver as opposed to the muscle in particularly the LBW individuals compared with that in controls (81), early pathogenesis of T2D. thereby not supporting the proposed hypothesis that high-fat diet induces alterations in mitochondrial function – not even in subjects at risk of developing insulin Lipotoxicity and mitochondrial function in resistance and T2D. Indeed, peripheral insulin resistance skeletal muscle tissue was induced by high-fat overfeeding in the LBW subjects only, but still there were no signs of dissociation between T2D is characterized by disturbances in fatty acid insulin resistance and mitochondrial dysfunction (81). metabolism, and mitochondrial dysfunction has been Supporting our findings, other recent studies have also associated with muscle insulin resistance in multiple observed normal mitochondrial function during of high- studies and has therefore been suggested to play an fat induced insulin resistance (86, 87). important role in the pathogenesis of insulin resistance and T2D (82, 83, 84). Mitochondrial function has been associated with deficient oxidative capacity resulting in The role of PGC1α in lipid overload increased amounts of IMCL species and hence lipotoxicity interfering with insulin signaling causing insulin Peroxisome proliferator-activated receptor γ resistance (82, 85). However, the cause of decreased coactivator-1 alpha (PGC1α) plays a central role as a oxidative capacity is not fully elucidated. metabolic sensor and regulator by regulating glucose The idea that mitochondrial deficiency occurs in homeostasis and promoting fatty acid oxidation via close association with impaired insulin action, and hence increasing mitochondrial function and activity (91). could be a general mechanism contributing to a variety PGC1α has therefore been suggested to play a key role of known metabolic defects in T2D, has been widely in the pathogenesis of T2D by preventing lipotoxicity. accepted although data are not fully convincing and have Indeed, severe caloric restriction, which improves insulin been challenged by recent studies. For example, only few sensitivity, increases PGC1α expression in skeletal muscle studies have linked reduced oxidative enzyme activity – of obese subjects (92). Conversely, infusion of lipids European Journal European of Endocrinology often caused by decreased mitochondrial content – to an decreases expression of PGC1α and nuclear-encoded evidence of functional impairment of the mitochondria. mitochondrial genes (93), and experimental high-fat Furthermore, most of the studies on the function of feeding in healthy humans also results in decreased the mitochondria have been performed using indirect PGC1α and mitochondrial gene expression in skeletal measures of oxidative capacity i.e. ATP production in muscle only after 3 days (89). Interestingly, high-fat the resting state as determined by nuclear magnetic and/or hypercaloric diets have been shown to promote resonance (NMR), and several studies have shown a alterations in mitochondrial oxidative phosphorylation dissociation between mitochondrial function and insulin (OXPHOS) activity and to decrease PGC1α gene sensitivity (86, 87). The most obvious metabolic defect of expression (90, 94). Impaired OXPHOS gene expression impaired mitochondrial function is reduced capacity for is anticipated to lower the capacity of the cell to handle aerobic ATP synthesis, either due to a lowered number of substrate in excess, which could also contribute to otherwise normal mitochondria or decreased capacity of exhaustion of mitochondria during longer periods of the individual mitochondria. Although such changes are high energy intake. Nevertheless, when studying the unlikely to cause complete loss of ATP synthesis, it may be expression of the OXPHOS and PGC1α genes in the young expected that significant changes will become unmasked healthy men, no significant effect of high-fat overfeeding under demanding conditions, such as in response to on mRNA levels was observed (95). These findings were energy-depleting exercise (88). further confirmed by the indifferent effect of high- We recently assessed in vivo mitochondrial function fat overfeeding on pathways associated with insulin by 31P-MRS after energy-depleting exercise in young resistance and OXPHOS performed by whole-genome healthy men born with a low birth weight (LBW) and at microarray analyses (95). This finding is in contrast to increased risk of developing T2D, and since diets high the study by Sparks and colleagues that found a diet high

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in fat downregulated genes necessary for OXPHOS and for instance, respiratory changes and ATP production. mitochondrial biogenesis (89). In a separate experiment, However, there were no significant differences inV PROOF ONLY max they fed mice a high-fat diet for 3 weeks and verified their measured either in the forearm flexor muscles or in the findings in humans as they found the same OXPHOS and tibialis anterior muscle of the leg and insulin-stimulated PGC1α mRNA to be downregulated by approximately glucose uptake between NBW and LBW subjects during 90% (89). However, the subjects included in this study control and overfeeding diets. were selected according to a high preference for dietary fat, as indicated by a food preference questionnaire. This Concluding remarks could possibly explain the lowered gene expression as IMCL could already have been accumulated in muscle Many studies have examined the interaction between of these subjects, and thereby alter their sensibility to lipotoxicity and insulin resistance, but whether skeletal overfeeding. The discrepancies between the studies could muscle lipotoxicity is a casual mechanism or an innocent be further explained by differences in the composition of bystander in insulin resistance and T2D is still not fully the intervention diet and duration of the intervention as elucidated. The results are somewhat conflicting, and the well as of the size of the study population. Furthermore, human data linking skeletal muscle lipotoxicity to insulin short-term elevation of lipid availability, by lipid infusion resistance are mostly correlative and limited by the lack reduces insulin-stimulated increase of ATP synthase flux of consistency and therefore do not provide any proof of in skeletal muscle and decrease PGC1α expression in causality. The inconsistent findings are further amplified healthy male subjects (94, 96). This is also in contrast to by the use of different methodology to determine IMCL as our findings; however, lipid infusions may yield different well as the selection of study participants. In addition, the metabolic responses due to the non-physiological nature dietary standardization of study participants seems to be of intravenous infusion. of importance as composition of the diet influences fatty Interestingly, LBW (a prediabetic phenotype) in acid composition to a great extent, and thus is a limitation twins has previously been shown to be associated with of human studies investigating IMCL composition, reduced expression of PGC1α in skeletal muscle (97). possibly explaining the large variations between studies. When exposed to high-fat overfeeding, the mRNA The cellular and molecular mechanisms causing levels of the OXPHOS genes, NDUFB6, UQCRB, ATP5O muscle insulin resistance are not fully understood. and PGC1α, were decreased by approximately 25% in However, the majority of studies agree that it is not the LBW subjects with a previously documented range of total amount of IMCL per se that causes insulin resistance, European Journal European of Endocrinology metabolic abnormalities in insulin-sensitive tissues but rather the accumulation of the lipid intermediates compared with healthy control subjects, and a similar as well as the cellular localization of the lipids. Finally, trend was observed for COX7A1. The significant many studies do agree that a dysfunctional or overloaded difference in ATP5O could indicate a prediabetic trait of adipose tissue and metabolic consequences hereof the LBW subjects, as Mootha et al. found this particular have been seen in prediabetic phenotypes including gene to be most significantly reduced in skeletal muscle individuals subjected to suboptimal fetal environment, of T2D patients (98). UQCRB status has also been found suggesting that lipotoxicity could be potentially more to be a strong predictor of T2D, which likewise could harmful to certain ‘at-risk’ groups of the population. This indicate an early prediabetic trait in LBW subjects (98). harmful effect can possibly be prevented and/or delayed During insulin stimulation, PGC1α gene expression was if the subcutaneous adipose tissue can expand sufficiently. significantly decreased in LBW compared with NBW Focus should therefore be on improved understanding of subjects during overfeeding, and a similar trend was the developmental origins and functions of adipose tissue observed in the remaining OXPHOS genes (99). depots throughout the body. The indifferent response observed between NBW and LBW subjects during control diet suggests that the difference in gene expression between NBW and Future areas of research LBW subjects is only evident during metabolic stress accompanying overfeeding. Assuming that altered The white adipose tissue has a central role in regulating transcriptional regulation will lead to physiologically energy homeostasis and insulin sensitivity, and relevant changes in mitochondrial function, we should impaired expandability of the subcutaneous adipose be able to measure alterations in in vivo estimations of, tissue may be a leading cause for storage of ectopic fat

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Received 10 June 2016 Revised version received 19 August 2016 Accepted 14 September 2016

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