Obesity is a chronic disease that is increasing at epidemic proportions. Our research group has been studying skeletal muscle metabolism in severely obese patients for more than 25 yr. These studies were possible initially because of collaborating surgeons providing abdominal muscle (rectus abdominus) biopsies that were examined in muscle strip preparations. These in vitro incubation studies were complimented with experiments using needle biopsies of a leg muscle (vastus lateralis) and skeletal muscle cell cultures derived from the tissue of lean and severely obese donors (11,26). In these preparations, we have observed a consistent metabolic profile in severely obese individuals (body mass index (BMI), ≥40 kg·m−2), which has led us to hypothesize that a constitutive “obesity metabolic program” that contributes to a positive lipid balance and insulin resistance is involved. This review will focus on our findings implicating the existence of a metabolic program in skeletal muscles of severely obese individuals.
THE METABOLIC PROFILE OF THE SKELETAL MUSCLE OF SEVERELY OBESE INDIVIDUALS
To determine if a reduction in fatty acid oxidation (FAO) in skeletal muscles was evident with obesity, we measured the rate of production of labeled carbon dioxide (14CO2) from 14C-labeled palmitate as an index of fat oxidation in rectus abdominus muscle strips (27). To our surprise, FAO did not differ between the muscles of lean (BMI, 23.8 ± 0.6 kg·m−2) and obese (BMI, 30.2 ± 0.8 kg·m−2) individuals but only exhibited a significant reduction (∼60%) in tissue from severely obese (BMI, 53.8 ± 0.4 kg·m−2) subjects (27). Similarly, in needle biopsies from the vastus lateralis, FAO (14C-labeled palmitate) was reduced by approximately 60% with severe obesity (3,29). These congruent findings in two muscle groups were suggestive of a relatively global defect because the tissues sampled were from distinct anatomical areas (abdominal vs leg) with differing functions and recruitment patterns (i.e., postural (rectus) vs locomotion (vastus)). We feel that these consistent findings (3,27,29) provide strong evidence for a reduction in FAO in skeletal muscles of severely obese individuals. These data are summarized in Figure 1.
Our subsequent research focused on identifying cellular mechanisms that could contribute to this reduction in FAO. Proteome analyses revealed an increase in glycolytic enzyme content that was hypothesized to reflect a metabolic shift toward glycolytic energy production to compensate for the decrement in FAO with severe obesity (24). In support, we reported that the ratio of phosphofructokinase to citrate synthase enzyme activities, a surrogate for muscle glycolytic capacity, was elevated in skeletal muscles of severely obese subjects (29). We also observed an elevated generation of lactate from incubated muscle strips, again suggesting an overall metabolic shift (17).
To examine processes involved in FAO directly, muscle biopsy samples were incubated with distinct fatty acids to study the carnitine-mediated transport of fatty acids into the mitochondria at carnitine palmitoyltransferase 1 (CPT-1) and downstream (29). With severe obesity, long-chain (palmitate) oxidation was depressed in conjunction with CPT-1 activity, indicating a possible defect at this step (29). However, the oxidation of palmitoyl carnitine, which enters the mitochondria independently of CPT-1, also was depressed, indicating that processes subsequent to CPT-1, such as β-oxidation and/or the tricarboxylic acid cycle (TCA), also contribute to the reduction in FAO. In support of this tenant, citrate synthase (a TCA cycle enzyme) and β-hydroxyacyl-CoA dehydrogenase (an enzyme involved with β-oxidation) activities were lower in the muscles of severely obese individuals (29). These findings are suggestive of a relatively encompassing metabolic program in skeletal muscles of severely obese individuals, where multiple processes are affected with a resultant decrement in FAO.
As indicated by these data, the metabolic program with severe obesity generally involves decrements in oxidative and increases in glycolytic metabolism. We also have reported that skeletal muscles of severely obese individuals are composed of a lower percentage of Type I muscle fibers (22,33). Type I, or red, muscle fibers typically are insulin sensitive and favor oxidative metabolism compared with Type II (white) muscle fibers; in support, insulin action in our strip preparation was related positively to the percentage of Type I muscle fibers (22). This predominance of Type II fibers with severe obesity is again suggestive of a phenotype that favors a low capacity for lipid oxidation and insulin resistance. However, it is important to note that fiber type, as determined by histochemical staining for myosin adenosine triphosphatase activity (22,33), may not always reflect specific metabolic processes. For example, we have reported that muscle fiber type is not altered in severely obese subjects after the substantial weight loss induced by gastric bypass surgery despite a marked improvement in insulin action (20,25). Such findings indicate that contractile (i.e., fiber type) and metabolic characteristics may not always be congruent.
We and others have reported that severely obese individuals have whole-body insulin resistance (32). Skeletal muscles comprise approximately 45% of body mass in a normal person and are responsible for approximately 75% of the glucose disposal after a meal. Therefore, it was reasonable to investigate mechanisms of insulin resistance in human muscles.
Using the muscle fiber strip preparation (14), we found that glucose transport was stimulated approximately 2.5-fold by insulin in tissue from lean controls, but there was little or no stimulation of glucose transport in muscles from severely obese patients either with or without type 2 diabetes. Glucose transport in muscles of severely obese patients, both diabetic and nondiabetic, also was resistant to the action of insulin-like growth factor 1 (13). Cumulative data demonstrated that glucose transport was stimulated by approximately threefold to fourfold for individuals with a BMI of 20 kg·m−2 or less, but there was a progressive decline in insulin responsiveness in individuals with a BMI of about 30 kg·m−2, after which there virtually was no insulin-induced stimulation (16). In addition to glucose transport, insulin stimulation of glycogen formation, glucose oxidation, and nonoxidized glycolysis also were depressed in muscles of severely obese patients (10). Lactate release was not stimulated by insulin, but basal (absence of insulin) lactate release was much higher in obese than nonobese controls, suggesting a preferential utilization of carbohydrate as a fuel source (17).
Muscle contraction stimulates glucose transport in a manner similar to insulin, that is, translocation of glucose transporters to the cell membrane. Thus, we asked the question whether muscles from obese individuals also were “resistant” to stimulation by muscle contraction. In obese Zucker rats, muscle contraction stimulated glucose transport normally, although there was severe insulin resistance (15). We were not able to make human muscle fiber strips contract but did observe that hypoxia and vanadate, two stimuli that are believed to function through pathways also activated by muscle contraction, stimulated glucose transport normally in muscle strips from severely obese insulin-resistant individuals (1,9). From these data, we concluded that the mechanism for the translocation of the insulin-sensitive glucose transporter (GLUT4) was functional and the defect must be upstream and within the signaling pathway, leading to insulin-mediated glucose transport. To investigate the effects of obesity on insulin signal transduction, we again used the muscle fiber strip preparation in the presence and absence of insulin. Insulin stimulation of insulin receptor and insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and activation of phosphatidylinositol 3-kinase and Akt (also known as protein kinase B) were reduced substantially with severe obesity (8,19).
To investigate differences in the insulin signaling pathway in severely obese subjects, we partially purified insulin receptors from biopsy tissue and found that the insulin receptors of severely obese subjects had lower tyrosine kinase activity than those of nonobese controls (10). When the insulin receptors from muscles of obese individuals were treated with a serine phosphatase, the tyrosine kinase activity was restored to normal. This suggests that insulin receptors are highly serine phosphorylated in muscles of severely obese individuals, and this inhibits activity, which is restored when the phosphate is removed (28,35). Phosphorylation of the insulin receptor and IRS-1 on tyrosine residues activates the signaling pathway, whereas serine phosphorylation inhibits signal transduction. IRS-1 from muscles of severely obese patients also was found to be hyperphosphorylated, especially on serine 312, which would inhibit activity (4). These changes in serine phosphorylation were accompanied by increased activities of several serine kinases, including protein kinase C (PKC) (28,35). PKC is activated by diacylglycerol, which is one of the lipids stored muscles of obese individuals. The involvement of PKC also was implicated by the finding that insulin resistance could be induced by a phorbol ester, which activates PKC, and insulin sensitivity restored in obese muscles with a PKC inhibitor (12). Based on these findings, our hypothesis is that several kinases are activated in muscles of severely obese individuals with subsequent serine phosphorylation of the insulin receptor and IRS-1, which in turn reduces activity. These modifications depress insulin signal transduction and stimulation of glucose transport, glycogen synthesis, glucose oxidation, and nonoxidized glycolysis.
CHARACTERISTICS OF MYOTUBES RAISED IN CULTURE FROM SEVERELY OBESE INDIVIDUALS
Satellite cells from muscle biopsy samples can be cultured into myoblasts and, subsequently, myotubes that closely resemble mature muscle fibers. In this preparation, the influence of factors such as neural input, hormonal concentrations, and physical activity level on metabolic characteristics essentially are removed because of the length and nature of the proliferation and differentiation phases; findings obtained in human skeletal muscle cells (HSkMC) raised in culture are thus thought to reflect a phenotype resulting from a specific DNA sequence (i.e., genetic) and/or from changes to the genome that do not involve a change in the nucleotide sequence (i.e., epigenetic). We initiated studies with the intent of determining if characteristics evident in vivo and in vitro were retained in HSkMC with severe obesity. This model also permitted experimental manipulation of variables to discern cellular mechanisms that could not be accomplished in intact humans.
Our initial experiments were designed to determine if the decrement we reported in FAO (3,27,29) was retained in HSkMC. As presented in Figure 1, the magnitude of the reduction in FAO with severe obesity virtually was identical in HSkMC compared with intact muscle strips or muscle homogenates (2,3,11,26). In addition, an index of oxidation efficiency (incomplete oxidation divided by complete oxidation) was similar between HSkMC and in vitro measurements in skeletal muscles (2,3,11,26). Indices indicating increased lipid partitioning toward storage (i.e.,14C incorporation into triacylglycerol, phospholipids, and diacylglycerol) also were approximate and even slightly elevated in HSkMC (2,3,11,26). These findings indicate that the metabolic signature evident in skeletal muscles of severely obese individuals in relation to FAO is maintained in HSkMC (Fig. 1).
Gene arrays and polymerase chain reaction (PCR) analyses indicated multiple differences in gene expression with severe obesity, with one of the more pronounced being a twofold elevation in stearoyl-CoA desaturase 1 (SCD-1) expression; this elevation in SCD-1 mRNA content also was evident in HSkMC (26). SCD-1 is a lipogenic enzyme that directs palmitoyl-CoA (C16:0) and stearoyl-CoA (C 18:0) toward lipid synthesis but has no readily discernible effects on FAO. To mimic the severely obese state, we overexpressed SCD-1 in HSkMC from lean subjects. This treatment elicited a reduction in FAO and concomitantly increased lipid storage, both of which are characteristics of HSkMC from severely obese individuals (26). The fact that both FAO and lipid storage were altered with overexpression suggests that SCD-1 may impart a multitiered level of control, with the ultimate result of lipid accumulation.
In terms of other cellular mechanisms, there are conflicting findings of whether a reduction in mitochondrial content or a decrement in mitochondrial function is responsible for the lower FAO evident with obesity. In HSkMC from severely obese donors, mitochondrial content, as determined by mitochondrial DNA copy number (mtDNA) and cytochrome c oxidase IV (COX-IV) protein content, was reduced significantly (11). However, FAO was equivalent between lean and obese individuals after correcting for these indices of mitochondrial content (i.e., FAO/mtDNA; FAO/COX-IV) (11). These data suggest that the mitochondria of severely obese individuals function normally and that the overall reduction in FAO can be attributed primarily to a reduction in mitochondrial content (11).
To examine if skeletal muscles from severely obese individuals are resistant to stimuli for mitochondrial biogenesis, PGC-1α, a transcriptional coactivator that stimulates mitochondrial biogenesis, was overexpressed in HSkMC (11). This manipulation increased mitochondrial content and FAO in myotubes from severely obese individuals; however, FAO remained depressed compared with that in lean controls, which suggests that the severely obese state limits both mitochondrial biogenesis and oxidative capacity via mechanisms that are independent of PGC-1α abundance (11). Together, these data obtained in HSkMC (11,26) suggest that lipid oxidation is reduced inherently in skeletal muscles of severely obese individuals because of impairments at several levels of lipid metabolism (i.e., increase SCD-1 expression, reduced mitochondrial content).
We questioned whether the insulin resistance and changes in insulin signal transduction that we observed in muscle tissue biopsies and in in vitro incubated muscle fiber strips of severely obese individuals would extend into primary cell culture. Insulin stimulation of IRS-1 tyrosine phosphorylation and Akt phosphorylation, both of which would increase signal transduction, were blunted significantly in HSkMC from severely obese patients (2,5). This “blunting” of insulin-stimulated IRS-1 tyrosine phosphorylation in muscle fiber strips of severely obese individuals was approximately 60% compared with that in lean controls and was reproduced essentially in HSkMC, whereas the degree of blunting of Akt activation was even greater in HSkMC than in intact muscles (2,5,8,19).
As mentioned in a previous section, IRS-1 becomes serine phosphorylated in insulin-resistant muscles, which inhibits downstream signaling. Therefore, serine 312 phospho-IRS-1 can be a useful marker of insulin resistance. Muscle serine 312-phospho-IRS-1 was elevated in both intact tissue biopsies and in HSkMC from severely obese subjects, compared with that in lean controls (Fig. 2). These data suggest that there are constitutive changes in insulin signaling in skeletal muscles of severely obese patients that are retained in HSkMC raised in culture.
THE IMPACT OF LIPID EXPOSURE ON THE METABOLIC PROGRAM
A high-fat, energy-rich diet likely is one of the primary factors contributing to the development of obesity and ectopic lipid accumulation. However, there is evidence that lean and obese individuals differ with respect to their ability to increase fatty acid oxidation in the face of an increased lipid load that can, in turn, influence the magnitude of positive lipid balance. Lipid alone also appears to be detrimental because relatively acute exposures can inhibit processes such as insulin signal transduction in skeletal muscles. As the effects of lipid exposure are encompassing and relevant to the obese condition, we have examined the ability of lipid exposure to increase FAO and induce insulin resistance in lean and severely obese individuals.
Metabolic flexibility is defined as the ability to adjust fuel utilization with respect to fuel availability. The capacity for metabolic flexibility is an important trait in the free-living environment, as not responding appropriately to dietary lipid or temporary excursions where dietary lipid is elevated could result in positive lipid balance and accumulation.
To examine metabolic flexibility, HSkMC from lean and severely obese subjects were incubated with a fatty acid mixture (palmitate:oleate) for 24 h and FAO determined with high-resolution respirometry (7). State 3 (adenosine diphosphate–stimulated) respiration with lipid (palmitate) as the substrate increased after the 24-h lipid exposure in HSkMC from lean subjects, reflecting metabolic flexibility. This increase in FAO was accompanied by an elevation in mtDNA and a trend for an increase in COX-IV protein content, both of which suggest that mitochondrial content increased (7). In contrast, there were no comparable responses to increased lipid presence in HSkMC from severely obese individuals (7). These findings suggest an impaired capacity for metabolic flexibility in response to lipid in skeletal muscles of severely obese individuals.
To gauge the capacity for metabolic flexibility in response to dietary lipid, we placed lean and severely obese individuals on a 5-d high-fat diet ((HFD) 65% of total energy from fat) and examined the responsiveness of genes controlling FAO and mitochondrial content in skeletal muscles (6). The mRNA content for peroxisome proliferator–activated receptor–α (PPAR-α), a broad transcriptional regulator that up-regulates FAO, increased in lean subjects after a single high-fat meal; in contrast, there was no change in PPAR-α expression in severely obese subjects (6). After the 5-d HFD, PPAR-α and the expression of other genes linked with enhancing lipid oxidation (PDK4, PGC-1α) increased in the lean subjects; however, we observed no concomitant changes in gene expression in muscles of severely obese individuals (6). With the HFD, acylcarnitine derivatives from long-chain fatty acids were not altered, indicating no adaptation at the level of CPT-1 in either the lean or severely obese individuals. However, shorter chain acylcarnitine (6–12 carbons) species decreased in the lean subjects with the HFD, suggestive of an increase in FAO. These findings (6,7) indicate an inability to increase FAO in skeletal muscles in response to lipid exposure with severe obesity. This impairment may be an underlying defect contributing to the lower mitochondrial content evident with severe obesity as muscles are subjected constantly to elevated lipid concentrations during normal activities such as an overnight fast and dietary fat consumption. An inability to increase FAO appropriately with lipid exposure also results in a positive lipid balance, which may predispose an individual to weight gain. This lack of metabolic flexibility may thus be a critical component of the metabolic program evident with severe obesity.
Muscle cells in culture are an excellent tool to investigate the mechanisms of insulin resistance. We have been interested in what treatments might cause insulin resistance in HSkMC from lean individuals and how we might reverse the insulin resistance in cells of severely obese subjects. Because HFD cause insulin resistance in skeletal muscles, we investigated the effects of incubating HSkMC from lean and severely obese subjects in fatty acids for 12 to 48 h. Consistent with our hypothesis, fatty acids caused insulin resistance in HSkMC from lean controls, increased IRS-1 serine 312 phosphorylation, and decreased insulin-stimulated IRS-1 tyrosine phosphorylation and Akt activation in cells from lean controls to values approximating those in myotubes from severely obese subjects (5). Because cells from severely obese subjects were already insulin resistant, there was no further effect of fatty acid incubation.
Activation of adenosine monophosphate kinase (AMPK) is known to reverse insulin resistance in animal models, and metformin may increase insulin sensitivity in humans through this mechanism. Therefore, we tested whether activation of AMPK could reverse insulin resistance in HSkMC from severely obese individuals. AICAR (an activator of AMPK) incubation rescued insulin signal transduction in HSkMC from severely obese subjects or cells from lean controls treated with fatty acids (5). These results suggest that treatment of insulin-sensitive skeletal muscles with fatty acids induces insulin resistance to a degree equivalent to HSkMC from severely obese subjects. Likewise, insulin resistance caused by either fatty acid treatment or severe obesity can be reversed through the activation of AMPK.
CAN THE METABOLIC PROGRAM OF SEVERE OBESITY BE EFFECTIVELY TREATED?
If our obesity metabolic program hypothesis is correct, a related question is whether the program can be “turned off” and metabolism can be returned to values similar to those in lean individuals. Two interventions that were available for us to test this question were weight loss induced by gastric bypass surgery and physical activity.
Fat Metabolism and Weight Loss
When examining the decrement in FAO with severe obesity, the classic “chicken-or-egg” question arises, that is, is FAO impaired before developing severe obesity and thus possibly contribute to weight gain or does the reduction in FAO develop as a consequence of being severely obese? One way of addressing this issue was using the HSkMC model as already discussed. However, another approach is to reverse the condition of severe obesity to the preseverely obese state and determine if FAO is, in turn, normalized. From a clinical perspective, it also is important to examine the effectiveness of weight loss in addressing the deficits in metabolism evident with severe obesity.
To determine if weight loss normalizes FAO, Berggren et al. (3) compared FAO in severely obese women who were weight stable for 1 yr or longer after gastric bypass surgery with those in lean controls and severely obese individuals. FAO in skeletal muscles (vastus lateralis) did not differ between the gastric bypass surgery/weight loss (BMI, 36.5 ± 3.5 kg·m−2) and severely obese (50.7 ± 3.9 kg·m−2) groups and was depressed compared with that in the lean (22.8 ± 1.2 kg·m−2) women. Studying individuals using a repeated-measures design before and approximately 1 yr after gastric bypass surgery, we also observed that FAO remained depressed in women who lost 55 kg to achieve a mean BMI of 30.5 ± 2.3 kg·m−2 (3). Tracer methodology (13C palmitate and 14C acetate) was used to compare FAO in lean, severely obese, and postgastric bypass patients who had lost more than 45 kg to achieve a BMI of 33.7 ± 9.9 kg·m−2 (34). Similar to skeletal muscles, whole-body FAO was depressed in the gastric bypass/weight loss and severely obese women both during rest and mild (50% V˙O2max) exercise (34). A comparison of fat utilization during submaximal exercise with indirect calorimetry also indicated that whole-body lipid oxidation was depressed in previously severely obese women who had lost weight via gastric bypass surgery compared with that in weight-matched controls (21).
Together, these observations, as summarized in Figure 1, indicate that the decrement in FAO with severe obesity remains evident despite pronounced weight loss and reversal of the severely obese state. If an impairment in FAO is linked with weight gain, an inability to normalize FAO with weight loss intervention may explain why some individuals are predisposed to weight regain after dietary interventions. In severely obese individuals, the mechanical limitations imposed by the gastric bypass procedure may be the only practical and effective intervention to ensure long-term weight loss.
Insulin Action and Weight Loss
Results from a number of laboratories have reported that weight loss is associated with an improvement in insulin action. However, the degree of obesity and insulin resistance in those studies was not as severe as in our patients. To test whether weight loss after gastric bypass could reverse the insulin resistance of severe obesity, we studied a group of women who lost approximately 50 kg after surgery and were weight stable for at least 3 months (surgery/weight loss group) (4). Because the experimental subjects still had a BMI of approximately 30 kg·m−2, the surgery/weight loss group was compared with 1) severely obese women, 2) weight- and age-matched women who were never severely obese, and 3) age-matched but lean (BMI, <25 kg·m−2) women. Whole-body insulin sensitivity (insulin sensitivity index (SI) determined from a frequently sampled intravenous glucose tolerance test) was much lower in severely obese individuals compared with that in the other groups (4). The SI of the surgery/weight loss group was not different than the lean group and was higher than in the weight-matched women. Likewise, muscle IRS-1 serine 312 phosphorylation in the surgery/weight loss group matched that of the lean group and significantly was lower than that of the severely obese or the weight-matched groups. Thus, the weight loss induced by gastric bypass not only reverses insulin resistance but actually improves insulin sensitivity to a degree that is superior to that seen in weight-matched controls. This improvement in insulin action cannot be attributed to increased physical activity after gastric bypass, which is equivalent between previously severely obese surgery patients and weight-matched sedentary controls (21). Prospective studies have confirmed that gastric bypass surgery dramatically enhances insulin action in severely obese patients (20,25).
In terms of possible mechanisms, we observed no change in the concentration of the insulin-sensitive glucose transporter (GLUT4) with weight loss (18). Insulin receptor concentration, however, doubled, which may contribute to the improvement in insulin action seen with the intervention (31). Gene array and real-time PCR analyses indicated that growth factor receptor–bound protein 14, glycerol-3-phosphate dehydrogenase, and myostatin were elevated with severe obesity and reduced with weight loss (30). Pathway analyses indicated the involvement of these genes in weight-loss responsive networks, which could improve insulin signaling, decrease triglyceride synthesis, and increase muscle mass (30). The predominance of insulin-resistant glycolytic muscle fibers evident with severe obesity (22) was not altered with gastric bypass surgery (20), although a higher initial percentage of Type I fibers was associated with a greater rate of weight reduction (33). In contrast, intramuscular triacylglycerol and long-chain fatty acyl-CoA concentrations (palmityl, stearate, and linoleate CoA) were reduced dramatically (20,25). This reduction in intramuscular lipid content could contribute to the improvement in insulin action seen with gastric bypass surgery as intracellular lipids can induce insulin resistance.
Fat Metabolism, Insulin Action, and Exercise
Classic responses to endurance-oriented exercise training include an increase in the capacity of skeletal muscles for FAO and an improvement in insulin action. Our laboratories have used relatively acute programs (7–10 consecutive days) to discern the effects of endurance-oriented exercise training on insulin action and FAO. This model is used because 1) there is little to no loss in body mass, thus minimizing the effect of this potentially confounding factor, and 2) it facilitates the recruitment and retention of populations typically not accustomed to exercise training. To examine the impact of exercise on insulin action, severely obese men trained for 7 consecutive days (60 min·d-1, ∼65% V˙O2peak) with insulin action determined via an oral glucose tolerance test (OGTT) in the sedentary condition and approximately 16 h after the final exercise bout (23). Exercise training reduced fasting and 2-h insulin concentrations and the insulin area under the curve during the OGTT, indicating improved insulin action.
A similar training prescription (10 consecutive days, 60 min·d-1, ∼70% V˙O2peak) was used to examine the effect of exercise on FAO (3). We studied previously severely obese individuals who had lost weight via gastric bypass surgery because of their ability to ambulate effectively and achieve and maintain the desired exercise intensity. In agreement with our previous findings, FAO was reduced and incomplete FAO was elevated in the gastric bypass/weight loss compared with those in lean and a group of obese, but not severely obese, subjects. The 10 d of exercise training increased FAO by approximately twofold in the lean and obese groups and, despite the initial impairment, also increased FAO in the gastric bypass/weight loss group to the extent that there was no difference between the lean, obese, and weight loss groups after the intervention. Incomplete oxidation also was normalized after exercise training (3). These findings (3,23) indicate that exercise training can be used to alleviate effectively the phenotype/metabolic program of insulin resistance and reduced FAO evident with severe obesity, although the cellular mechanisms remain to be defined (see Fig. 1).
Severe obesity (BMI, ≥40 kg·m−2) is associated with insulin resistance and a reduced capacity for fatty acid oxidation in skeletal muscles. These characteristics remain intact in HSkMC raised in culture, which has led us to hypothesize that the skeletal muscle of severely obese individuals displays an inherent global metabolic program (see Fig. 3). We believe that this concept represents a paradigm shift in our perception of obesity. For example, the deficit in FAO and inability to increase FAO appropriately in response to ingested lipid (lack of metabolic flexibility) may predispose an individual toward ectopic lipid accumulation and weight gain and possibly the development of the severely obese state. The present findings also indicate that the metabolic program linked with insulin resistance can be induced by fatty acid exposure.
As presented in Figure 3, weight loss via gastric bypass surgery can turn off components of this metabolic program as insulin sensitivity is restored or even enhanced compared with that in weight-matched controls. However, gastric bypass/weight loss does not rescue the decrement in FAO, which may explain a propensity for weight regain after or a resistance to diet-induced weight loss and why the mechanical limitations imposed by the gastric bypass procedure are needed for an effective intervention. Endurance-oriented exercise training can improve FAO and insulin action in severely obese individuals, indicating that this patient population is not “exercise resistant”; exercise should thus be considered as an adjunct to weight loss intervention. The biological mechanisms linked with these perturbations and interventions are yet to be discerned largely. In conclusion, it is hoped that the research summarized in this review can aid in preventing and/or treating the severely obese condition.
This study was supported by the National Institutes of Health (J.A. Houmard, W.J. Pories, G.L. Dohm), Johnson and Johnson (W.J. Pories, G.L. Dohm), and GlaxoSmithKline (W.J. Pories, G.L. Dohm).
The authors declare no conflicts of interest.
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