High dietary fat intake leads to insulin resistance in skeletal muscle, and this represents a major risk factor for type 2 diabetes and cardiovascular disease. Mitochondrial dysfunction and oxidative stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the H(2)O(2)-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial H(2)O(2) emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial H(2)O(2) emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity.

The highest amount of weekly exercise, with minimal weight change, had widespread beneficial effects on the lipoprotein profile. The improvements were related to the amount of activity and not to the intensity of exercise or improvement in fitness.

Differences in chromatin organization are key to the multiplicity of cell states that arise from a single genetic background, yet the landscapes of in vivo tissues remain largely uncharted. Here we mapped chromatin genome-wide in a large and diverse collection of human tissues and stem cells. The maps yield unprecedented annotations of functional genomic elements and their regulation across developmental stages, lineages, and cellular environments. They also reveal global features of the epigenome, related to nuclear architecture, that also vary across cellular phenotypes. Specifically, developmental specification is accompanied by progressive chromatin restriction as the default state transitions from dynamic remodeling to generalized compaction. Exposure to serum in vitro triggers a distinct transition that involves de novo establishment of domains with features of constitutive heterochromatin. We describe how these global chromatin state transitions relate to chromosome and nuclear architecture, and discuss their implications for lineage fidelity, cellular senescence and reprogramming.

The purpose of this study was to discern cellular mechanisms that contribute to the suppression of lipid oxidation in the skeletal muscle of obese individuals. Muscle was obtained from obese [body mass index (BMI), 38.3 +/- 3.1 kg/m(2)] and lean (BMI, 23.8 +/- 0.9 kg/m(2)) women, and fatty acid oxidation was studied by measuring (14)CO(2) production from (14)C-labeled fatty acids. Palmitate oxidation, which is at least partially dependent on carnitine palmitoyltransferase-1 (CPT-1) activity, was depressed (P < 0.05) by approximately 50% with obesity (6.8 +/- 2.2 vs. 13.7 +/- 1.4 nmole CO(2).g(-1).h(-1)). The CPT-1-independent event of palmitoyl carnitine oxidation was also depressed (P < 0.01) by approximately 45%. There were significant negative relationships (P < 0.05) for adiposity with palmitate (r = -0.76) and palmitoyl carnitine (r = -0.82) oxidation. Muscle CPT-1 and citrate synthase activity, an index of mitochondrial content, were also significantly (P < 0.05) reduced ( approximately 35%) with obesity. CPT-1 (r = -0.48) and citrate synthase (r = -0.65) activities were significantly (P < 0.05) related to adiposity. These data suggest that lesions at CPT-1 and post-CPT-1 events, such as mitochondrial content, contribute to the reduced reliance on fat oxidation evident in human skeletal muscle with obesity.

Physical activity enhances insulin action in obese/overweight individuals. However, the exercise prescription required for the optimal enhancement is not known. The purpose of this study was to test the hypothesis that exercise training consisting of vigorous-intensity activity would enhance insulin sensitivity more substantially than moderate-intensity activity. Sedentary, overweight/obese subjects (n = 154) were randomly assigned to either control or an exercise group for 6 mo: 1) low-volume/moderate-intensity group [ approximately 12 miles walking/wk at 40-55% peak O2 consumption (Vo2 peak)], 2) low-volume/high-intensity group ( approximately 12 miles jogging/wk at 65-80% Vo2 peak), and 3) high-volume/high-intensity group ( approximately 20 miles jogging/wk at 65-80% Vo2 peak). Training volume (miles/wk) was achieved by exercising approximately 115 min/wk (low-volume/high-intensity group) or approximately 170 min/wk (low-volume/moderate-intensity and high-volume/high-intensity groups). Insulin action was measured with an insulin sensitivity index (SI) from an intravenous glucose tolerance test. In the control group, there was a decrement (P < 0.05) in SI. In contrast, all the exercise groups significantly (P < 0.05) increased SI; the relative increment in the low-volume/moderate-intensity and high-volume/high-intensity groups ( approximately 85%) were greater than in the low-volume/high-intensity group ( approximately 40%). In conclusion, physical activity encompassing a wide range of intensity and volume minimizes the insulin resistance that develops with a sedentary lifestyle. However, an exercise prescription that incorporated approximately 170 min of exercise/wk improved insulin sensitivity more substantially than a program utilizing approximately 115 min of exercise/wk, regardless of exercise intensity and volume. Total exercise duration should thus be considered when designing training programs with the intent of improving insulin action.

; 10.1152/ajpendo.00416.2001.-The purpose of this study was to test the hypothesis that muscle fiber type is related to obesity. Fiber type was compared 1) in lean and obese women, 2) in Caucasian (C) and African-American (AA) women, and 3) in obese individuals who lost weight after gastric bypass surgery. When lean (body mass index 24.0 Ϯ 0.9 kg/m 2 , n ϭ 28) and obese (34.8 Ϯ 0.9 kg/m 2 , n ϭ 25) women were compared, there were significant (P Ͻ 0.05) differences in muscle fiber type. The obese women possessed fewer type I (41.5 Ϯ 1.8 vs. 54.6 Ϯ 1.8%) and more type IIb (25.1 Ϯ 1.5 vs. 14.4 Ϯ 1.5%) fibers than the lean women. When ethnicity was accounted for, the percentage of type IIb fibers in obese AA was significantly higher than in obese C (31.0 Ϯ 2.4% vs. 19.2 Ϯ 1.9%); fewer type I fibers were also found in obese AA (34.5 Ϯ 2.8% vs. 48.6 Ϯ 2.2%). These data are consistent with the higher incidence of obesity and greater weight gain reported in AA women. With weight loss intervention, there was a positive relationship (r ϭ 0.72, P Ͻ 0.005) between the percentage of excess weight loss and the percentage of type I fibers in morbidly obese patients. These findings indicate that there is a relationship between muscle fiber type and obesity. adiposity; African-American; insulin resistance; morbid obesity; skeletal muscle SKELETAL MUSCLE IS A HETEROGENEOUS organ consisting of different muscle fiber phenotypes. In human skeletal muscle, histochemical staining for pH-sensitive myosin ATPase activity has revealed two major classifications of fiber type, the type I and type II fibers (3,28,31). The fast-twitch, type II fibers can be broadly categorized into type IIa and type IIb fibers, although other subclasses exist (3,29,31). The type I, or slow-twitch, muscle fibers tend to be oxidative and vascularized, whereas the type IIb fibers (fast twitch) are glycolytic in nature (28, 31). The type I fibers are also insulin sensitive compared with type II muscle (8,13,17).In humans, there can be substantial heterogeneity of muscle fiber types within a given mixed muscle group. Simoneau and Bouchard (32) concluded that, in the vastus lateralis, Ն25% of the North American Caucasian population possessed either less than 35% or more than 65% type I fibers; a range of 13-98% type I fibers has been reported (31). Several factors may be linked with such variance. We have observed that obese individuals exhibit fewer type I and more type IIb muscle fibers than lean subjects (9). Other research has reported a negative relationship between adiposity and the relative percentage of type I muscle fibers (9, 21, 36) and an increased percentage of type IIb muscle fibers in patients with type 2 diabetes (9, 23), in their insulin-resistant offspring (27), and in obese subjects (18,19,21,23). Such findings make it tempting to speculate that there is a relationship between muscle fiber composition and obesity.The purpose of the current study was to test the hypothesis that muscle fiber type is related to obesity. We tested this hypothesis in...

Ablation of peroxisome proliferator activated receptor (PPAR) ␣, a lipid-activated transcription factor that regulates expression of ␤-oxidative genes, results in profound metabolic abnormalities in liver and heart. In the present study we used PPAR␣ knockout (KO) mice to determine whether this transcription factor is essential for regulating fuel metabolism in skeletal muscle. When animals were challenged with exhaustive exercise or starvation, KO mice exhibited lower serum levels of glucose, lactate, and ketones and higher nonesterified fatty acids than wild type (WT) littermates. During exercise, KO mice exhausted earlier than WT and exhibited greater rates of glycogen depletion in liver but not skeletal muscle. Fatty acid oxidative capacity was similar between muscles of WT and KO when animals were fed and only 28% lower in KO muscles when animals were starved. Exercise-induced regulation and starvation-induced regulation of pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, two classical and robustly responsive PPAR␣ target genes, were similar between WT and KO in skeletal muscle but markedly different between genotypes in heart. Real time quantitative PCR analyses showed that unlike in liver and heart, in mouse skeletal muscle PPAR␦ is severalfold more abundant than either PPAR␣ or PPAR␥. In both human and rodent myocytes, the highly selective PPAR␦ agonist GW742 increased fatty acid oxidation about 2-fold and induced expression of several lipid regulatory genes, including pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, responses that were similar to those elicited by the PPAR␣ agonist GW647. These results show redundancy in the functions of PPARs ␣ and ␦ as transcriptional regulators of fatty acid homeostasis and suggest that in skeletal muscle high levels of the ␦-subtype can compensate for deficiency of PPAR␣.Peroxisome proliferator activated receptors (PPARs) 1 ␣, ␦, and ␥ comprise a family of nuclear hormone receptors that regulate systemic fatty acid metabolism via ligand-dependent transcriptional activation of target genes (1). Strong evidence indicates that their endogenous ligands consist of fatty acids and/or lipid metabolites and that they function to mediate adaptive metabolic responses to changes in systemic fuel availability (1, 2). PPAR␣, which is expressed most abundantly in tissues that are characterized by high rates of fatty acid oxidation (FAO), is considered the primary subtype that mediates lipid-induced activation of FAO genes (3). This premise is based largely on studies of PPAR␣ knockout (KO) mice, which, compared with wild type (WT) littermates, exhibit low rates of ␤-oxidation and abnormal accumulation of neutral lipids in both cardiac and hepatic tissues (4, 5). The metabolic phenotype of KO mice is associated with decreased expression of FAO genes and failure of liver and heart to induce ␤-oxidative pathways in response to physiological or pharmacological perturbations in lipid metabolism (4 -6). Taken together, these studies indicate that, at least in rodents,...

Obesity and type 2 diabetes are strongly associated with abnormal lipid metabolism and accumulation of intramyocellular triacylglycerol, but the underlying cause of these perturbations are yet unknown. Herein, we show that the lipogenic gene, stearoyl-CoA desaturase 1 (SCD1), is robustly up-regulated in skeletal muscle from extremely obese humans. High expression and activity of SCD1, an enzyme that catalyzes the synthesis of monounsaturated fatty acids, corresponded with low rates of fatty acid oxidation, increased triacylglycerol synthesis and increased monounsaturation of muscle lipids. Elevated SCD1 expression and abnormal lipid partitioning were retained in primary skeletal myocytes derived from obese compared to lean donors, implying that these traits might be driven by epigenetic and/or heritable mechanisms. Overexpression of human SCD1 in myotubes from lean subjects was sufficient to mimic the obese phenotype. These results suggest that elevated expression of SCD1 in skeletal muscle contributes to abnormal lipid metabolism and progression of obesity.