Previous studies have suggested that insulin resistance develops secondary to diminished fat oxidation and resultant accumulation of cytosolic lipid molecules that impair insulin signaling. Contrary to this model, the present study used targeted metabolomics to find that obesity-related insulin resistance in skeletal muscle is characterized by excessive beta-oxidation, impaired switching to carbohydrate substrate during the fasted-to-fed transition, and coincident depletion of organic acid intermediates of the tricarboxylic acid cycle. In cultured myotubes, lipid-induced insulin resistance was prevented by manipulations that restrict fatty acid uptake into mitochondria. These results were recapitulated in mice lacking malonyl-CoA decarboxylase (MCD), an enzyme that promotes mitochondrial beta-oxidation by relieving malonyl-CoA-mediated inhibition of carnitine palmitoyltransferase 1. Thus, mcd(-/-) mice exhibit reduced rates of fat catabolism and resist diet-induced glucose intolerance despite high intramuscular levels of long-chain acyl-CoAs. These findings reveal a strong connection between skeletal muscle insulin resistance and lipid-induced mitochondrial stress.

Background Significant evidence indicates that the failing heart is “energy-starved”. During the development of heart failure, the capacity of the heart to utilize fatty acids, the chief fuel, is diminished. Identification of alternate pathways for myocardial fuel oxidation could unveil novel strategies to treat heart failure. Methods and Results Quantitative mitochondrial proteomics was used to identify energy metabolic derangements that occur during the development of cardiac hypertrophy and heart failure in well-defined mouse models. As expected, amounts of proteins involved in fatty acid utilization were downregulated in myocardial samples from the failing heart. Conversely, expression of β-hydroxybutyrate dehydrogenase 1 (BDH1), a key enzyme in the ketone oxidation pathway, was increased in the heart failure samples. Studies of relative oxidation studies in an isolated heart preparation using ex vivo NMR combined with targeted quantitative myocardial metabolomic profiling using mass spectrometry revealed that the hypertrophied and failing heart shifts to oxidizing ketone bodies as a fuel source in the context of reduced capacity to oxidize fatty acids. Distinct myocardial metabolomic signatures of ketone oxidation were identified. Conclusions These results indicate that the hypertrophied and failing heart shifts to ketone bodies as a significant fuel source for oxidative ATP production. Specific metabolite biosignatures of in vivo cardiac ketone utilization were identified. Future studies aimed at determining whether this fuel shift is adaptive or maladaptive could unveil new therapeutic strategies for heart failure.

Peroxisome proliferator-activated receptor-␥ co-activator 1␣ (PGC1␣) is a promiscuous co-activator that plays a key role in regulating mitochondrial biogenesis and fuel homeostasis. Emergent evidence links decreased skeletal muscle PGC1␣ activity and coincident impairments in mitochondrial performance to the development of insulin resistance in humans. Here we used rodent models to demonstrate that muscle mitochondrial efficiency is compromised by diet-induced obesity and is subsequently rescued by exercise training. Chronic high fat feeding caused accelerated rates of incomplete fatty acid oxidation and accumulation of ␤-oxidative intermediates. The capacity of muscle mitochondria to fully oxidize a heavy influx of fatty acid depended on factors such as fiber type and exercise training and was positively correlated with expression levels of PGC1␣. Likewise, an efficient lipid-induced substrate switch in cultured myocytes depended on adenovirus-mediated increases in PGC1␣ expression. Our results supported a novel paradigm in which a high lipid supply, occurring under conditions of low PGC1␣, provokes a disconnect between mitochondrial ␤-oxidation and tricarboxylic acid cycle activity. Conversely, the metabolic remodeling that occurred in response to PGC1␣ overexpression favored a shift from incomplete to complete ␤-oxidation. We proposed that PGC1␣ enables muscle mitochondria to better cope with a high lipid load, possibly reflecting a fundamental metabolic benefit of exercise training.Obesity and type 2 diabetes are two closely associated diseases that continue to affect Westernized societies at epidemic rates (1). Results from both epidemiological and animal studies suggest that the risk of developing these diseases is increased by consumption of a high fat diet (2), which has been attributed in part to increased intramuscular triacylglycerol storage and adverse changes in skeletal muscle energy metabolism (3). Moreover, mounting evidence from animal and cellbased models indicates that lipid oversupply to skeletal muscle results in functional perturbations that eventually manifest as impaired insulin action (2, 4, 5). Together, these and other reports have established a compelling connection between muscle lipid dysregulation and impaired metabolic control at both the cellular and systemic levels. Despite intense investigation, a clear understanding of the biochemical and molecular mechanisms that mediate lipid-induced muscle dysfunction has remained elusive.Similar to high fat feeding, exercise training increases skeletal muscle supply and storage of lipid substrates (6). However, in contrast to the adverse events provoked by a high fat diet, exercise is known to promote muscle as well as whole body metabolic fitness (7). These observations suggest that physical activity somehow enhances the capacity of the muscle to tolerate and/or adapt to a high lipid load. Indeed, contractile activity leads to dramatic adjustments in oxidative fuel metabolism that are largely mediated by an increase in muscle mitochondria...

Lipid infusion or ingestion of a high-fat diet results in insulin resistance, but the mechanism underlying this phenomenon remains unclear. Here we show that, in rats fed a high-fat diet, whole-animal, muscle and liver insulin resistance is ameliorated following hepatic overexpression of malonyl-coenzyme A (CoA) decarboxylase (MCD), an enzyme that affects lipid partitioning. MCD overexpression decreased circulating free fatty acid (FFA) and liver triglyceride content. In skeletal muscle, levels of triglyceride and long-chain acyl-CoA (LC-CoA)-two candidate mediators of insulin resistance-were either increased or unchanged. Metabolic profiling of 36 acylcarnitine species by tandem mass spectrometry revealed a unique decrease in the concentration of one lipid-derived metabolite, beta-OH-butyrate, in muscle of MCD-overexpressing animals. The best explanation for our findings is that hepatic expression of MCD lowered circulating FFA levels, which led to lowering of muscle beta-OH-butyrate levels and improvement of insulin sensitivity.