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Genetic activation of pyruvate dehydrogenase alters oxidative substrate selection to induce skeletal muscle insulin resistance.

ABSTRACT: The pyruvate dehydrogenase complex (PDH) has been hypothesized to link lipid exposure to skeletal muscle insulin resistance through a glucose-fatty acid cycle in which increased fatty acid oxidation increases acetyl-CoA concentrations, thereby inactivating PDH and decreasing glucose oxidation. However, whether fatty acids induce insulin resistance by decreasing PDH flux remains unknown. To genetically examine this hypothesis we assessed relative rates of pyruvate dehydrogenase flux/mitochondrial oxidative flux and insulin-stimulated rates of muscle glucose metabolism in awake mice lacking pyruvate dehydrogenase kinase 2 and 4 [double knockout (DKO)], which results in constitutively activated PDH. Surprisingly, increased glucose oxidation in DKO muscle was accompanied by reduced insulin-stimulated muscle glucose uptake. Preferential myocellular glucose utilization in DKO mice decreased fatty acid oxidation, resulting in increased reesterification of acyl-CoAs into diacylglycerol and triacylglycerol, with subsequent activation of PKC-? and inhibition of insulin signaling in muscle. In contrast, other putative mediators of muscle insulin resistance, including muscle acylcarnitines, ceramides, reactive oxygen species production, and oxidative stress markers, were not increased. These findings demonstrate that modulation of oxidative substrate selection to increase muscle glucose utilization surprisingly results in muscle insulin resistance, offering genetic evidence against the glucose-fatty acid cycle hypothesis of muscle insulin resistance.

SUBMITTER: Rahimi Y

PROVIDER: S-EPMC4246337 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Genetic activation of pyruvate dehydrogenase alters oxidative substrate selection to induce skeletal muscle insulin resistance.

Rahimi Yasmeen Y Camporez João-Paulo G JP Petersen Max C MC Pesta Dominik D Perry Rachel J RJ Jurczak Michael J MJ Cline Gary W GW Shulman Gerald I GI

Proceedings of the National Academy of Sciences of the United States of America 20141103 46

The pyruvate dehydrogenase complex (PDH) has been hypothesized to link lipid exposure to skeletal muscle insulin resistance through a glucose-fatty acid cycle in which increased fatty acid oxidation increases acetyl-CoA concentrations, thereby inactivating PDH and decreasing glucose oxidation. However, whether fatty acids induce insulin resistance by decreasing PDH flux remains unknown. To genetically examine this hypothesis we assessed relative rates of pyruvate dehydrogenase flux/mitochondrial ...[more]

PMID: 25368185

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Project description:Maternal obesity can program metabolic syndrome in offspring but the mechanisms are not well characterized. Moreover, the consequences of maternal overnutrition in the absence of frank obesity remain poorly understood. This study aimed to determine the effects of maternal consumption of a high fat-sucrose diet on the skeletal muscle metabolic and transcriptional profiles of adult offspring. Female Sprague Dawley rats were fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. Although maternal weights were not different between groups at conception or weaning, HFD dams were ~22% heavier than chow fed dams from mid-pregnancy until 4 days post-partum. Adult male offspring of HFD dams were not heavier than controls but demonstrated features of insulin resistance including elevated plasma insulin concentration (+40%, P<0.05). Next Generation mRNA Sequencing was used to identify differentially expressed genes in the soleus muscle of offspring, and Gene Set Enrichment Analysis (GSEA) to detect coordinated changes that are characteristic of a biological function. GSEA identified 15 pathways enriched for up-regulated genes, including cytokine signaling (P<0.005), starch and sucrose metabolism (P<0.017), and inflammatory response (P<0.024). A further 8 pathways were significantly enriched for down-regulated genes including oxidative phosphorylation (P<0.004) and electron transport (P<0.022). Western blots confirmed a ~60% reduction in the phosphorylation of the insulin signaling protein Akt (P<0.05) and ~70% reduction in mitochondrial complexes II (P<0.05) and V expression (P<0.05). On a normal diet, offspring of HFD dams developed an insulin resistant phenotype, with transcriptional evidence of muscle cytokine activation, inflammation and mitochondrial dysfunction. These data indicate that maternal overnutrition, even in the absence of pre-pregnancy obesity can promote metabolic dysregulation and predispose offspring to type 2 diabetes. Messenger RNA profile of skeletal muscle of male offspring from female Sprague Dawley rats fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. There were 5 HFD samples compared to 6 NFD control samples.

Project description:Aims/hypothesisMitochondria operate in networks, adapting to external stresses and changes in cellular metabolic demand and are subject to various quality control mechanisms. On the basis of these traits, we here hypothesise that the regulation of mitochondrial networks in skeletal muscle is hampered in humans with compromised oxidative capacity and insulin sensitivity.MethodsIn a cross-sectional design, we compared four groups of participants (selected from previous studies) ranging in aerobic capacity and insulin sensitivity, i.e. participants with type 2 diabetes (n = 11), obese participants without diabetes (n = 12), lean individuals (n = 10) and endurance-trained athletes (n = 12); basal, overnight fasted muscle biopsies were newly analysed for the current study and we compared the levels of essential mitochondrial dynamics and quality control regulatory proteins in skeletal muscle tissue.ResultsType 2 diabetes patients and obese participants were older than lean participants and athletes (58.6 ± 4.0 and 56.7 ± 7.2 vs 21.8 ± 2.5 and 25.1 ± 4.3 years, p < 0.001, respectively) and displayed a higher BMI (32.4 ± 3.7 and 31.0 ± 3.7 vs 22.1 ± 1.8 and 21.0 ± 1.5 kg/m2, p < 0.001, respectively) than lean individuals and endurance-trained athletes. Fission protein 1 (FIS1) and optic atrophy protein 1 (OPA1) protein content was highest in muscle from athletes and lowest in participants with type 2 diabetes and obesity, respectively (FIS1: 1.86 ± 0.79 vs 0.79 ± 0.51 AU, p = 0.002; and OPA1: 1.55 ± 0.64 vs 0.76 ± 0.52 AU, p = 0.014), which coincided with mitochondrial network fragmentation in individuals with type 2 diabetes, as assessed by confocal microscopy in a subset of type 2 diabetes patients vs endurance-trained athletes (n = 6). Furthermore, lean individuals and athletes displayed a mitonuclear protein balance that was different from obese participants and those with type 2 diabetes. Mitonuclear protein balance also associated with heat shock protein 60 (HSP60) protein levels, which were higher in athletes when compared with participants with obesity (p = 0.048) and type 2 diabetes (p = 0.002), indicative for activation of the mitochondrial unfolded protein response. Finally, OPA1, FIS1 and HSP60 correlated positively with aerobic capacity (r = 0.48, p = 0.0001; r = 0.55, p < 0.001 and r = 0.61, p < 0.0001, respectively) and insulin sensitivity (r = 0.40, p = 0.008; r = 0.44, p = 0.003 and r = 0.48, p = 0.001, respectively).Conclusions/interpretationCollectively, our data suggest that mitochondrial dynamics and quality control in skeletal muscle are linked to oxidative capacity in humans, which may play a role in the maintenance of muscle insulin sensitivity. CLINICAL TRIAL REGISTRY: numbers NCT00943059, NCT01298375 and NL1888 Graphical abstract.

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Genetic activation of pyruvate dehydrogenase alters oxidative substrate selection to induce skeletal muscle insulin resistance.

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Genetic activation of pyruvate dehydrogenase alters oxidative substrate selection to induce skeletal muscle insulin resistance.

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