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High-fat diets cause insulin resistance despite an increase in muscle mitochondria.

ABSTRACT: It has been hypothesized that insulin resistance is mediated by a deficiency of mitochondria in skeletal muscle. In keeping with this hypothesis, high-fat diets that cause insulin resistance have been reported to result in a decrease in muscle mitochondria. In contrast, we found that feeding rats high-fat diets that cause muscle insulin resistance results in a concomitant gradual increase in muscle mitochondria. This adaptation appears to be mediated by activation of peroxisome proliferator-activated receptor (PPAR)delta by fatty acids, which results in a gradual, posttranscriptionally regulated increase in PPAR gamma coactivator 1alpha (PGC-1alpha) protein expression. Similarly, overexpression of PPARdelta results in a large increase in PGC-1alpha protein in the absence of any increase in PGC-1alpha mRNA. We interpret our findings as evidence that raising free fatty acids results in an increase in mitochondria by activating PPARdelta, which mediates a posttranscriptional increase in PGC-1alpha. Our findings argue against the concept that insulin resistance is mediated by a deficiency of muscle mitochondria.

SUBMITTER: Hancock CR

PROVIDER: S-EPMC2409421 | biostudies-other | 2008 Jun

REPOSITORIES: biostudies-other

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High-fat diets cause insulin resistance despite an increase in muscle mitochondria.

Hancock Chad R CR Han Dong-Ho DH Chen May M Terada Shin S Yasuda Toshihiro T Wright David C DC Holloszy John O JO

Proceedings of the National Academy of Sciences of the United States of America 20080528 22

It has been hypothesized that insulin resistance is mediated by a deficiency of mitochondria in skeletal muscle. In keeping with this hypothesis, high-fat diets that cause insulin resistance have been reported to result in a decrease in muscle mitochondria. In contrast, we found that feeding rats high-fat diets that cause muscle insulin resistance results in a concomitant gradual increase in muscle mitochondria. This adaptation appears to be mediated by activation of peroxisome proliferator-acti ...[more]

PMID: 18509063

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Project description:BackgroundType 2 diabetes mellitus and muscle insulin resistance have been associated with reduced capacity of skeletal muscle mitochondria, possibly as a result of increased intake of dietary fat. Here, we examined the hypothesis that a prolonged high-fat diet consumption (HFD) increases the saturation of muscle mitochondrial membrane phospholipids causing impaired mitochondrial oxidative capacity and possibly insulin resistance.MethodologyC57BL/6J mice were fed an 8-week or 20-week low fat diet (10 kcal%; LFD) or HFD (45 kcal%). Skeletal muscle mitochondria were isolated and fatty acid (FA) composition of skeletal muscle mitochondrial phospholipids was analyzed by thin-layer chromatography followed by GC. High-resolution respirometry was used to assess oxidation of pyruvate and fatty acids by mitochondria. Insulin sensitivity was estimated by HOMA-IR.Principal findingsAt 8 weeks, mono-unsaturated FA (16?1n7, 18?1n7 and 18?1n9) were decreased (-4.0%, p<0.001), whereas saturated FA (16?0) were increased (+3.2%, p<0.001) in phospholipids of HFD vs. LFD mitochondria. Interestingly, 20 weeks of HFD descreased mono-unsaturated FA while n-6 poly-unsaturated FA (18?2n6, 20?4n6, 22?5n6) showed a pronounced increase (+4.0%, p<0.001). Despite increased saturation of muscle mitochondrial phospholipids after the 8-week HFD, mitochondrial oxidation of both pyruvate and fatty acids were similar between LFD and HFD mice. After 20 weeks of HFD, the increase in n-6 poly-unsaturated FA was accompanied by enhanced maximal capacity of the electron transport chain (+49%, p?=?0.002) and a tendency for increased ADP-stimulated respiration, but only when fuelled by a lipid-derived substrate. Insulin sensitivity in HFD mice was reduced at both 8 and 20 weeks.Conclusions/interpretationOur findings do not support the concept that prolonged HF feeding leads to increased saturation of skeletal muscle mitochondrial phospholipids resulting in a decrease in mitochondrial fat oxidative capacity and (muscle) insulin resistance.

Project description:Recent discovery reveals HFD insult can cause insulin resistance very rapidly, but the underlying mechanism is still not well understood. We performed a short term experiment in a Diet Induced Insulin resistance mouse model. Objective: Insulin resistance (IR) is one of the earliest predictors of type 2 diabetes. However, diagnosis of IR is limited. High fat fed mouse models provide key insights into IR. We hypothesized that early features of IR are associated with persistent changes in gene expression (GE) and endeavoured to (a) develop novel methods for improving signal:noise in analysis of human GE using mouse models; (b) identify a GE motif that accurately diagnoses IR in humans; and (c) identify novel biology associated with IR in humans. Methods: We integrated human muscle GE data with longitudinal mouse GE data and developed an unbiased three-level cross-species analysis platform (single-gene, gene-set and networks) to generate a gene expression motif (GEM) indicative of IR. A logistic regression classification model validated GEM in 3 independent human datasets (n =115). Results: This GEM of 93 genes substantially improved diagnosis of IR compared to routine clinical measures across multiple independent datasets. Individuals misclassified by GEM possessed other metabolic features raising the possibility that they represent a separate metabolic subclass. The GEM was enriched in pathways previously implicated in insulin action and revealed novel associations between Î²-catenin and Jak1 and IR. Functional analyses using small molecule inhibitors showed an important role for these proteins in insulin action. Conclusions: This study shows that systems approaches for identifying molecular signatures provides a powerful way to stratify individuals into discrete metabolic groups. Moreover, we speculate that the Î²-catenin pathway may represent a novel biomarker for IR in humans that warrant future investigation. Comparison of gene expression in muscle tissue during High Fat Diet (HFD) time course (day 5 and day 42). Chow diet will serve as control for HFD. 4 samples per group serve as experimental replicates.

Dataset Information

High-fat diets cause insulin resistance despite an increase in muscle mitochondria.

Publications

High-fat diets cause insulin resistance despite an increase in muscle mitochondria.

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