Abstract
High-fat diet (HFD) induced obesity and concomitant development of insulin resistance (IR) and type 2 diabetes mellitus have been linked to mitochondrial dysfunction. However, it is not clear whether mitochondrial dysfunction is a direct effect of a HFD, or if mitochondrial function is reduced with increased HFD duration. We hypothesized that the function of mitochondrial oxidative and lipid metabolism functions in skeletal muscle mitochondria for HFD mice are similar, or elevated, relative to standard diet (SD) mice; thereby, IR is neither cause nor consequence of mitochondrial dysfunction. We applied a chemical probe approach to identify functionally reactive ATPases and nucleotide-binding proteins in mitochondria isolated from skeletal muscle of C57Bl/6J mice fed HFD or SD chow for 2-, 8-, or 16-weeks; feeding time points known to induce IR. A total of 293 probe-labeled proteins were identified by mass spectrometry-based proteomics, of which 54 differed in abundance between HFD and SD mice. We found proteins associated with the TCA cycle, oxidative phosphorylation (OXPHOS), and lipid metabolism were altered in function when comparing SD to HFD fed mice at 2-weeks, however by 16-weeks HFD mice had TCA cycle, β-oxidation, and respiratory chain function at levels similar to or higher than SD mice.
Highlights
Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease [1], and its etiology involves complex interactions between genetic and environmental factors including physical inactivity, increased caloric intake, and obesity [2]
Insulin resistance is defined as a relative impairment in the ability of insulin to exert its effects on glucose and lipid metabolism in target tissues [3]
Studies have shown the down-regulation of genes encoding mitochondrial enzymes [7,8], decreased mitochondrial density [9], and lower respiratory chain activity [9], but other studies found no mitochondrial dysfunction in insulin resistant skeletal muscle [10,11,12,13]
Summary
Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease [1], and its etiology involves complex interactions between genetic and environmental factors including physical inactivity, increased caloric intake, and obesity [2]. Studies have shown the down-regulation of genes encoding mitochondrial enzymes [7,8], decreased mitochondrial density [9], and lower respiratory chain activity [9], but other studies found no mitochondrial dysfunction in insulin resistant skeletal muscle [10,11,12,13]. Rodent studies indicate that muscle IR is primarily due to fat overconsumption and lipid accumulation, rather than mitochondrial dysfunction [14] These findings complement studies in which skeletal muscle from C57Bl/6J mice fed a HFD for 5- or 20-weeks had increased mitochondrial fatty acid oxidative capacity, higher activity of oxidative phosphorylation enzymes, and elevated protein expression of PGC1a and mitochondrial respiratory chain subunits with concomitant impairment in glucose clearance and insulin action [15]. Whether mitochondrial function is elevated, reduced, or maintained due to HFD, and whether mitochondrial biogenesis or impairment occurs is not clear
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