Activity-Based Protein Profiling Reveals Mitochondrial Oxidative Enzyme Impairment and Restoration in Diet-Induced Obese Mice

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.

MicroRNA-149 Inhibits PARP-2 and Promotes Mitochondrial Biogenesis via SIRT-1/PGC-1α Network in Skeletal Muscle

“…Earlier studies have shown that HFD downregulates genes necessary for oxidative phosphorylation and mitochondrial biogenesis in mouse skeletal muscles (25,26). In this study, we have examined how HFD affects skeletal muscle metabolism by modulating mitochondrial function and biogenesis.…”

Mitochondrial Metabolism and Insulin Action

“…At a similar time Garcia-Roves also showed that high-fat feeding with daily heparin injections in rats resulted in mitochondrial biogenesis in skeletal muscle [207] and subsequent work by the same lab the following year confirmed that oversupply of dietary lipid produced insulin resistance, despite an increase in mitochondria in muscle [208]. Since the time of these publications, a number of other groups have shown that diets rich in fat increase mitochondrial biogenesis in muscle, despite the fact that the same diets robustly induce whole-body and muscle-specific insulin resistance [209][210][211]. One interpretation of these findings is that skeletal muscle is mounting an appropriate response to the increase in caloric load, by upregulating catabolic pathways, however this response is inadequate or mismatched with the elevation in nutrient intake, thus resulting in ectopic lipid accumulation in muscle and insulin resistance.…”

Altered apolipoprotein C expression in association with cognition impairments and hippocampus volume in schizophrenia and bipolar disorder

“…The relationship between metabolic problems, such as obesity, diabetes and elevated lipids, and the expression of Apo has been frequently investigated in the general population (Padrao, Ferreira, Vitorino, & Amado, 2012;Ramachandran et al, 2012;Sadler et al, 2012). Due to antipsychotic medications in SZ and mood stabilisers in BD, those patients have an increased risk for metabolic disturbances and altered lipid metabolism (Gibbons, Thomas, Scarr, & Dean, 2010), ultimately contributing to an increased risk for cardiovascular disease (Meyer et al, 2008).…”