Mitochondrial Dysfunction is Not a Causative Factor in the Pathogenesis of Obesity

The causal role of mitochondrial dysfunction and mtDNA mutagenesis in the etiology of obesity and type 2 diabetes remains equivocal. We revisited this controversy by measuring mtDNA copy number, protein content of mitochondrial respiratory chain subunits (COX –II and –IV) and mitochondrial COX activity in the vastus lateralis of lean and obese men (N=9/group). Obese men had significantly higher total body weight (44%) and fat mass (140%) compared to the lean controls (P<0.01). Interestingly, there were no differences in mtDNA copy number, COX‐II and COX‐IV protein content, and COX activity. Should mitochondrial dysfunction be implicated as a causal factor in the pathogenesis of obesity, we hypothesized that the polymerase gamma (PolG) mutator mice, reported to have systemic mitochondrial dysfunction, would have higher total body weight and fat mass compared to age‐matched littermate wild‐type controls (N=12/group). Surprisingly, we observed a significant decrease in total body weight (39%), abdominal (8‐fold) and retroperitoneal (15‐fold) fat content in PolG mice along with a reduction in skeletal muscle mtDNA copy number (2.5‐fold), COX‐IV (80%) content, and COX activity (51%) vs. WT mice. We conclude that the disconnect between adiposity and mitochondrial capacity in lean vs. obese men and PolG vs. WT mice undermines the causative role of mitochondrial dysfunction in obesity. Research supported by CIHR.