Impact of Environmental and Genetic Regulation of Skeletal Muscle Metabolism on Metabolic Response in Women with Overweight or Obesity: Molecular and Cellular Analyses and Genetic Association Studies

Abstract

The following doctoral thesis focuses on genetic and environmental factors that influence skeletal muscle metabolism in women with overweight or obesity. The effects of Acyl-CoA Synthetase Long-Chain 5 (ACSL5) genotype on fatty acid metabolism was studied in vitro, ex vivo and in vivo. The effects of the environmental toxicant mono-(2ethylhexyl) phthalate (MEHP) was also studied in vitro and in vivo. Statistical analyses illustrated how ACSL5 rs2419621 [T] allele carriers, with overweight or obesity had a greater reduction in their fat mass and visceral fat and greater increases in their percentage lean mass post diet/exercise intervention vs. non-carriers. This was paralleled with increased in vitro and in vivo fatty acid oxidation and ex vivo mitochondrial respiration within [T] allele carriers vs. non-carriers. Interestingly, it was noted that carriers of the polymorphism had increased levels of the ACSL5 683aa isoform in skeletal muscle, which was found to be localized in the mitochondria to a greater extent, playing a greater role in fatty acid oxidation vs. 739aa isoform. This explains in part why carriers of the polymorphism are more responsive to lifestyle interventions vs. non-carriers. Studies conducted in women with obesity who participated in the National Health and Nutrition Examination Survey (NHANES) demonstrated an association between increased urinary MEHP and increased plasma fatty acid levels. In vitro work in C2C12 myotubes exposed to MEHP displayed a reduction in fatty acid oxidation and mitochondrial respiration. An increase in basal glycolysis was paralleled with increased levels of hexokinase II protein expression in C2C12 myotubes exposed to increasing levels of MEHP. Thus, these results suggest that increased exposure to MEHP as well as urinary MEHP contributes towards dysfunction in glucose and fatty acid utilization at both the muscle and whole-body level. Hence, women with obesity may be more susceptible to the metabolic effects of MEHP, increasing their chances of metabolic dysfunction. The following thesis, provides a more comprehensive view on the effects of both genetics and environmental factors on metabolic response within women with overweight and obesity. This provides insights into factors that should be considered for personalized medicine, to improve treatment options for combatting this disease.