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.

Obesity is a current epidemic in the United States. Greater than one third of adults and nearly one fifth of children are classified as obese (Ogden, 2014). Increased awareness of this problem has triggered interest into the potentially causal agents in our environment. These agents, termed obesogens, are a type of teratogen hypothesized to work during embryonic development by programming offspring to store excess fat. A type of teratogen, obesogens are also typically reprotoxic, affecting germline development and embryonic viability. These noxious teratogens span a variety of different chemical classes including estrogen mimics, metals and metalloids, biocides, and even voluntary exposures like cigarette smoke. The goal of this work is to use the soil nematode, Caenorhabditis elegans to model the reprotoxic and obesogenic events that take place as a result of chronic, low-dose exposure to these agents. C. elegans is especially well suited to this end. The organism has a straightforward biology, a short lifespan on the order of days, and relevant lipid metabolic gene homology to humans. We characterize here the resultant effects on egg-laying, hatching, and embryo viability after chronic parental exposure to obesogens. Through this, we are able to best recapitulate the low-dose exposure for our obesogen screen. Here, chronic, sub-lethal parental exposure to the obesogens screened yielded viable offspring that exhibited increased percentages of body area lipid stained and induced differences in stained lipid localization. Reduced pharyngeal pumping rates in two of our offspring groups highlights the potential for lasting changes on behavioral phenotype as well. Lastly, we employed phylogenetic guided analysis to functionally assess putative C. elegans nuclear hormone receptors (NHRs) to human Peroxisome Proliferator Activated Receptors (PPARs). These human PPARs have implications in lipid metabolism and obesity. We report here novel findings that NHR-85 and SEX-1 may act to repress lipid storage in the nematode, thereby serving as potential homologs of human PPARα. The results presented in this study highlight the lasting effects of chronic parental exposure to noxious environmental teratogens on the function of the reproductive system. Furthermore, the nematode can be used as an in vivo model to screen sublethal doses of these teratogens for their potential to act as obesogens. Bioinformatics guided analysis of C. elegans NHR homologs to human NHRs can continue to yield novel insight on this fat storage and its regulation in the nematode.