Immunometabolic Factors Associated with Variations in Body Composition and Exercise Response in Diet-Sensitive and Diet-Resistant Women with Obesity

Abstract

Over the past 20 years, our collaborative research team at the Ottawa Hospital and the University of Ottawa have extensively investigated molecular and metabolic differences between individuals with obesity in the highest (DS) and lowest (DR) quintiles for rate of weight loss following 6 weeks of caloric restriction. Research on these cohorts of individuals with extreme phenotypes in diet-response has revealed that DS individuals have several skeletal muscle metabolic advantages, including increased proportions of type I oxidative fibres, increased mitochondrial proton leak, enhanced fatty acid metabolism, and a greater antioxidant capacity. Regular physical exercise provides a vast array of beneficial effects to metabolic health, including increases in skeletal muscle mitochondrial bioenergetic capacity and muscle cross-sectional area, leading to the hypothesis that exercise may be particularly beneficial to women with diet-resistant obesity. The overall aim of this thesis was to determine whether six weeks of exercise training improves skeletal muscle mitochondrial function and attenuates chronic low-grade inflammation in women with obesity previously identified as diet-sensitive (DS) and diet-resistant (DR). Here, we demonstrate that exercise training improves body composition, enhances cellular maximal respiration, and increases mitochondrial length preferentially in DR women. Contrary to our hypothesis, exercise training increased skeletal muscle IKK-NFκB inflammatory signaling to a greater extent in DR individuals, despite improvements in systemic cytokine concentrations. In response to an inflammatory challenge, LPS-treated primary myotubes derived from DR and DS skeletal muscle responded similarly and respiratory capacity was preserved. Taken together, these findings suggest that exercise can be especially beneficial as part of a treatment plan for DR individuals, and that DS and DR skeletal muscle have systemic and mechanistic differences in inflammatory responses.