Exercise Response in Humans with Obesity

Our preliminary data implicates inflamed adipose tissue as a factor that may lead to biochemical abnormalities in muscle and attenuate some of the adaptive responses to exercise in obese individuals. The objective of this project is to evaluate a hypothesis that adipose tissue inflammation activates inflammatory cascades in skeletal muscle that, in turn, attenuate molecular responses to exercise. Aim 1 will determine how adipose tissue phenotype influences skeletal muscle function and exercise response parameters in humans. Humans with obesity will complete studies to assess molecular response to acute exercise from protein synthesis rates, mRNA of exercise-responsive genes, and activation of signaling proteins in skeletal muscle. Subcutaneous adipose tissue (SAT) and intermuscular adipose tissue (IMAT) will be assessed using a combination of non-invasive imaging and biopsy-based molecular phenotyping. This aim will determine if acute exercise response is attenuated with increasing IMAT or in people with inflamed adipose tissue phenotype. Aim 2 will determine the mechanisms by which SAT and IMAT secretomes influence muscle phenotype and exercise response. Primary muscle cultures and adipose explants (SAT and IMAT) will be generated from participants in Aim 1. Myotubes will be exposed to conditioned media from IMAT, inflamed SAT, or non- inflamed SAT to evaluate their influence on molecular phenotype and exercise response pathways. Genetic and pharmacological approaches will be used to target key inflammatory pathways in skeletal muscle (TLR4, IKK, JAK/STAT) to assess their roles in exercise response in vitro. The contribution of the proposed research is expected to be a detailed understanding of the mechanistic links between adipose tissue inflammation, local inflammatory responses in skeletal muscle, and molecular response to acute exercise. The knowledge gained in the proposed study will have a positive impact because “exercise resistance” represents a significant barrier to the prevention and reversal of disease and disability in humans, and understanding the role of anatomically distinct adipose tissue pools in skeletal muscle physiology may lead to new approaches to enhance the beneficial adaptations to exercise in populations that stand to benefit most. Discovering new ways to enhance training responses in people, particularly those at risk for metabolic disorders, will have significant benefit since exercise non-responders have increased risk for metabolic disease.