Integration of Insulin Sensitivity in Adipose Tissue and Skeletal Muscle, and the Role of Exercise on Muscle Lipid Regulation
Creators: name: Schleh, Michael
Publisher: name: My University
Year: 2022
Subjects: subject: Obesity and insulin resistance
subject: Adipose tissue lipolysis
subject: Insulin-mediated glucose uptake
subject: Skeletal muscle lipid droplet
subject: High-intensity interval training
subject: Kinesiology and Sports
subject: Health Sciences

description: Obesity is a major public health problem, and a leading risk factor for cardio-metabolic disorders, including insulin resistance, which underlies many obesity-related diseases. Although most adults with obesity are insulin resistant, some are relatively insulin sensitive, with minimal obesity-related disease risk-factors. Mounting evidence suggests that differences in the regulation of fatty acid (FA) release from abdominal subcutaneous adipose tissue (aSAT), as well as alterations in the regulation muscle lipids may be important contributors to the variability in insulin sensitivity in this population. Additionally, although some of the important health benefits of exercise, including enhanced insulin sensitivity, have been attributed to changes in muscle lipid metabolism, the effects of exercise muscle lipid regulation remain unclear. The overall aims of this dissertation were to examine the integrated relationship between skeletal muscle insulin sensitivity with aSAT morphology and metabolism, as well as to assess the effects of exercise on muscle lipid regulation. In Project 1, we found that in a cohort of 66 adults with obesity, insulin-mediated suppression of FA rate of appearance in the circulation (FA Ra suppression) was the strongest predictor of insulin-mediated glucose uptake (r=0.51, p&lt;0.01). Importantly, proteomics analysis revealed that fibrotic content in aSAT may be an important contributor in determining the FA release in response to insulin. We also found those with low FA Ra suppression had a relatively high concentration of long-chain acylcarnitines (p=0.02) and triacylglycerol (p&lt;0.01) in skeletal muscle, suggesting that persistent elevations in FA availability in those with low FA suppression in response to insulin may unfavorably impact muscle lipid profile. Project 2 expanded on these findings from Project 1 by demonstrating insulin resistance was accompanied by increased accumulation of large-sized lipid droplets (LD) in close proximity to the plasma membrane of the myocyte, which may contribute to insulin resistance. In Project 2 we also found that our insulin resistant cohort exhibited blunted interaction between the insulin receptor and key regulatory proteins (cluster of differentiation factor 36 [CD36] and Fyn), which was accompanied by impaired insulin signaling downstream of the insulin receptor. In Project 3, we examined the effect of 12 weeks of exercise training (comparing high-intensity interval training [HIIT] and moderate-intensity continuous training [MICT]) on changes in the size and number of LDs in skeletal, as well as their distribution in either the intramyofibrillar (IMF) or subsarcolemmal (SS) regions of the myocyte. Training (both HIIT and MICT) increased intramyocellular lipid content (p&lt;0.01), and this expansion in muscle lipid content was attributed to an increased number of LD per µm2 (p&lt;0.01) specifically within the IMF region of the myocyte. Findings from Project 3 also suggest that selective LD degradation (“lipophagy”) may be upregulated the day after a session of exercise, but this response appeared to be transient because our measure of lipophagy was no longer elevated when measured 4 days after a session of exercise. Interestingly, despite the robust difference in exercise stimulus between MICT and HIIT, the effects of these exercise programs on intramyocellular LDs were remarkably similar. Overall, findings from my dissertation sheds light on an important cross-talk between adipose tissue and skeletal muscle, by which FA release from adipose tissue can alter muscle lipid regulation, as well as impair insulin sensitivity, and exercise can modify how (and where) muscle lipids are stored.