Adipose tissue metabolic function, structure, and overall adipose tissue ;;health” are key mediators of obesity-related cardio-metabolic abnormalities, including insulin resistance, which plays a central role in the development of many chronic diseases.Excessive fatty acid release from subcutaneous adipose tissue (SAT) is one of the most important factors underlying insulin resistance.Other major factors in SAT that are linked to abnormalities in metabolic health include adipose tissue inflammation, extracellular matrix composition and structure, adipogenesis, and angiogenesis. However, despite some recent advances, understanding the role of SAT on metabolic health in human obesity is rather limited.In addition, although exercise is often-prescribed in attempt to improve cardio-metabolic health, it remains unclear whether exercise can impart adaptations in adipose tissue that contribute to improvements in whole-body metabolic health in obesity.The overall objectives of this dissertation were to assess how subcutaneous adipose tissue may contribute to whole-body metabolic outcomes in obesity, and whether exercise can modify adipose tissue in a manner that improves markers of metabolic health. In STUDY #1, insulin sensitivity (frequently sampled intravenous tolerance test; FSIVGTT) and systemic fatty acid rate of appearance in plasma (FA Ra; stable isotope dilution methods) were measured in 21 obese adults (BMI = 34±1 kg/m2; age = 30±1 yrs), and FA Ra was found to be an important determinant of insulin resistance (R2=0.21; P=0.04).In addition, skeletal muscle samples collected from subjects who were insulin resistant had higher markers of skeletal muscle inflammation known to inhibit insulin signaling (e.g., phosphorylated c-Jun N-terminal kinase) compared with the more insulin sensitive subjects (P<0.05). Given the importance of basal fatty acid mobilization rates on insulin resistance (as reported in STUDY #1), STUDY #2 aimed to identify factors in SAT that may underlie low vs. high rates of fatty acid mobilization in obese adults. FA Ra (stable isotope dilution methods) and insulin sensitivity (hyperinsulinemic-euglycemic clamp) were measured in 30 obese adults (BMI = 38±1 kg/m2; age = 30±2 yrs). Confirming results from STUDY #1, insulin sensitivity was inversely proportional to FA Ra (R2=0.50; P<0.001).In addition, SAT from subjects with low FA Ra had significantly lower (P<0.05) markers of lipase activation and higher abundance (P<0.05) of glycerol-3-phosphate acyltransferase (GPAT), which is a primary enzyme regulating fatty acid esterification. Microarray and pathway analysis also indicated lower fibrosis and lower SAPK/JNK pathway activation in obese adults with low FA Ra compared to those with high FA Ra (P<0.05). Finally, in STUDY #3, overweight-to-obese adults who exercise regularly (ACTIVE: BMI 29±1 kg/m2; age = 27±1 yr; n=8) or were sedentary (SED: BMI 27±1 kg/m2; age = 27±2 yr; n=12) were recruited to examine the effects of exercise (chronic and acute) on adipose tissue. In both groups, acute exercise increased SAT mRNA expression of VEGFA, an important regulator of angiogenic processes.In line with this finding, SAT from ACTIVE subjects had a higher mRNA expression of the endothelial cell marker, CD31, compared with SED, suggesting regular exposure to exercise may increase SAT capillarization. Together, findings from this dissertation provide novel insights into how alterations in SAT structure and metabolic function can greatly impact insulin resistance, and whole-body metabolic health. These data may help lead to development of treatments (lifestyle or pharmaceutical) to target and treat important mediators of insulin resistance and other obesity-related cardio-metabolic diseases.
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Effects of Subcutaneous Adipose Tissue on Metabolic Health in Obesity
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