Protection Against Insulin Resistance in Obesity is Accompanied by Low Rates of Systemic Fatty Acid Mobilization and Attenuated Markers of Fibrosis and Inflammation in Adipose Tissue
Authors: Van Pelt Douglas W , Wang Abigail Y , Horowitz Jeffrey F 
Published: November 2023

Our lab and others have demonstrated that the rate of fatty acid mobilization from adipose tissue is an important determinant of the degree of insulin resistance in obesity. The primary aim of this study was to determine factors in adipose tissue that may explain why some obese adults preserve a low rate of fatty acid mobilization, which may help protect them from developing insulin resistance. We measured basal fatty acid rate of appearance in plasma (FA Ra) via 13C‐palmitate isotope dilution and insulin resistance using a hyperinsulinemic‐euglycemic clamp in 28 obese adults (body mass index [BMI]: 37±1 kg/m2) after an overnight fast. We also obtained adipose tissue biopsy samples for assessment of mRNA expression (qPCR) and protein abundance (Immunoblot) of factors involved in regulating fatty acid storage, extracellular matrix, inflammation, and immune response. Across the entire cohort, FA Ra was negatively correlated with insulin‐mediated glucose disposal (R2=0.47; p<0.001). We divided the full cohort into tertiles based on their FA Ra, and compared subjects with the lowest FA Ra (LOW‐FA: 7.1 ± 0.3 μmol/kg FM/min; n=9) with those with the highest FA Ra (HIGH‐FA: 18.4 ± 0.7 3 μmol/kg FM/min; n=9). Importantly, there were no differences in age (28±2 vs 34±3 y; p=0.32), BMI (36±1 vs 37±1 kg/m2; p=0.62), and fat mass (45±5 vs 52±2 kg; p=0.32) between HIGH‐FA and LOW‐FA, respectively. As expected, insulin‐mediated glucose disposal was significantly higher in LOW‐FA compared with HIGH‐FA (13.4±0.7 vs 7.9±1.0 mg/kg FFM/min; p=0.002). In the adipose tissue, LOW‐FA had a 3‐fold greater protein abundance of a key enzyme regulating triacylglycerol synthesis, glycerol‐3‐phosphate acyltransferase 1 (GPAT1), compared with HIGH‐FA (p=0.02). In addition, the abundance of phosphorylated hormone sensitive lipase (p‐HSLser660), which provides a crude index of lipase activity, tended to be lower in LOW‐FA vs. HIGH‐FA (p=0.10). We also found mRNA expression of collagen VI (Col6a1), which has been linked to excess adipose tissue fibrosis and insulin resistance in obesity, to be lower in LOW‐FA vs. HIGH‐FA (p=0.02). The expression of Col6a1 was also positively correlated with the degree of FA Ra across all 28 subjects in our study (R2=0.29; p=0.003). Compared with HIGH‐FA, LOW‐FA exhibited a lower mRNA expression of the class II histocompatibility antigen HLA‐DRB1 (p=0.04), which is involved in antigen presentation, along with a trend for lower evidence of macrophage infiltration (galectin 3; p=0.09). Finally, phosphorylated c‐Jun N‐terminal kinase 1 (p‐JNKthr183/tyr185) abundance was lower in LOW‐FA vs. HIGH‐FA (p=0.04), providing additional support for a lower inflammation in the LOW‐FA group. Our findings suggest that increased expression of factors regulating triglyceride storage in adipose tissue, along with lower fibrosis, immune response, and inflammatory pathway activation, accompany a relatively low rate of fatty acid mobilization in obesity, which may help protect against the development of insulin resistance.

Support or Funding Information

Supported by NIH‐NIDDK Grants #R01‐DK077966, #P30‐DK089503, The University of Michigan CTSA: NIH‐IL1RR02RR024986, and the University of Michigan UROP Summer Biomedical and Life Sciences Research Fellowship