Elucidating the roles of stearoyl-CoA desaturase 1 in adipocyte fatty acid metabolism and cellular function

Abstract

Worldwide obesity rates have risen to epidemic proportions, with over 600 million obese individuals across the globe. These individuals are prone to obesity-related health complications, including type 2 diabetes, hypertension, cancer, and cardiovascular disease. Obesity also coincides with the expansion of adipose tissue, which has an important role storing excess calories in the form of triacylglycerol (TAG) within adipocyte lipid droplets. The predominant fatty acids (FAs), comprising adipocyte TAGs, are monounsaturated FAs, which are produced by stearoyl-CoA desaturase 1 (SCD1). Specifically, SCD1 converts saturated FAs palmitate (PA) and stearate (SA) into palmitoleate and oleate, respectively. Interestingly, whole-body SCD1-deficiency is associated with reduced lipogenesis and adiposity. This places SCD1 as a potential target for obesity therapies; however, our understanding of the mechanisms linking SCD1 with changes in adipocyte function remains unclear. This thesis provides important new insights into how SCD1 impacts adipocyte FA metabolism and cellular function. Using a specific SCD1 inhibitor, changes in lipid metabolism, global gene expression, inflammation, cellular stress, and basal insulin signaling were assessed in 3T3-L1 adipocytes. Results demonstrated that SCD1 inhibition caused a reduction in TAGs and phospholipids, which coincided with the downregulation of genes associated with the biosynthesis of these lipid fractions. Cellular diacylglycerols were increased with SCD1 inhibition and insulin signaling was partially impaired. In contrast, markers of cellular stress were unaltered. Furthermore, the FA composition of each lipid fraction was dramatically modified, with SCD1-inhibited adipocytes specifically upregulating the elongation of PA to SA. Stable isotope tracer experiments revealed that this elongation was occurring via elongase 6. Additionally, reduced SCD1 activity in adipocytes exacerbated the effects of exogenous SA on markers of inflammation. Taken together, SCD1 activity has many indirect influences on adipocyte metabolism in addition to its role in FA desaturation. Importantly, SCD1 facilitates the storage of FAs in TAGs and the ability of adipocytes to handle exogenous FAs. SCD1 also prevents saturated FA and DAG accumulation, and preserves insulin signaling in adipocytes. Ultimately this thesis highlights the importance of SCD1 in the maintenance of adipocyte cellular function, and emphasizes the wide-ranging impact of SCD1 on adipocyte FA metabolism.