ATGL-catalyzed biosynthesis mediates the upregulation of fatty acid hydroxy fatty acids (FAHFA) levels in white adipose tissue with fasting

FAHFAs are a family of bioactive lipids. A subclass of these, palmitic acid hydroxy stearic acids (PAHSAs) have anti-inflammatory and anti-diabetic effects. Adipose tissue PAHSA levels are upregulated with increased de novo lipogenesis and fasting and downregulated with insulin resistance and obesity. Adipose triglyceride lipase (ATGL) regulates FAHFAs through two distinct mechanisms: hydrolysis of triacylglycerol (TG)-containing FAHFAs and catalyzing formation of the ester bond found in all FAHFAs through a transacylase reaction. ATGL mediates the increase of PAHSAs with fasting in white adipose tissue (WAT), but the mechanism for this has not been determined. Here, we show that multiple FAHFAs are dynamically regulated with fasting and short-term refeeding in both perigonadal (PG) and subcutaneous (SQ) WAT due to ATGL transacylase activity. Our in vivo studies with stable isotopes demonstrate that de novo FAHFA synthesis is upregulated with fasting. This observation along with the fact that FAHFA-TGs are unchanged (SQ WAT) or increased (PG WAT) with fasting and FAHFA hydrolysis is unchanged, suggests that the primary mechanism by which FAHFAs increase in WAT with fasting is de novo synthesis. Using adipose tissue-specific ATGL knock out mice, we show that ATGL is required for the fasting-induced upregulation of endogenous levels and de novo synthesis of multiple FAHFAs. Altogether, this study shows that fasting upregulates multiple FAHFAs by increasing ATGL-mediated synthesis of FAHFAs, inferring that fasting, a physiological state that is classically known to activate the lipase activity of ATGL, also stimulates its transacylase activity.