Lipokine 5-PAHSA is Regulated by Adipose Triglyceride Lipase and Primes Adipocytes for de novo Lipogenesis in Mice

Branched esters of palmitic acid and hydroxy-stearic acid (PAHSA) are anti-inflammatory and anti-diabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the crosstalk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using 2H2O revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol/fatty acid (TAG/FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG-estolides) in WAT. Utilization of 13C isotope tracers and dynamic metabolomics documented that 5-PAHSA primed adipocytes for glucose metabolism in a different way from insulin, promoting DNL, and impeding TAG synthesis. In summary, our data revealed new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA, its relation to insulin action in adipocytes, and independently confirmed a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis.