Systemic and Organ-Specific Insulin Sensitizing Mechanisms of PAHSAs—Comments on Zhou and Santoro et al. PAHSAs Enhance Hepatic and Systemic Insulin Sensitivity through Direct and Indirect Mechanisms, J Clin Invest. 2019;129(10):4138–4150

Fatty acid esters of hydroxy fatty acids (FAHFAs) have been identified as a novel class of bioactive lipids with beneficial effects on insulin secretion, glucose metabolism and metabolic inflammation. Palmitic acid-hydroxystearic acids (PAHSAs), a subgroup of FAHFAs, are reduced in serum and fat of insulin resistant mice and humans. A recent paper complements previous studies by demonstrating that exogenous PAHSAs act as insulin sensitizers in mice with a strong action on liver through both direct (inhibiting cyclic AMP signaling in hepatocytes) and indirect (reducing adipose tissue lipolysis and its contribution to hepatic glucose production) effects.