A Novel Function of Nonadecanoic Acid in Regulating Glucose Homeostasis

ABSTRACT Circulating odd‐chain fatty acids (OCFAs), such as pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0), inversely associate with metabolic syndrome‐related type 2 diabetes mellitus (T2DM), cardiovascular disease, and all‐cause mortality. However, the physiological function of nonadecanoic acid (C19:0) remains unclear. In this study, we identify an inverse association between plasma C19:0 levels and T2DM in the Kazakh population in Xinjiang, China. Investigations using diet‐induced obese (DIO) and db/db mouse models revealed that C19:0 has the potential to improve glucose tolerance and enhance insulin sensitivity. Mechanistically, our data demonstrate that C19:0 acts as an endogenous ligand for GPR120, mediating metabolic benefits both in vitro and in vivo. Further analyses indicate that 2‐hydroxyacyl‐CoA lyase (HACL1) directly participates in the biosynthesis of C19:0, with its expression regulated by peroxisome proliferator‐activated receptor α (PPARα). Elevated palmitic acid (PA) levels in obesity suppress PPARα via miR548ab release, thereby impairing the PPARα–HACL1–C19:0 signaling pathway. Collectively, these findings establish a novel association between C19:0 and T2DM and elucidate a distinct mechanism accounting for reduced circulating C19:0 levels in obesity.