HAQ and AQ-MPYS Modulate Fatty Acid Metabolism and Immune Tolerance at Homoeostasis

MPYS/STING senses cyclic dinucleotides (CDNs) and promotes inflammation. During out-of-Africa early human migration, common human MPYS alleles R71H-G230A-R293Q (HAQ) replaced G230A-R293Q (AQ) suggesting a strong natural selection on human MPYS. Using HAQ and AQ knock-in mice, we found that HAQ mice had more fat mass than the AQ mice on a chow diet supporting the thrifty gene hypothesis. Mechanistically, adult AQ or MPYS-/- mice had more epididymal adipose tissue (eWAT) suppressive regulatory T cells and M2-macrophages than HAQ or WT mice at the steady-state. Conditional knockout mice and adoptive cell transfer indicated a cell-intrinsic control of fatty acid metabolism and immune tolerance by MPYS. Unlike the HAQ mice, which are defective in CDNs responses, the AQ mice retain CDNs responses. Finally, MPYS interacts with fatty acid metabolites acyl-CoA, lysophosphatidic acid, phosphatidic acid, and diglyceride at the steady-state. MPYS/STING ligand ADU-S100 inhibited lipogenesis in white adipocytes. Together, we propose that HAQ has a pro-lipogenesis function that is more important than the CDNs sensing function of AQ in early humans revealing a fundamental function of human MPYS.