PGC-1β Suppresses Saturated Fatty Acid-induced Macrophage Inflammation by Inhibiting TAK1 Activation

Inflammation of infiltrated macrophages in adipose tissue is a key contributor to the initiation of adipose insulin resistance. These macrophages are exposed to high local concentrations of free fatty acids (FFAs) and can be proinflammatory activated by saturated fatty acids (SFAs). However, the regulatory mechanisms on SFA-induced macrophage inflammation are still elusive. Peroxisome proliferator-activated receptor gamma coactivator-1b (PGC-1b) is a member of the PGC-1 family of transcriptional coactivators and has been reported to play a key role in SFAs metabolism and in the regulation of inflammatory signaling. However, it remains unclear whether PGC-1 beta is involved in SFA-induced macrophage inflammation. In this study, we found that PGC-1 beta expression was significantly decreased in response to palmitic acid (PA) in macrophages in a dose dependent manner. PGC-1 beta inhibited PA induced TNF alpha, MCP-1, and IL-1 beta mRNA and protein expressions. Furthermore, PGC-1 beta significantly antagonized PA induced macrophage nuclear factor-kappa B (NF-kappa B) p65 and JUN N-terminal kinase activation. Mechanistically, we revealed that TGF-beta-activated kinase 1 (TAK1) and its adaptor protein TAK1 binding protein 1 (TAB1) played a dominant role in the regulatory effects of PGC-1 beta. We confirmed that PGC-1 beta inhibited downstream inflammatory signals via binding with TAB1 and thus preventing TAB1/TAK1 binding and TAK1 activation. Finally, we showed that PGC-1 beta overexpression in PA treated macrophages improved adipocytes PI3K-Akt insulin signaling in a paracrine fashion. Collectively, our results uncovered a novel mechanism on how macrophage inflammation induced by SFAs was regulated and suggest a potential target in the treatment of obesity induced insulin resistance. (C) 2016 IUBMB Life