The mechanism of macrophage activation by down-regulation of fatty acid synthase in obesity

Abstract

It is well known that obesity induces inflammation through in vivo studies. However, the mechanistic studies of how an event of inflammation links to obesity are still under investigation. Here, we found that in macrophages of an obese mouse, both mRNA and protein expression of Fatty Acid Synthase (FASN) is down-regulated. They also show a significant accumulation of intra-cellular acetyl coenzyme A, a precursor of fatty acid synthase, as well as lipid droplet in cytoplasm. Acetyl coenzyme A accumulation resulted in an increase of histone acetylation which ultimately caused the transcriptional up-regulation of various inflammatory genes such as IL-1β and iNOS. The FASN knock-down macrophages produced more IL-1β and iNOS compared to control macrophages whereas their level decreased back to normal when FASN is rescued by over expression. In addition, the expression of CD36, an external fatty acid transporter, was increased in FASN knock-down macrophages. Thus, there were much more external fatty acid accumulation occurred in cytoplasm. When CD36 is blocked by its inhibitor (SSO), IL-1β and iNOS decreased correspondingly which suggests that FASN knock-down macrophages may facilitate the uptake of external fatty acids through CD36 and that the accumulation of those fatty acids induces inflammation. Together, these findings suggest that obesity-induced down-regulation of FASN causes inflammation through promoting histone acetylation and an accumulation of external free fatty acids up-taken by CD36.