Gut microbiota control host lipid deposition through HDAC9-driven PPARγ acetylation

Abstract The healthy gut microbiota communities play a complex and significant role in lipid absorption and deposition, leading to multiple health benefits. Here, we confirmed an impaired absorption and deposition function in germ-free pigs and mice, which was partially reversed after human fecal microbiota transplantation. By integrating single-cell data from adipose tissue, we identified HDAC9 as a key regulator, marked by the presence of a population of small mature adipocytes exhibiting high HDAC9 and low PPARγ expression in germ-free pigs. HDAC9 deficiency of preadipocytes drove FABP4/5-mediated lipid deposition by directly targeting PPARγ expression and acetylation modification. Finally, we verified the interaction between gut microbiota and host HDAC9/PPARγ/FABP4/5 signaling cascade might be microbial receptors (ie, Dectin1 or TLRs)-dependent rather than microbial metabolites. Altogether, our study uncovers the gut microbiota-HDAC9-PPARγ axis as a key regulator of adipocyte function and lipid deposition, offering a potential therapeutic target for lipid-related metabolic diseases.