The Role of Adipose-Specific Free Fatty Acid Receptor 2 in Obesity and Associated Metabolic Dysfunction

Obesity and related metabolic disorders are often characterized by chronic adipose tissue inflammation, driving systemic insulin resistance and general metabolic dysfunction. Free Fatty Acid Receptor 2 (FFA2/GPR43) has emerged as a potential modulator of adipocyte function, inflammation, and metabolism. To investigate the role of FFA2 expressed in the adipose tissue, we generated adipose-specific FFA2 knockout mice (Adipoq-F2-KO) and assessed metabolic outcomes under normal chow and high-fat, high-sugar Western diet conditions, both with and without dietary fiber supplementation. We found that adiposespecific FFA2 deletion had minimal metabolic consequences under standard dietary conditions but significantly reduced body weight and adiposity when mice were fed a fibersupplemented Western diet. Surprisingly, these lighter knockout mice exhibited heightened adipose inflammation, characterized by increased macrophage infiltration and pro-inflammatory cytokine expression, independent of differences in food intake or energy expenditure. Transcriptomic and fecal analyses indicated impaired intestinal lipid absorption as a primary driver of reduced adiposity, suggesting disrupted adiposeintestinal communication. Furthermore, in vitro knockdown experiments in adipocytes revealed that loss of FFA2 impaired adipocyte maturation, lipid storage, and antiinflammatory signaling. Further studies using intestinal epithelial cells exposed to adipocyte conditioned media implicated adipose-derived signals in driving intestinal dysfunction. Collectively, our findings highlight adipose-specific FFA2 as critical in regulating adipose tissue inflammation, lipid metabolism, and inter-organ communication, suggesting it as a potential therapeutic target for metabolic disease.