Adipocyte- Specific FFA2 Deletion Leads to Increased Adipose Inflammation and Is Associated with Altered Intestinal Lipid Handling

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) 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 standard chow and high-fat, high-sugar Western diet conditions, with and without dietary fiber supplementation. We found that adipose-specific FFA2 deletion had minimal metabolic consequences under standard dietary conditions but significantly reduced body weight and adiposity when mice were fed a fiber (fructooligosaccharide)-supplemented Western diet. Subsequent fecal analyses and transcriptomic profiling indicated impaired intestinal lipid absorption as the primary driver of reduced adiposity, suggesting disrupted adipose-intestinal communication. Unexpectedly, the lighter Adipoq-F2-KO mice also exhibited heightened adipose inflammation, characterized by increased macrophage infiltration and pro-inflammatory cytokine expression. Furthermore, in vitro loss-of-function experiments in adipocytes revealed that FFA2 knockdown impaired adipocyte maturation, lipid storage, and anti-inflammatory signaling. Additional 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. The data uploaded here specifically contains the comparison of mRNA from mature white adipocytes of FFA2 fl/fl mice compared to RNA from Adipoq-F2-KO mice when both are on a normal chow diet. Overall design: This RNA sequencing dataset was generated to assess baseline transcriptional differences in mature adipocytes resulting from adipocyte-specific deletion of Free Fatty Acid Receptor 2 (FFA2) in mice maintained under standard dietary conditions. Adipoq-F2-KO mice were generated by crossing FFA2 floxed mice (FFA2^fl/fl) with Adiponectin-Cre transgenic mice, enabling adipocyte-specific knockout of FFA2. Male Adipoq-F2-KO mice and their FFA2^fl/fl littermate controls were co-housed and maintained on a standard chow diet (Teklad LM-485) until 20 weeks of age. At this timepoint, mature adipocytes were isolated from perigonadal adipose tissue, and total RNA was extracted for sequencing. RNA integrity was confirmed prior to library preparation and bulk RNA sequencing, which was performed by the UIC sequencing core facility. Differential gene expression analysis was conducted to compare Adipoq-F2-KO and control samples under basal (non-obesogenic) conditions, to identify FFA2-regulated transcriptional programs in adipose tissue independent of dietary challenge.