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

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. This RNA sequencing dataset was generated to examine intestinal transcriptomic changes associated with adipose-specific deletion of Free Fatty Acid Receptor 2 (FFA2) in mice exposed to a Western diet supplemented with dietary fiber. Male Adipoq-F2-KO mice were generated by crossing FFA2 floxed mice (FFA2^fl/fl) with Adiponectin-Cre transgenic mice, resulting in adipocyte-specific FFA2 deletion. Littermate FFA2^fl/fl control and Adipoq-F2-KO mice were co-housed from birth and maintained on standard chow (Teklad LM-485) until 12 weeks of age. At this time point, mice were transitioned to a custom-modified high-fat/high-sugar Western diet supplemented with 10% fructooligosaccharides (FOS; D20021208, Research Diets, Inc.). After two weeks on this diet—once genotype-dependent differences in body weight were evident—mice were euthanized for tissue collection. Jejunal mucosa was isolated, and RNA was extracted for sequencing. RNA integrity was verified prior to library preparation, and bulk RNA sequencing was conducted by the UIC sequencing core facility. The resulting data were used to perform differential gene expression analysis between Adipoq-F2-KO and control mice, with the goal of identifying fiber-responsive, FFA2-regulated transcriptomic changes in the small intestine under obesogenic dietary challenge.