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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\u2010specific FFA2 knockout mice (Adipoq\u2010F2\u2010KO) and assessed metabolic outcomes under standard laboratory chow and high\u2010fat, high\u2010sugar Western diet conditions, with and without dietary fiber supplementation. We found that adipose\u2010specific FFA2 deletion had minimal metabolic consequences under standard dietary conditions but significantly reduced body weight and adiposity when mice were fed a fiber (fructooligosaccharide)\u2010supplemented Western diet. Subsequent fecal analyses and transcriptomic profiling indicated impaired intestinal lipid absorption as the primary driver of reduced adiposity, suggesting disrupted adipose\u2010intestinal communication. Unexpectedly, the lighter Adipoq\u2010F2\u2010KO mice also exhibited heightened adipose inflammation, characterized by increased macrophage infiltration and pro\u2010inflammatory cytokine expression. Furthermore, in\u00a0vitro loss\u2010of\u2010function experiments in adipocytes revealed that FFA2 knockdown impaired adipocyte maturation, lipid storage, and anti\u2010inflammatory signaling. Additional studies using intestinal epithelial cells exposed to adipocyte\u2010conditioned media implicated adipose\u2010derived signals in driving intestinal dysfunction. Collectively, our findings highlight adipose\u2010specific FFA2 as critical in regulating adipose tissue inflammation, lipid metabolism, and inter\u2010organ communication.<\/jats:p>","DOI":"10.14814\/phy2.70875","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T06:41:46Z","timestamp":1777963306000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adipocyte\u2010specific\n                    <scp>FFA2<\/scp>\n                    deletion leads to increased adipose inflammation and is associated with altered intestinal lipid handling in mice"],"prefix":"10.14814","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2851-1817","authenticated-orcid":false,"given":"Chioma","family":"Nnyamah","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Boyett","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barton","family":"Wicksteed","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nupur","family":"Pandya","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Xu","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Corona\u2010Avila","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Sweis","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa","family":"St. George","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J.","family":"Den Hartigh","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Nutrition University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abeer M.","family":"Mahmoud","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Cordoba\u2010Chacon","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medha","family":"Priyadarshini","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2176-5654","authenticated-orcid":false,"given":"Brian T.","family":"Layden","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"},{"name":"Jesse Brown Veterans Affairs Medical Center  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11040750"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","unstructured":"American Diabetes Association. 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