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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE302985 | GEO | 2025/09/23

REPOSITORIES: GEO

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Project description:Maternal obesity is linked with increased adverse outcomes for mother and fetus. However, the metabolic impact of excessive fat accumulation within the altered hormonal context of pregnancy is not well understood. We used a murine model of obesity, the high fat diet-fed C57BL/6J mouse to determine adipose tissue-mediated molecular mechanisms driving metabolic dysfunction throughout pregnancy. Remarkably, obese mice exhibited a normalization of visceral fat accumulation at late-stage pregnancy (-53%, P<0.001 E18.5) to achieve levels comparable in mass (per gram of body weight) to that of non pregnant, control diet fed mice. Moreover, whilst obese pregnant mice showed a marked glucose intolerance and apparent insulin resistance at mid-stage pregnancy (E14.5), glucose homeostasis converged with that of lean pregnant mice at late-stage pregnancy, suggesting an unexpected amelioration of the worsening metabolic dysfunction in obese pregnant mice. Transcriptomic analysis of the late-stage visceral fat indicated reduced de novo lipogenic drive (Me1, Fasn, Scd1, Dgat2), retinol metabolism (Rdh11, Rbp4) and inflammation (Mcp1, Tnfα) in obese pregnant mice that was confirmed functionally by their lower adipose proinflammatory macrophage density. Elevated expression of estrogen receptor a (ERα) in visceral adipose tissue was identified as potential unifying mechanism for the transcriptional changes and reduced adiposity of late stage obese pregnancy. Support for a role for ERα was provided by experiments showing that the ERα selective agonist PPT suppressed lipogenesis in primary mouse adipocytes and suppressed Me1, Fasn, SCD1 and Dgat2 mRNA levels in mature female human ChubS7 clonal fat cells. Our data reveal a novel role for elevated visceral adipocyte estrogen signaling as a protective mechanism against visceral fat hypertrophy and inflammation in late pregnancy. Pregnant high fat, pregnant control fat, non pregnant high fat, non pregnant control fat. Five biologial replictes each (20 samples).

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

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