Dietary Fructooligosaccharide Is Associated with Improved Insulin Resistance, Reduced Romboutsia ilealis Abundance, and Modulation of GLP-1 Production in High-Fat Diet-Induced Obese Mice

Background/Objectives: Obesity disrupts glucose homeostasis and insulin signaling, partly through altered gut hormone secretion and intestinal inflammation. Our previous work demonstrated that fructooligosaccharides (FOS), a prebiotic fiber, suppressed colonic inflammation, and modulated gut microbiota when administered with vitamin D supplementation. However, the effects of FOS on metabolic alterations, glucagon-like peptide-1 (GLP-1) production under obesogenic stimulation remains unclear. Here, we examined the effects of FOS on insulin resistance and GLP-1 production in high-fat diet (HFD)—induced obese mice. Methods: Six-week-old male and female C57BL/6J mice were assigned to control or HFDs ± 5% FOS for 10 weeks. Body weight, visceral fat, fasting glucose, insulin, triglycerides, and insulin resistance index (HOMA-IR) were assessed. Serum GLP-1 was quantified by ELISA. Colonic expressions of Glp1r, Pi3k, and Akt were evaluated by qRT-PCR and western blotting, respectively. Cecal abundance of Akkermansia muciniphila (AM), Dubosiella newyorkensis (DN), and Romboutsia ilealis (RI) was quantified by qPCR. Results: FOS attenuated HFD-induced metabolic dysfunction, lowering serum insulin and HOMA-IR in both sexes. Notably, FOS elicited sex-dependent physical improvements of which it suppressed body weight gain by 10% in male mice and reduced visceral fat accumulation by 36% in female mice. The phenotypic changes in male mice were associated with an increase in GLP-1. Further, FOS modulated colonic PI3K/Akt signaling in a sex-dependent manner and downregulated HFD-associated increases in Glp1r mRNA expression. Consistent with our previous work, FOS suppressed RI abundance, and this reduction was associated with lower colonic Tlr4 mRNA expression and improved insulin-resistance index. Conclusions: FOS improves insulin sensitivity in HFD-induced obesity and specifically enhanced GLP-1 production in male mice. Though the mechanism remained elucidated, the observed phenotype changes may be attributed to a combination of altered colonic PI3K/Akt pathways and targeted bacterial shifts. These effects appear to be sex-dependent and support FOS as a promising dietary strategy for maintenance of metabolic health.