(P28-30-26) Fructooligosaccharides Improve Insulin and GLP‑1 Profiles and Modulate Colonic PI3K/Akt and GLP‑1 Receptor Signaling in High‑Fat Diet‑Induced Obese Mice

Objectives: To determine whether fructooligosaccharide (FOS) supplementation improves insulin sensitivity and glucagon‑like peptide‑1 (GLP‑1) secretion, modulates colonic PI3K/Akt and GLP‑1 receptor (GLP‑1R) signaling, and alters gut microbiota composition in high‑fat diet (HFD)‑induced obese mice.

Methods: Six-weeks old male and female C57BL/6J mice (n = 5/sex/group) were randomly assigned to a control diet (CON) or 60% HFD ± 5% FOS for 10 weeks. Fasting serum insulin and total GLP‑1 were quantified. Colonic PI3K, Akt, GLP‑1R, TLR4 mRNA, and Akt protein levels were measured. Relative abundance of Akkermansia muciniphila (AM), Dubosiella newyorkensis, (DN) and Romboutsia ilealis (RI) was determined by real-time PCR. Correlations were tested between cecal bacterial abundance, serum GLP-1, insulin, and colonic gene and protein expression metrics.

Results: Data are expressed as Mean ± SEM. FOS suppressed fasting insulin by 2-fold in HFD mice (p < 0.05), but no effect in CON mice, accompanied with a 198% increase in circulating GLP‑1 compared to non-supplemented HFD males (p < 0.011), and no change in females. Unexpectedly, colonic Pi3k and Akt mRNA expressions were downregulated by 3- and 4-fold, respectively, only in HFD-fed females upon FOS treatment. Unlike circulating GLP-1 where the effect of FOS was mainly targeting male, colonic Glp1r mRNA expression was 2-fold lower in FOS-treated female mice though protein level was unaltered, suggesting possible post-transcriptional regulation at a sex-dependent manner. The abundance of RI, a pathobiont, was elevated by HFD, which was suppressed by FOS intake regardless of sex (p < 0.001), which positively correlated with colonic Tlr4 mRNA (r= 0.603; p < 0.05), linking FOS-responsive microbes to inflammatory signaling. FOS did not alter AM and DN. abundance among HFD mice.

Conclusions: FOS supplementation improves insulin and GLP‑1 profiles and modulates colonic PI3K/Akt and GLP‑1R signaling in a sex‑dependent manner. FOS reshapes the microbiome, with RI emerging as a potential mediator of host inflammatory and metabolic pathways. These findings support the gut microbiota–GLP‑1–PI3K/Akt axis as a potential target for FOS to mitigate metabolic dysfunction.

Funding Sources: Texas State University Research Enhancement Program 2024, and institutional startup funds.