(P20-063-25) High-Fat Diet-Induced Obesity Alters Hypothalamic Signaling and Gut Microbiota Composition, Leading to Anxiety-Like Behaviors in Mice

Objectives: Obesity is a risk factor for cognitive impairments, including anxiety and other mood disorders. The underlying mechanisms linking obesity to brain dysfunction remain incompletely understood, but emerging evidence suggests that both hypothalamic insulin resistance and gut microbiota alterations may play a role. We aimed to investigate the effects of high-fat diet (HFD)-induced obesity on behavior, hypothalamic signaling, and gut microbial composition, with focus on the relationship between these factors and cognitive function.

Methods: Male C57BL/6 mice were fed either a low-fat diet (LFD) or an HFD for 15 weeks. Body weight and adiposity were measured, and fear conditioning test was conducted. Hypothalamic mRNA expression of IRS2 and STAT3 was measured by PCR. Gut microbial composition was assessed using 16S rRNA sequencing to identify differences in microbial communities.

Results: Mice fed the HFD showed significant increases in body weight and adiposity. HFD increased long-term context and cue-dependent % time spent frozen, indicative of anxiety-like behavior. HFD-fed mice exhibited decreased IRS2 expression and increased STAT3 expression in the hypothalamus, suggesting impaired insulin signaling and metabolism. Gut microbiome analysis revealed distinct clustering of microbial communities between HFD- and LFD-fed mice. HFD feeding decreased the abundance of Clostridium, while increasing the abundance of the short-chain fatty acid-producing Lachnospiraceae, Kineothrix, and Oscillospiraceae.

Conclusions: Our findings suggest that HFD-induced obesity is associated with both behavioral deficits, including anxiety-like symptoms, and alterations in hypothalamic signaling pathways that may contribute to cognitive impairments. Furthermore, HFD feeding leads to significant changes in the gut microbiota, with potential implications for neurometabolic pathways. These results provide new insights into the complex interactions between diet, brain function, and gut microbiota, and highlight the importance of targeting multiple systems in the treatment of obesity-related cognitive impairments.

Funding Sources: Georgia State University’s Brains & Behavior Seed Grant