VIP Knockout Mice Are Resistant to Diet-Induced Obesity (DIO): Sex-Specific Differences Depend on Genotype and Duration of Diet Exposure

Obesity is a 21st-century epidemic that afflicts more than 42% of adults worldwide and is associated with several comorbidities, including type 2 diabetes and heart disease. Vasoactive intestinal peptide (VIP) is a metabolic gut hormone involved in energy homeostasis. Research has revealed that VIP’s amino acid sequence is 100% identical across most mammals, including humans, rodents, and livestock. Our laboratory has observed that VIP knock-out (KO) mice have gut microbiota dysbiosis similar to that reported in inflammatory bowel disease mouse models. This gut microbiota dysbiosis was related to weight loss. Indeed, VIP KO mice are leaner compared to wild-type (WT) littermates. Based on these observations, we hypothesize that VIP-deficient mice are resistant to diet-induced obesity (DIO). To verify our hypothesis, we studied male and female VIP WT, heterozygous (HET), and homozygous mutant or KO mice (n ≤ 5/group). Mice were placed on low- and high-fat diets ad libitum for 12 weeks, monitoring food, water consumption and body weights weekly for 12 weeks. At week 17, blood, tissues (liver, kidney, and jejunum), and fecal samples were harvested. Our data revealed that VIP KO mice were highly resistant to DIO gaining only ≈40% body weight compared to WT littermates (p≤0.0001). We observed a sex-specific difference: female VIP KO mice gained more weight than KO males in weeks 1-4, but less in weeks 8-12 (p≤0.0001) on high-fat diet while HETs gained ≈ 70% of their body weight compared to WT littermates that gained 100% (p≤0.01) only in males on low fat diet. Furthermore, 16S sequencing of fecal samples revealed distinct changes in bacterial abundance in KO mice, independent of sex. In addition, bacterial richness increased significantly under the high-fat diet in a genotype-independent manner (p≤0.01). These data strongly indicate that VIP-deficient mice are resistant to DIO. Therefore, understanding the role of VIP in DIO could provide a promising therapeutic approach for treating obesity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.