Apolipoprotein AIV (ApoAIV) and cholecystokinin (CCK) are well-known satiating signals that are stimulated by fat consumption. Peripheral ApoAIV and CCK interact to prolong satiating signals. In the present study, we hypothesized that ApoAIV and CCK control energy homeostasis in response to high-fat diet feeding. To test this hypothesis, energy homeostasis in ApoAIV and CCK double knockout (ApoAIV/CCK-KO), ApoAIV knockout (ApoAIV-KO), and CCK knockout (CCK-KO) mice were monitored. When animals were maintained on a low-fat diet, ApoAIV/CCK-KO, ApoAIV-KO, and CCK-KO mice had comparable energy intake and expenditure, body weight, fat mass, fat absorption, and plasma parameters relative to the controls. In contrast, these KO mice exhibited impaired lipid transport to epididymal fat pads in response to intraduodenal infusion of dietary lipids. Furthermore, ApoAIV-KO mice had upregulated levels of CCK receptor 2 (CCK2R) in the small intestine while ApoAIV/CCK-KO mice had upregulated levels of CCK2R in the brown adipose tissue. After 20 wk of a high-fat diet, ApoAIV-KO and CCK-KO mice had comparable body weight and fat mass, as well as lower energy expenditure at some time points. However, ApoAIV/CCK-KO mice exhibited reduced body weight and adiposity relative to wild-type mice, despite having normal food intake. Furthermore, ApoAIV/CCK-KO mice displayed normal fat absorption and locomotor activity, as well as enhanced energy expenditure. These observations suggest that mice lacking ApoAIV and CCK have reduced body weight and adiposity, possibly due to impaired lipid transport and elevated energy expenditure.

Obesity-driven inflammation disrupts gut barrier integrity and promotes inflammatory bowel disease (IBD). Emerging evidence highlights gut hormones—including glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), peptide YY (PYY), cholecystokinin (CCK), and apolipoprotein A4 (APOA4)—as key regulators of metabolism and mucosal immunity. This review outlines known mechanisms and explores therapeutic prospects in IBD. GLP-1 improves glycemic control, induces weight loss, and preserves intestinal barrier function, while GLP-2 enhances epithelial repair and reduces pro-inflammatory cytokine expression in animal models of colitis. GIP facilitates lipid clearance, enhances insulin sensitivity, and limits systemic inflammation. PYY and CCK slow gastric emptying, suppress appetite, and attenuate colonic inflammation via neural pathways. APOA4 regulates lipid transport, increases energy expenditure, and exerts antioxidant and anti-inflammatory effects that alleviate experimental colitis. Synergistic interactions—such as GLP-1/PYY co-administration, PYY-stimulated APOA4 production, and APOA4-enhanced CCK activity—suggest that multi-hormone combinations may offer amplified therapeutic benefits. While preclinical data are promising, clinical evidence supporting gut hormone therapies in IBD remains limited. Dual GIP/GLP-1 receptor agonists improve metabolic and inflammatory parameters, but in clinical use, they are associated with gastrointestinal side effects that warrant further investigation. Future research should evaluate combination therapies in preclinical IBD models, elucidate shared neural and receptor-mediated pathways, and define optimal strategies for applying gut hormone synergy in human IBD. These efforts may uncover safer, metabolically tailored treatments for IBD, particularly in patients with coexisting obesity or metabolic dysfunction.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading contributor to liver-related morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown promise in improving MASLD-related outcomes, but their effect on hepatic fibrosis remains unclear. This study evaluated the impact of GLP-1 RA therapy on liver fibrosis, utilizing the validated fibrosis-4 (FIB-4) index as a noninvasive marker of fibrosis severity. Methods: In this retrospective cohort study, we identified patients within a large academic health system with MASLD, a baseline FIB-4 ≥ 1.3 (indicating intermediate or higher risk of hepatic fibrosis), and at least two GLP-1 RA prescriptions within a 90-day period between 2020 and 2024. Patients with cirrhosis or alcohol use disorder were excluded. Values were collected at treatment initiation and 12 months later. One-tailed paired t-tests assessed differences in FIB-4 and secondary outcomes, and multivariable linear regression identified independent predictors of FIB-4 change. Results: Among 229 patients with MASLD who were treated with GLP-1 RAs, 29 had a baseline FIB-4 ≥ 1.3. After 12 months, mean FIB-4 decreased by 0.21 from 1.94 to 1.73 (95% confidence interval (CI) −0.38 to −0.05; P = 0.019). Significant reductions were also observed in AST (−15.8 U/L), ALT (−21.9 U/L), body mass index (BMI, −2.6 kg/m2), and hemoglobin A1c (A1c, −1.1%; all P < 0.001). On multivariable analysis, baseline FIB-4 index was the strongest predictor of FIB-4 change (β = −0.538; P < 0.001), and FIB-4 improvement was independent of BMI change (β = 0.020; P = 0.243). Conclusion: In patients with MASLD at intermediate or higher risk of hepatic fibrosis, GLP-1 RA therapy was associated with significant reductions in FIB-4, AST, ALT, BMI, and A1c over 12 months, supporting a potential antifibrotic effect. The FIB-4 index may serve as a practical noninvasive marker for monitoring fibrosis response in MASLD.