What does this research mean for the field?

Co-infusion of a GIP receptor agonist and leptin in the nucleus of the solitary tract does not additively reduce food intake in rats with high-fat diet-induced leptin resistance compared to GIP agonism alone. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This study investigates whether GIP receptor agonism enhances the effects of leptin to reduce food intake in the nucleus of the solitary tract.

June 7, 2026

2459-P: Nucleus of the Solitary Tract GIPR Agonism Fails to Additively Reduce Food Intake with Leptin Co-Infusion

Key Points

This study investigates whether GIP receptor agonism enhances the effects of leptin to reduce food intake in the nucleus of the solitary tract.
Male Sprague-Dawley rats underwent stereotaxic surgery targeting the nucleus of the solitary tract.
Rats received different treatments including DA-GIP infusion, leptin infusion, or their combination after fasting.
Feeding studies measured food intake 24 hours post-infusion.
NTS leptin infusion did not reduce food intake in hyperphagic rats (p>0.05).
DA-GIP infusion significantly lowered food intake (103±8 kcal) compared to saline (119±6 kcal, n=9) and leptin (114±8 kcal, n=6) infusions (p<0.05).
GIP and leptin co-infusion did not further decrease food intake compared to DA-GIP alone (97±4 kcal, n=5, p>0.05).

Abstract

Introduction and Objective: Obesity is rapidly growing in prevalence worldwide, largely driven by modern lifestyles that promote excessive calorie consumption and reduced energy expenditure. Incretin-based therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists and glucose-dependent insulinotropic polypeptide (GIP) receptor/GLP-1 receptor (GIPR/GLP-1R) co-agonists have shown significant clinical efficacy in treating obesity by lowering food intake. Leptin receptor signaling resistance is a hallmark of obesity that is induced by high-fat (HF) diets. Therefore, we sought to test whether GIP interacts with leptin in the nucleus of the solitary tract (NTS) to additively reduce food intake. Methods: Male Sprague-Dawley rats (300-320g) underwent stereotaxic surgery targeting the NTS while avoiding the area postrema (AP) to directly infuse DA-GIP (GIPR agonist) and/or leptin. Rats received chow or 3d HF diet to induce hyperphagia with central leptin resistance. Feeding studies were performed with an acute NTS infusion (0.2uL/site over 5min) given to 10-12h fasted rats before refeeding. Results: HF NTS leptin infusion failed to reduce food intake compared to HF NTS saline rats (p0.05), verifying central leptin resistance, while NTS DA-GIP infusion lowered food intake at 24-hours (p0.05). However, HF NTS DA-GIP+leptin co-infusion did not additively reduce food intake compared to DA-GIP alone (p0.05) (HF NTS saline 119±6kcal (n=9), HF NTS leptin 114±8kcal (n=6), HF NTS GIP 103±8kcal (n=6), HF NTS DA-GIP+leptin 97±4kcal (n=5)). Conclusion: Future studies should knock down leptin receptor in the NTS to verify that GIPR and leptin receptor do not interact additively or synergistically to lower food intake. Disclosure M.T. Wang: None. K. Bruce: None. Z. Yang: None. A. Garrido: None. D. Moslemian: None. T. Lam: None. Funding Canadian Institutes of Health Research (PJT-183901) to T.K.T.L.

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