What question did this study set out to answer?

This study aims to investigate the role of TGR5 agonism in the nucleus of the solitary tract on insulin sensitivity in male rats.

June 7, 2026

2461-P: TGR5 Agonism in the Nucleus of the Solitary Tract Enhances Insulin Action

Key Points

This study aims to investigate the role of TGR5 agonism in the nucleus of the solitary tract on insulin sensitivity in male rats.
Male rats underwent stereotaxic surgery targeting the nucleus of the solitary tract.
Rats were fed high-fat or regular chow diet for 3 days before hyperinsulinemic clamps with TGR5 agonist infusion.
Tritiated glucose infusion was used to assess glucose kinetics during clamps.
High-fat diet increased food intake and hepatic insulin resistance (HF diet: 6.6 mg/kg/min vs RC: 1.8 mg/kg/min, p<0.001).
TGR5 agonist infusion significantly increased glucose infusion rates (CCDC: 16.0 mg/kg/min vs Sal: 9.4 mg/kg/min, p<0.001).
CCDC infusion suppressed glucose production (CCDC: 2.8 mg/kg/min vs Sal: 6.6 mg/kg/min, p<0.01), independent of weight change.

Abstract

Introduction and Objective: Obesity and type 2 diabetes are intertwined global epidemics, highlighting the urgent need for therapies that lower weight and glucose. The bile acid responsive Takeda G-protein-coupled receptor 5 (TGR5) has emerged as a potential target as TGR5 activation in the nucleus of the solitary tract (NTS) lowers food intake and systemic TGR5 agonism improves insulin sensitivity, yet the site of action for glucoregulatory effects is unknown. Here, we investigate whether TGR5 agonism in the NTS regulates insulin sensitivity in male rats. Methods: Stereotaxic surgery targeting the NTS was performed, followed by intra-venous (IV) and -arterial catheterization. After recovery, rats were fed regular chow (RC) or high-fat (HF) diet enriched with 10% lard for 3d. We performed pancreatic hyperinsulinemic (2.0 mU/kg/min)-euglycemic clamps with NTS infusion of the specific TGR5 agonist CCDC (0.36 μL/hr; 3.5hr) and IV tritiated glucose infusion for glucose kinetics assessment. Results: First, we confirmed that 3d HF vs RC induced hyperphagia HF: 246.5 ± 15.3 vs RC: 184.9 ± 10.9 kcal, p0.001, n=6,8 and hepatic insulin resistance (i.e., impaired the ability of hyperinsulinemia to lower glucose production HF: 6.6 ± 0.7 vs RC:1.8 ± 0.4 mg/kg/min, p0.001, n=6, 8), independent of changes in weight HF: 319 ± 12.1 vs RC: 325 ± 6.2 g, p0.05, n=6,8. Next, we discovered that CCDC vs saline (sal) NTS infusion for 3.5hr increased exogenous glucose infusion CCDC: 16.0 ±1.2 vs Sal: 9.4 ±0.8 mg/kg/min, p0.001, n=6/group required to maintain euglycemia during the hyperinsulinemic clamps. This acute increase in insulin sensitivity induced by CCDC was due to marked suppression of glucose production CCDC: 2.8 ± 1.0 vs Sal: 6.6±0.7 mg/kg/min, p0.01, n=6/group, but independent of changes in weight. Conclusion: Together, these findings demonstrate that TGR5 agonism in the NTS reverses HF-diet-induced hepatic insulin resistance. Disclosure D. Moslemian: None. K. Bruce: None. A. Garrido: None. Z. Yang: None. T. Lam: None. Funding Canadian Institutes of Health Research (PJT-189957) to T.K.T.L

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