208-OR: Comparable Improvement in NAFLD, Weight Loss, and Lipid Metabolism in Rats Treated with Dual GLP-1–GIP Receptor Agonist (Tirzepatide) and Gastric Sleeve

Background: Bariatric surgery is increasingly utilized as a weight management and metabolic control procedure, hence the name metabolic Surgery. Metabolic surgery is currently considered as an effective procedure for the treatment of diabetes providing a phenomenal hope for a long-lasting remission of diabetes. The use of combined GIPR and GLP-1R activation has recently emerged as a novel therapeutic tool in the treatment of T2D that produces profound weight loss, glycemic control, and lipid lowering. Tirzepatide (LY3298176) is a novel dual GIP and GLP-1 receptor agonist.

Objectives: The aim of this study is to evaluate the difference between GLP-1/GIP receptor agonist (Tirzepatide) treatment vs bariatric surgery on weight loss, NAFLD, insulin signaling and insulin resistance in SD rats.

Methods: Sprague-Dawley rats between the age of 4-6 weeks were either placed on regular rat chow diet (n=7) or cafeteria diet "high-fat/carbohydrate diet" ad libitum (n=42). After 21 weeks, rats on high fat diet were divided into either Obese control (n=6) gastric sleeve (n=6), Semaglutide 10nM/Kg (n=6), or various concentrations of Tirzepatide (10nM/Kg (n=6), 50nM/Kg (n=6) or 100nM/Kg (n=6). The treatments lasted for six weeks before animals were euthanized. Weight, OGTT, as well as liver biopsy analysis and gene expression analysis was performed.

Results: Gastric sleeve resulted in about 15.5 % weight loss compared to 10.7% in Semaglutide, and 5.0%, 14.9% and 17.7% in the 10, 50 and 100 nM/Kg Tirzepatide groups. Glucose tolerance was improved after all treatments. NAFLD was also improved in all treatment with surgery and 100 nM/Kg Tirzepatide showing highest improvement. Additionally, gene expression of lipid metabolism markers such as ANGPTL3 and 8 were markedly reduced in all treatments.

Conclusions: Tirzepatide is a novel dual GIP and GLP-1 receptor agonist that can lead to improved metabolic conditions similar to sleeve gastrectomy.