142-OR: Tirzepatide, a Dual GIP and GLP-1 Receptor Agonist, Mediates Its Anorexigenic Effect in Mice Due to a Reduction in Homeostatic and Reward-Related Feeding

Tirzepatide (TZP), a novel dual GIP and GLP-1 receptor agonist, has demonstrated clinically meaningful weight loss in type 2 diabetes mellitus (T2DM) patients. Preclinical data indicate that TZP lowers body weight due to a reduction in caloric intake; however, associated effects on feeding behavior have not been studied. To investigate how TZP affects homeostatic feeding, we examined its effect on markers of satiation (meal size), satiety (meal frequency) and hunger (time-interval between meals) in obese mice. Chronic treatment with TZP dose-dependently lowered body weight and food intake in high-fat fed mice. This reduction in total daily caloric intake was underlined by a reduction in meal size and frequency throughout a 14-day treatment period. Indicating that TZP’s effect on total energy intake is associated with reduced hunger and increased satiety. One driver of the current obesity epidemic is the consumption of highly palatable/calorically dense foods. To determine whether the anorexigenic action of TZP is associated with reward-related feeding, we exposed lean and obese mice to two-choice diet paradigms ((low-fat (6% of kcal from fat) vs. high-fat (40% or 60% of kcal from fat) diets). Importantly, we found that while TZP decreased total calories consumed, it also altered macronutrient preference by increasing the intake of a low-fat diet and reducing intake of a high-fat diet. Furthermore, when exposed to a series of two-choice bottle tests, TZP reduced the consumption of nutritive (fructose and sucrose) and non-nutritive (sucralose) tastants, suggesting that TZP’s anorexigenic action may be linked to the taste and caloric content of food. Taken together, these data indicate that TZP’s ability to lower daily energy intake is mediated by both a reduction in homeostatic and reward-driven food intake.