Tirzepatide suppresses palatable food intake by selectively reducing preference for fat in rodents.

Abstract

To investigate the role of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists alone or combined with glucagon-like peptide-1 receptor (GLP-1R) agonists to regulate palatable food intake and the role of specific macronutrients in these preferences. To understand this regulation, we treated mice and rats on several choice diet paradigms of chow and a palatable food option with individual or dual GIPR and GLP-1R agonists. In mice, the dual agonist tirzepatide suppressed total caloric intake, while promoting the intake of chow over a high fat/sucrose diet. Surprisingly, GIPR agonism alone did not alter food choice. The food intake shift observed with tirzepatide in wild-type mice was completely absent in GLP-1R knockout mice, suggesting that GIPR signalling does not regulate food preference. Tirzepatide also selectively suppressed the intake of palatable food but not chow in a rat two-diet choice model. This suppression was specific to lipids, as GLP-1R agonist and dual agonist treatment in rats on a choice paradigm assessing individual palatable macronutrients robustly inhibited the intake of Crisco (lipid) without decreasing the intake of a sucrose (carbohydrate) solution. Decreasing preference for high-caloric, high-fat foods is a powerful action of GLP-1R and dual GIPR/GLP-1R agonist therapeutics, which may contribute to the weight loss success of these drugs.