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

Abstract

Aim: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: diet preference; dual GIP/GLP-1 receptor agonists; food intake; obesity; tirzepatide.

Figure 1.. Individual GIP and Dual GIP/GLP-1 Receptor Agonism on Choice Diet Preference between Chow and 40% High-Fat Diet (HFD) or Chow and 60% HFD for 5 Days in Mice.

Effect of once daily injections [vehicle, GIP-085, or tirzepatide (TZP)] on daily intake of choice between chow (A) and 40% HFD (B) and in a separate group of mice choice between chow (C) and 60% HFD (D). Five-day cumulative intake of chow (E), intake of HFD (F), and body weight change (G) for both choice experiments. Daily average intake of chow and HFD as Kcals (H) and as a percentage of total Kcal intake (I) for both choice experiments. For panels E-I, comparisons made within a choice experiment are indicated with letter sets (a,b or x,z) and comparisons of the same treatment between choice experiment are indicated by asterisks. N=6–8 per treatment group.

Figure 2.. Chronic 14-day Dual GIP/GLP-1 Receptor Agonism on Choice Diet Preference between Chow and 60% High-Fat Diet (HFD) in Mice.

Effect of once daily injections [vehicle or tirzepatide (TZP)] on daily (A) and 14-day cumulative (B) chow intake, and daily (C) and 14-day cumulative (D) 60% HFD intake. 14-day cumulative weight change (E). Daily average intake of chow and 60% HFD as Kcals (F) and as a percentage of total Kcal intake (H). Direct comparisons are indicated with asterisks. N=5–6 per treatment group.

Figure 3.. Tirzepatide Dose Response and Two-Choice Preference Intake in Diet-Induced Obese Rats.

Once daily tirzepatide injection dose response [vehicle or 0.3, 1, 3, 10, 30 nmol/kg tirzepatide (TZP)] on daily food intake (A), 15-day cumulative food intake (B), and body weight change (C). N=5 per treatment group. Effect of once daily injections [vehicle, tirzepatide (TZP), or sibutramine] on daily chow (D) and gubra diet (E) intake. 21-day cumulative chow intake (F), gubra diet intake (G), and weight change (H). Daily average intake of chow and gubra diet as Kcals (I) and as a percentage of total Kcal intake (J). Fat mass (K) and lean mass (L) as a percentage of body weight at baseline and week 3 of treatment. Direct comparisons are indicated with letter sets (a,b,c or x,y,z). For panels K-L, comparisons of the same treatment between timepoints are indicated by asterisks. N=8 per treatment group.

Figure 4.. Individual or Combined GIP and GLP-1 Receptor Agonism on Choice Diet Preference between Chow, Crisco, Sucrose, and Water in Rats.

Effect of once daily IP injections [vehicle, GIP-085 (300nmol/kg), GLP-140 (100nmol/kg), or combined GIP-085/GLP-140 (Combo)] of daily (A) and 8-day cumulative (B) chow intake, daily (C) and 8-day cumulative (D) Crisco intake, daily (E) and 8-day cumulative (F) sucrose intake (10% solution), and daily (G) and 8-day cumulative (H) water intake. 8-day cumulative body weight change (I). Daily average intake of chow, sucrose, and Crisco as total Kcals (J), as a % of total Kcal intake (K), and the ratio of sucrose to Crisco Kcal intake (L). Direct comparisons are indicated with letter sets (a,b or x,z or m,n).

Figure 5.. GLP-1 Receptor Knockout Eliminates Dual GIP/GLP-1 Receptor Agonism-Induced Preference Shift between 5-Day Choice Chow and 60% High-Fat Diet (HFD) in Mice.

Effect of once daily injections [vehicle or tirzepatide (TZP)] in wildtype (WT) and GLP-1 receptor knockout (KO) mice on daily intake of chow (A) and 60% HFD (B). Five-day cumulative intake of chow (C), intake of 60% HFD (D), and body weight change (E). Daily average intake of chow and 60% HFD as Kcals (F) and as a percentage of total Kcal intake (G). Direct comparisons are indicated with letter sets (a,b or x,z). N=4–6 per treatment group.