High-fat diet changes the temporal profile of GLP-1 receptor-mediated hypophagia in rats

Abstract

Overconsumption of a high-fat diet promotes weight gain that can result in obesity and associated comorbidities, including Type 2 diabetes mellitus. Consumption of a high-fat diet also alters gut-brain communication. Glucagon-like peptide 1 (GLP-1) is an important gastrointestinal signal that modulates both short- and long-term energy balance and is integral in maintenance of glucose homeostasis. In the current study, we investigated whether high-fat diets (40% or 81% kcal from fat) modulated the ability of the GLP-1 receptor (GLP-1r) agonists exendin-4 (Ex4) and liraglutide to reduce food intake and body weight. We observed that rats maintained on high-fat diets had a delayed acute anorexic response to peripheral administration of Ex4 or liraglutide compared with low-fat diet-fed rats (17% kcal from fat). However, once suppression of food intake in response to Ex4 or liraglutide started, the effect persisted for a longer time in the high-fat diet-fed rats compared with low-fat diet-fed rats. In contrast, centrally administered Ex4 suppressed food intake similarly between high-fat diet-fed and low-fat diet-fed rats. Chronic consumption of a high-fat diet did not change the pharmacokinetics of Ex4 but increased intestinal Glp1r expression and decreased hindbrain Glp1r expression. Taken together, these findings demonstrate that dietary composition alters the temporal profile of the anorectic response to exogenous GLP-1r agonists.

Keywords: exendin-4; food intake; glucagon-like peptide 1; liraglutide; obesity.

Fig. 1.

High-fat diet alters time profile of IP Ex4-induced hypophagia. A: body mass (left), lean mass (middle), and fat mass (right). Caloric intake during the 0–2-h (B), 2–4-h (C), 0–24-h (D), 24–48-h (E), and 0–48-h (F) intervals following intraperitoneal administration of saline (S), 3 μg/kg Ex4 (3), 10 μg/kg Ex4 (10), or 33 μg/kg Ex4 (33). Body mass change during the 0–24-h (G) and 0–48-h (H) intervals following Ex4 administration. Rats were on their respective diet for 6 wk (n = 9–10 per group). *P < 0.05 vs. LFD; †P < 0.05 vs. saline treatment within same diet; §P < 0.05 vs. similar Ex4 dose LFD; ^P < 0.05 vs. similar Ex4 dose MFD; ^a,b,c,dP < 0.05, different letters indicate significant differences between dosage groups.

Fig. 2.

High-fat diet alters time profile of intraperitoneal Ex4 flat dose-induced hypophagia. A: body mass (left), lean mass (middle), and fat mass (right). Caloric intake during the 0–2-h (B), 2–4-h (C), 0–24-h, 24–48-h, 48–72-h, and 72–96-h intervals (D) following intraperitoneal administration of saline (S) or 15 μg Ex4 (Ex4). E: body mass change during the 0–24-h interval following Ex4 administration. Rats were on their respective diet for 13 wk (n = 13 or 14/group). *P < 0.05 vs. LFD; ^a,bP < 0.05, different letters indicate significant differences between treatment groups; †P < 0.05 vs. saline treatment within same diet; §P < 0.05 vs. Ex4 treatment LFD.

Fig. 3.

High-fat diet alters time profile of intraperitoneal liraglutide-induced hypophagia. A: body mass (left), lean mass (middle), and fat mass (right). Caloric intake during the 0–2-h (B), 2–4-h (C), 0–24-h, 24–48-h, 48–72-h, 72–96-h, and 96–120-h (D) intervals following intraperitoneal administration of either saline (S) or 300 μg/kg liraglutide (L). E: body mass change during the 0–24-h interval following intraperitoneal administration of saline (S) or liraglutide (L). Rats were on their respective diet for 16 wk (n = 13 or 14/group). *P < 0.05 vs. LFD; †P < 0.05 vs. saline treatment within same diet; §P < 0.05 vs. liraglutide treatment LFD.

Fig. 4.

High-fat diet does not alter time profile of I3VT Ex4-induced hypophagia. Caloric intake during the 0–2-h (A), 2–4-h (B), and 0–24-h (C) intervals following I3VT administration of either saline (S) or 0.1 μg Ex4 (Ex4). Rats were on their respective diet for 6 wk (n = 4–6/group). ^a,bP < 0.05, different letters indicate significant differences between treatment groups.

Fig. 5.

High-fat diet does not alter Ex4 pharmacokinetics. Serum Ex4 levels before (0) and following (2, 4, and 24 h) intraperitoneal administration of 33 μg/kg Ex4. Rats were on their respective diet for 11 wk (n = 19–20/group). *P < 0.05 vs. 0-h time point.

Fig. 6.

Glp1r and Gcg gene expression and GLP-1 protein levels. A: Glp1r expression in whole hypothalamus, NTS, distal ileum (n = 10–14/group), and nodose ganglion (n = 5–6/group). B: Gcg expression in NTS and distal ileum (n = 10–14/group). C: total GLP-1 levels in hypothalamus, NTS, and distal ileum (n = 7–14/group). Rats were on their respective diet for 24 wk. *P < 0.05 vs. LFD.