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.

Long Term Exendin-4 Treatment Reduces Food Intake and Body Weight and Alters Expression of Brain Homeostatic and Reward Markers

“…In the current study, the food intake reduction effect persisted longer in HF-fed than chow-fed rats. Similar results have been demonstrated using both EX-4 and another long-acting GLP-1 analog liraglutide (42). A study by Hayes et al (26), however, showed that chow intake was decreased persistently and significantly throughout 7 days of EX-4 treatments.…”

Neural Control of Energy Balance: Translating Circuits to Therapies

“…Over the past two decades, it has become apparent that many of the currently available anti-diabetic drugs also act directly in the CNS (Table 1 and Figure 2). For instance, Liraglutide and Exenatide are known to act both in the periphery and at the level of the brain (Mul et al, 2013; Sisley et al, 2014). However, one recent study demonstrates that the glucose-lowering effects of Liraglutide are independent of GLP-1 receptor signaling in the brain (Sisley et al, 2014).…”

Estradiol modulates the anorexic response to central glucagon-like peptide 1

“…Previous studies have demonstrated that high fat diet-induced obesity impairs response to peripheral GLP-1, raising the possibility that increased body mass and adiposity could do the same for central GLP-1 (Mul et al, 2013; Williams et al, 2011). This was assessed in an experiment testing responsiveness to third ventricular infusion of Ex4 in animals fed a low fat chow diet and obese animals maintained on a high fat diet (Mul et al, 2013).…”

“…Previous studies have demonstrated that high fat diet-induced obesity impairs response to peripheral GLP-1, raising the possibility that increased body mass and adiposity could do the same for central GLP-1 (Mul et al, 2013; Williams et al, 2011). This was assessed in an experiment testing responsiveness to third ventricular infusion of Ex4 in animals fed a low fat chow diet and obese animals maintained on a high fat diet (Mul et al, 2013). The effects of central Ex4 were equivalent across groups, indicating that responsiveness to central GLP-1R stimulation is not altered by increased body weight and adiposity, making it unlikely that these factors are responsible for the behavioral difference in our study of EB- and oil-treated OVX rats.…”