Concurrent pharmacological modification of cannabinoid-1 and glucagon-like peptide-1 receptor activity affects feeding behavior and body weight in rats fed a free-choice, high-carbohydrate diet

Abstract

To extend preliminary studies on the effects on food intake of the combined use of cannabinoid (CB) 1 and glucagon-like peptide-1 (GLP-1) receptor agonists and antagonists, the effect of these drugs on the feeding behavior in rats maintained on a free-choice, high-carbohydrate diet was investigated over a longer period of time. Rats were fed a standard diet for 3 days and then fed with both the standard and the high-sucrose chow. After 4 days of the high-calorie diet, the following combination treatments were administered daily by an intraperitoneal injection for the next 3 days: 1 mg/kg AM 251 (a CB1 receptor antagonist) or 1 mg/kg WIN 55,212-2 (a CB1 receptor agonist) together with 3 µg/kg exendin-4 (Ex-4, a GLP-1 receptor agonist) or 160 µg/kg exendin (9-39) [Ex (9-39), a GLP-1 receptor antagonist]. The total daily caloric intake and body weight were significantly reduced in rats treated with Ex-4 and AM 251 or WIN 55,212-2 compared with either of the drugs injected alone and the saline-injected controls. Both drug combinations selectively inhibited ingestion of the high-sucrose chow. Although Ex (9-39) administration did not significantly affect food consumption, it resulted in a marked body weight gain, indicating that the GLP-1 receptor antagonist caused a positive energy balance. It is concluded that AM 251 or WIN 55,212-2 and Ex-4, injected together, exert additive, inhibitory effects on the consumption of high-sugar food.

Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice

“…Several recent studies have suggested a potential interaction between incretin receptors and CB1, particularly with regard to food intake (E. Bojanowska, 2011; Patel et al, 2014; Radziszewska et al, 2014). However, there is a lack of data as to how CB1 would influence the entero-insular axis if both incretin and insulin secretion are impacted by the same receptor system.…”

Can We Selectively Reduce Appetite for Energy-Dense Foods? An Overview of Pharmacological Strategies for Modification of Food Preference Behavior

“…, food-seeking) behavior. On the other hand, the results obtained in our laboratory indicated that AM 251 was not able to reduce selectively food consumption in male Wistar rats that were offered a choice between sweet and normal rat chow [ 82 , 83 ]. This discrepancy may result from different experimental conditions ( e.g.…”

“…[ 78 ] and Radziszewska et al . [ 82 ], respectively) as well as from different sensitivity of male and female rats to the CB1 receptor antagonists, an event found originally in mice [ 84 ]. Moreover, AM 251 used at doses comparable to those that specifically decreased sweet food intake in female rats in the aforementioned study by Mathes et al .…”

“…, a decrease in palatable food intake and simultaneous increase in regular food intake, were obtained in rats co-injected with GLP-1 and an inhibitor of dipeptidyl peptidase IV (an enzyme responsible for GLP-1 degradation, inagliptin) maintained on a two-choice diet consisting of standard chow and a high-fat/high-sugar chow [ 309 ]. Exendin-4 and AM 251 is another drug combination that involves the long-lasting GLP-1 analogue and has been demonstrated to inhibit selectively high-sucrose diet intake in rats [ 82 ]. Although the GLP-1 agonist used in that study was able, as such, to decrease sweet food consumption, the blockade of the CB1 receptor by AM 251 significantly enhanced this effect.…”

“…Although the GLP-1 agonist used in that study was able, as such, to decrease sweet food consumption, the blockade of the CB1 receptor by AM 251 significantly enhanced this effect. Surprisingly, the effect of co-injection of exendin-4 and WIN 55, 212-2, a CB1 receptor agonist, on the selective inhibition of palatable food intake was even more spectacular and resulted not only in almost complete suppression of high-sucrose food consumption but also in an increase in the standard food consumption and reduction in body weight [ 82 ]. Hence, administration of GLP-1 agonists, regardless of whether alone or in combination with other drugs that potentiate their action, seems to be a promising approach aimed at specifically reducing appetite for palatable, high-calorie foods.…”