Cannabinoid CB(1) Receptors in the Intestinal Epithelium Are Required for Acute Western-Diet Preferences in Mice

The endocannabinoid system plays an important role in the intake of palatable food. For example, endocannabinoid signaling in the upper small-intestinal epithelium is increased (i) in rats after tasting dietary fats, which promotes intake of fats, and (ii) in a mouse model of diet-induced obesity, which promotes overeating via impaired nutrient-induced gut–brain satiation signaling. We now utilized a combination of genetic, pharmacological, and behavioral approaches to identify roles for cannabinoid CB(1)Rs in upper small-intestinal epithelium in preferences for a western-style diet (WD, high-fat/sucrose) versus a standard rodent diet (SD, low-fat/no sucrose). Mice were maintained on SD in automated feeding chambers. During testing, mice were given simultaneous access to SD and WD, and intakes were recorded. Mice displayed large preferences for the WD, which were inhibited by systemic pretreatment with the cannabinoid CB(1)R antagonist/inverse agonist, AM251, for up to 3 h. We next used our novel intestinal epithelium-specific conditional cannabinoid CB(1)R-deficient mice (IntCB(1)−/−) to investigate if intestinal CB(1)Rs are necessary for WD preferences. Similar to AM251 treatment, preferences for WD were largely absent in IntCB(1)−/− mice when compared to control mice for up to 6 h. Together, these data suggest that CB(1)Rs in the murine intestinal epithelium are required for acute WD preferences.