Cannabinoid CB1 Receptors in the Intestinal Epithelium Are Required for Acute Western-Diet Preferences in Mice

Abstract

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 CB1Rs 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 CB1R antagonist/inverse agonist, AM251, for up to 3 h. We next used our novel intestinal epithelium-specific conditional cannabinoid CB1R-deficient mice (IntCB1−/−) to investigate if intestinal CB1Rs are necessary for WD preferences. Similar to AM251 treatment, preferences for WD were largely absent in IntCB1−/− mice when compared to control mice for up to 6 h. Together, these data suggest that CB1Rs in the murine intestinal epithelium are required for acute WD preferences.

UPLC-MS/MS Method for Analysis of Endocannabinoid and Related Lipid Metabolism in Mouse Mucosal Tissue

“…Several biochemical and molecular assays are common for analyzing eCB system activity including qPCR-based analysis of expression of genes for specific components of the system (e.g., eCB biosynthetic and degradative enzymes) (Argueta et al, 2019;Avalos et al, 2020). Importantly, however, quantitating levels of gene expression does not provide a full -and at times accurate -depiction of the state of eCB system activity.…”

The Peripheral Cannabinoid Receptor Type 1 (CB1) as a Molecular Target for Modulating Body Weight in Man

“…Selective knockdown of CB1 in adipose tissue [21], the liver [22], or skeletal muscle [23] all prevent diet-induced obesity or hyperphagia. Mice in whom CB1 was selectively knocked down in the intestinal epithelium did not have the preference for a Western style diet (with reduced caloric intake and meal size) normally observed in wild-type mice [24]. In a preclinical model of cachexia, it was recently shown that the potent, selective CB1/CB2 agonist WIN55,212-2 led to a significant reduction in the cachexia index and significantly prevented the cachexia-induced increase in gastric emptying [25].…”

“…Argueta and DiPatrizio showed that the hyperphagia in mice given free access to a high-fat and sucrose diet was inhibited by a peripherally restricted CB 1 antagonist [45]. These researchers went on to show that mice in whom CB 1 was selectively knocked down in the intestinal epithelium did not have the preference for the high-fat and sucrose diet [24]. Thus, endogenous activation of CB 1 in the intestine increases the palatability of food through gut-brain communication.…”

Endocannabinoids and the Gut-Brain Control of Food Intake and Obesity

“…To test the necessity for CB 1 Rs in the intestinal epithelium in the intake of palatable foods, we developed transgenic mice (Cnr1 tm1 . 1 mrl /Vil-CRE ERT2) that are conditionally deficient in CB 1 Rs in the intestinal epithelium (referred to as IntCB 1 -/-mice) [ 63 ]. Mice were maintained on standard rodent chow low in fats and sugars, then given access for the first time to a palatable western-style diet high in fats and sugars (Research Diets D12079B; 40% kcals from fats and 43% from carbohydrates [ 64 ]), and preferences for western diet were measured.…”