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.
Highlights
Humans and other mammals, when given a choice, generally prefer food that contains fats, sugars, or a combination of both [1]
Vehicle-treated mice displayed robust preferences for Western Diet (WD) when compared to standard rodent laboratory diet (SD), an effect inhibited by AM251 by 3 h (Figure 1a, from 84.7 ± 7.1% total kcals from WD in vehicle-treated mice compared to 58.7 ± 8.3% in AM251-treated mice; p = 0.042)
Vehicle-treated mice displayed significant reductions in preference for WD during the 12–24 h interval when compared to AM251-treated mice, (Figure 1d, from 70.9 ± 8.7% total kcals from WD in vehicle-treated mice compared to 93.85 ± 3.57% in AM251-treated mice; p = 0.024)
Summary
Humans and other mammals, when given a choice, generally prefer food that contains fats, sugars, or a combination of both [1]. We reported that tasting dietary lipids was sufficient to increase levels of eCBs in the rat upper small-intestinal epithelium, which required an intact vagus nerve, and pharmacological inhibition of cannabinoid subtype-1 receptors (CB1 Rs) in the periphery blocked consumption of lipids [14,15]. Levels of eCBs in the upper small-intestinal epithelium were increased in mice maintained for eight weeks on a western-style diet high in fat and sugar (WD) when compared to mice fed a standard diet low in fat and sugar, and pharmacological inhibition of CB1 Rs in the periphery blocked overeating associated with WD-induced obesity [17].
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