Endocannabinoids: An appetite for fat

Abstract

It has been known for decades that marijuana causes the “munchies,” i.e., a hunger for palatable food, and for more than 10 y that endocannabinoids (eCBs), in some ways marijuana's counterpart in the organism, are orexigenic mediators (1). When injected in the hypothalamus (HT) or nucleus accumbens (NAc), two key brain areas for the homeostatic and hedonic control of food intake, these compounds stimulate food consumption by acting at the cannabinoid CB1 receptor, one of the two G protein-coupled receptors for marijuana's psychotropic and appetite-inducing component, Δ9-tetrahydrocannabinol (2, 3). Conversely, systemic pharmacological blockade of CB1 receptors causes anorectic effects in rodents exposed to palatable food, or food-deprived for a few hours, and in obese animals (3–6). The two most studied eCBs, anandamide and 2-arachidonoylglycerol (2-AG), are considered local mediators produced by cells only following stimulation, and in this they differ from other signals controlling food intake, which are released into the bloodstream and/or prestored in vesicles (1). What makes the eCBs similar to most orexigenic signals is the fact that their concentrations in the HT and NAc, but also in the proximal intestine, which transmits to the brain the state of “emptiness” or “fullness” of the gut, increase during food deprivation and decrease immediately after food consumption (3, 7, 8). This mechanism is presumably caused by the opposing effects on eCB levels of hormones such as leptin, on the one hand, and ghrelin and corticosterone, on the other hand, the levels of which also vary during food deprivation and refeeding (1, 6). These food intake- and hormone-sensitive changes in eCB signaling are thought to play a key role in the regulation of (i) the release of central neurotransmitters and neuropeptides controlling food intake and (ii) the activity of vagal fibers from the duodenum to the brainstem, which signal gastric distension (1). In this scenario, the results of the elegant study by DiPatrizio and coworkers published in PNAS (9), although in full agreement with the general orexigenic function of eCBs and CB1 receptors, might seem somewhat surprising. In fact, the authors report that a fatty meal elevates eCBs selectively in the rat proximal small intestine, and propose that this effect: (i) is induced by the orosensory properties of the meal; (ii) is mediated by vagal afferent and efferent terminals, and (iii) reinforces fat intake via CB1 receptor activation (9).