The endocannabinoid system as a link between homoeostatic and hedonic pathways involved in energy balance regulation

International Journal of Obesity (2009) 33, S18–S24 & 2009 Macmillan Publishers Limited All rights reserved 0307-0565/09 $32.00 www.nature.com/ijo REVIEW The endocannabinoid system as a link between homoeostatic and hedonic pathways involved in energy balance regulation V Di Marzo1, A Ligresti1 and L Cristino2 1 Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Pozzuoli (NA), Italy and 2Endocannabinoid Research Group, Institute of Cybernetics, National Research Council, Pozzuoli (NA), Italy The endocannabinoid system (ECS) and, in particular, cannabinoid CB1 receptors, their endogenous agonists (the endocannabinoids anandamide and 2-arachidonoylglycerol) and enzymes for the biosynthesis and degradation of the latter mediators are emerging as key players in the control of all aspects of food intake and energy balance. The ECS is involved in stimulating both the homoeostatic (that is, the sensing of deficient energy balance and gastrointestinal load) and the hedonic (that is, the sensing of the salience and the incentive/motivational value of nutrients) aspects of food intake. The orexigenic effects of endocannabinoids are exerted in the brain by CB1-mediated stimulatory and inhibitory effects on hypothalamic orexigenic and anorectic neuropeptides, respectively; by facilitatory actions on dopamine release in the nucleus accumbens shell; and by regulating the activity of sensory and vagal fibres in brainstem–duodenum neural connections. In turn, the levels of anandamide and 2-arachidonoylglycerol and/or CB1 receptors in the brain are under the control of leptin, ghrelin and glucocorticoids in the hypothalamus, under that of dopamine in the limbic forebrain and under that of cholecystokinin and ghrelin in the brainstem. These bi-directional communications between the ECS and other key players in energy balance ensure local mediators such as the endocannabinoids to act in a way coordinated in both ‘space’ and ‘time’ to enhance food intake, particularly after a few hours of food deprivation. Alterations of such communications are, however, also among the underlying causes of overactivity of the ECS in hyperphagia and obesity, a phenomenon that provided the rationale for the development of anti-obesity drugs from CB1 receptor antagonists. International Journal of Obesity (2009) 33, S18–S24; doi:10.1038/ijo.2009.67 Keywords: cannabinoid; energy balance; food intake; anandamide; 2-arachidonoylglycerol; CB1 Brief introduction to the endocannabinoid system It has been known for a long time that smoking preparations from Cannabis sativa, such as marijuana and hashish, and self-administering the major psychoactive principle of this plant, D9-tetrahydrocannabinol (THC), stimulate an appetite, especially for very palatable foods (the ‘munchies’).1 Therefore, it is not surprising to find THC or its synthetic analogue, nabilone, among the drugs approved in the US and other countries to increase body weight in cancer and AIDS patients, and to inhibit chemotherapy-induced emesis. The molecular mechanisms through which marijuana stimulates an appetite and inhibits vomiting have been Correspondence: Dr V Di Marzo, Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Via Campi Flegrei 34, Comprensorio Olivetti, Pozzuoli (NA) 80078, Italy. E-mail: characterized only relatively recently, when a specific binding site for THC was identified in the CNS, including in brain nuclei that control reward, motivation and satiety. In fact, we now know that THC binds to and activates not only the cannabinoid CB1 receptor but also another specific G-protein-coupled receptor, the cannabinoid CB2 receptor, which is expressed abundantly in several immune cells and tissues. Brain CB1 receptors are coupled, among other things, to neurotransmitter release inhibition, whereas CB2 receptors participate in the regulation of cytokine release and immune cell function.2 The discovery of CB1 and CB2 receptors led to the finding of endogenous compounds capable of binding to and activating them: the endocannabinoids (ECs). The two best-studied ECs are N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) (Figure 1). It is now well established that these two ECs are not stored in secretory vesicles but are biosynthesized de novo after an increase in intracellular concentrations of Ca2 þ within a framework of phospholipid-originated metabolic reactions. The endocannabinoid system and food intake V Di Marzo et al S19 Figure 1 Chemical structures of the two most studied endocannabinoids. In fact, both the formation of the two direct and distinct biosynthetic precursors for anandamide and 2-AG and their conversion into the two ECs are catalysed by Ca2 þ -sensitive enzymes.3 This means that the whole cascade of EC production is triggered ‘on demand’, usually in response to an acute or chronic perturbation of cell homoeostasis and with the function of returning the cell to its steady state before this perturbation. The cannabinoid receptors, the ECs and the proteins catalysing EC biosynthesis and inactivation constitute the EC system (ECS).3 It is now clear that the activation or blockade of CB1 receptors can significantly influence eating behaviours in both animals and men. The increased food intake caused by marijuana smoking in humans was shown to be because of an augmentation of food consumed as ‘between-meal’ snacks rather than by an increase in meal size per se.1 In satiated rats, doses of 0.5, 1.0 and 2.0 mg kg–1 of oral THC produce substantial hyperphagia during the first hour of testing. Subsequently, rats compensate for this effect so that 24-h intakes are similar to those in vehicle-treated animals. Like THC, anandamide (0, 1.0, 5.0 or 10.0 mg kg–1, subcutaneously) stimulates feeding, with a marked reduction in the ‘between-meal’ latency. Apart from its more frequent and/or rapid onset, cannabinoid-induced eating retains the normal, species-typical pattern that is characteristic of normal free-feeding rats.4 Studies carried out in guinea pigs show that the orexigenic effect of a CB1 agonist is manifested by increases not only in meal frequency but also in the amount of food eaten per meal. On the other hand, CB1 antagonist administration to this species produces an anorexic effect associated with decreases in both meal frequency and duration.5 In the next sections, we review the mechanisms proposed so far through which CB1 receptors and ECs control all aspects of food intake, thus providing an ideal link between homoeostatic and hedonic pathways involved in energy-balance regulation. Homoeostatic pathways: the hypothalamic endocannabinoid system and food intake Cannabinoid CB1 receptors are widely expressed in all hypothalamic nuclei at both the somatic and, predominantly, the axonal level. CB1-immunoreactive axons innervate densely the majority of hypothalamic nuclei in the mouse, except for the suprachiasmatic and latera (...truncated)