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

The endocannabinoid system (ECS) and, in particular, cannabinoid CB(1) 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 CB(1)-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 CB(1) 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 CB(1) receptor antagonists.