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

Abstract

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.

Endocannabinoid signal in the gut controls dietary fat intake

“…Our study identifies the intestinal endocannabinoid system as an essential component of this process. Endocannabinoids and their attending cell-surface receptors are found throughout the body and are known to participate in the control of food intake (2,19). Although much attention has focused on endocannabinoid signaling in the brain (19), the role of peripheral endocannabinoids in food intake is increasingly recognized (20)(21)(22).…”

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

“…Furthermore, CART interacts with other important mediators such as the cannabinoid CB 1 receptor, insulin and leptin, involved in the regulation of feeding [157,158,150]. On the other hand, ICV administration of CART was accompanied by a decrease in plasma insulin and leptin levels and an increase in lipid oxidation, which limits fat storage [159].…”

A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans

“…In fact, the endocannabinoid system (ECS), which comprises the cannabinoid receptors, the endogenous ligands and the enzymes responsible for synthesis and degradation of endocannabinoids, is present in all strategic tissues controlling energy balance (Cota & Woods 2005) and it has been involved in the pathogenesis of obesity (Di Marzo et al 2009, Quarta et al 2010. Besides its important role in the hypothalamus and brain reward system in controlling food intake, elements of the ECS are also expressed in key peripheral tissues controlling metabolism, i.e.…”