The endocannabinoid system

Cannabinoid receptors belong to the G protein-coupled receptor superfamily and their activation modulates adenylate-cyclase, potassium and calcium channels and transcription factors such as mitogen-activated protein kinase [6,11]. The CB1 cannabinoid receptor is widely expressed in the central nervous system as well as in the periphery, while CB2 is mainly expressed in immune cells. In the central nervous system, CB1 is predominantly expressed presynaptically, modulating the release of neurotransmitters, including γ-aminobutyric acid (GABA), dopamine, noradrenaline, glutamate and serotonin [12].

The discovery of specific receptors mediating the actions of cannabis led to the search for endogenous ligands for cannabinoid receptors. The first endogenous cannabinoid, arachidonoyl ethanolamide, was identified in 1992 and was named anandamide, from the Sanskrit word ‘ananda’, meaning internal ecstasy [13,14]. Thus, both plant-derived (Δ9-THC) and endogenous (anandamide) agonists bind to the same cannabinoid receptors (Figure ​(Figure1).1). Since the discovery of anandamide, other polyunsaturated fatty acid derivatives acting as functional agonists of cannabinoid receptors have been characterized and collectively termed endocannabinoids [15]. In contrast to classical neurotransmitters such as the catecholamines, endocannabinoids are not stored in the interior of synaptic vesicles because of the high lipophilicity of these ligands [6]. These findings led to the conclusion that the endocannabinoid system acts “on demand”, meaning that the endocannabinoids are synthesized and released upon physiological or pathological stimulation [6].

Figure 1

Both Δ9-tetrahydrocannabinol, the psychoactive component of Cannabis sativa, and anandamide, an endogenous neurotransmitter in the human brain, bind to the same cannabinoid receptor. (Photos/Diagrams from the Max Planck Institute of Psychiatry …

The endocannabinoid system and the regulation of food intake and energy metabolism

Since the 19th century the use of cannabis has been reported to stimulate appetite and to increase the consumption of sweet and tasty food, sometimes resulting in significant weight gain [4,16]. The recent description of the endocannabinoid system, not only in the central nervous system but also in peripheral tissues, points to its involvement in the regulation of appetite, food intake and energy metabolism [17–20]. Numerous experimental data have confirmed this hypothesis and will be briefly summarized below, while clinical results will be presented in the next topic of this article.

Endocannabinoid actions in the central nervous system

It has already been demonstrated that endocannabinoids initiate appetite by stimulation of CB1 receptors in hypothalamic areas involved in the control of food intake, such as the ventromedial hypothalamus (VMH) [21] (Figure ​(Figure2).2). For instance, the injection of anandamide in the VMH of pre-satiated rats induces hyperphagia, which is prevented by previous hypothalamic administration of the selective CB1 cannabinoid antagonist rimonabant [22]. Using another experimental approach, Kirkham et al. [23] evaluated endocannabinoid levels in relation to the feeding behavior of rats in the hypothalamus and in the limbic forebrain, including the shell area of the nucleus accumbens, which is known to be linked to eating motivation. Endocannabinoid levels increased during fasting and declined during feeding, while no changes were detected in satiated rats. On the other hand, endocannabinoid levels in the cerebellum, which is not directly involved in the control of food intake, were unaffected by feeding behavior. Moreover, the injection of endocannabinoids into the nucleus accumbens induced feeding behavior, an effect that was also attenuated by rimonabant [23].

Figure 2

The involvement of the endocannabinoid (EC) system over-activity in the pathophysiology of the metabolic syndrome. Adapted from [20] and [17].

The experimental model of CB1 receptor knockout (CB1-/-) mice has also been used to clarify the involvement of the endocannabinoid system in the regulation of energy metabolism. An elegant study conducted by Ravinet-Trillou et al. compared CB1-/- knockout male mice with wild-type animals (CB1+/+) exposed either to a standard laboratory regimen or to a high-fat diet (HFD) [24]. When maintained on the standard diet, CB1-/- mice are lean and their body weight and adiposity are, respectively, 24 and 60% lower than that of CB1+/+ mice. CB1-/- mice submitted to the HFD do not develop obesity and do not display hyperphagia in contrast to CB1+/+ mice, and their feeding efficiency remains low. Furthermore, the insulin resistance that occurs in HFD-fed mice is not present in CB1-/- mice. These results led to the conclusion that CB1 receptors are involved not only in the development of diet-induced obesity but also in peripheral metabolic regulations [24]. These results were confirmed by Cota et al. [25], who showed that CB1-/- mice exhibit reduced spontaneous caloric intake and total fat mass, decreased body weight, and hypophagia, when compared with CB1+/+ littermates. Moreover, in young CB1-/- mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1-/- mice, metabolic factors appear to contribute to the lean phenotype [25].

Another study carried out in mice submitted to HFD showed that a short-lasting reduction of food intake induced by a chronic oral treatment with rimonabant is dissociated from the long-lasting reduction of body weight and obesity. Moreover, rimonabant reverses the insulin resistance and lowered plasma leptin, insulin, and free fatty acid levels in this model of diet-induced obesity [26].

It is also noteworthy that Δ9-THC increases not only total food intake but also specifically increases the consumption of sweets, suggesting an interaction between the effect of the drug and the palatability of the food [27]. Another investigation confirmed this notion showing that different routes of Δ9-THC administration (oral, smoke inhalation or suppository) induced an effect on food selection [28]. Moreover, this selective action on food choice was confirmed in a number of animal studies, in which a potential role of cannabinoids in modulating the interaction of different pathways involved in the brain ‘reward’ system was hypothesized [29,30]. Thus, endocannabinoid signaling is involved orexigenically in both the homeostatic and the hedonistic control of food intake [31].