Endocannabinoid system in appetite regulation

Smoking cannabis is a potent stimulator of appetite, and is sometimes prescribed for medicinal purposes to stimulate eating. How cannabis causes this was not understood until the discovery of the receptor that the active ingredient, tetrahydrocannibinol (THC), was acting upon. This receptor is part of the endocannabinoid system and is called CB1. The first natural ligand for the CB1 receptor, anandamide, was identified in 1992, and, like THC, is a member of the endocannabinoid (EC) family. Both of these substances activate the EC system and enhance appetite. The role of the EC system in appetite regulation was not fully explored until 1994 following the discovery of a CB1 selective antagonist, Rimonabant. Antagonism of the CB1 receptor was had significant appetite reducing and weight reduction effects. This factor, coupled to the appetite enhancing affects of anandamide and THC and because the CB1 receptor and endocannabinoids are expressed in brain regions associated with appetite regulation, provided the impetus for the drive in research centered around how the EC system is implicated in appetite regulation.

Studies involving rodents confirmed the role of the EC system and the CB1 receptor in appetite regulation; Mice lacking the CB1 receptor reduce their food intake, even after fasting, and lose weight compared to wild type mice and when wild type mice receive a dose of the CB1 antagonist Rimonabant, food intake is also decreased (Di Marzo et al, 2001). These results imply that the CB1 receptor is responsible for the changes observed in food intake. This has resulted in the release of the CB1 antagonist, Rimonabant, trade name Acomplia, as an anti-obesity drug.

Acomplia

"Accomplia Rimonabant", an antagonist of the CB1 receptor, was licensed to be prescribed for obesity in 2006 in countries within the European Union. It was produced by the French pharmaceutical company Sanofi. This release of an anti-obesity drug is significant as it is the first new anti-obesity drug to be prescribed since the 1970’s.

The anti-obesity actions of Acomplia involve a short term reduction in appetite accompanied by a long term decrease in body fat. Human testing of Acomplia began in 2000 where results were very encouraging: obese individuals lost around 3 – 4kg over 4 months, whereas control patients who only lost about 1kg. A second trial investigating its short term effects found significant decreases in food intake, particularly of foods with high calorie and fat content. A larger phase III trial, using over 6000 patients and conducted over 2 years, began in 2001, with obese patients being treated either with Acomplia or a placebo. After one year Acomplia caused ≥5% weight loss in 62% of patients and ≥ 10% in 32% of patients, significantly more than patients receiving a placebo The endocannabinoids and the CB1 receptor are expressed in brain regions implicated in the control of appetite and so it was thought likely that the effects on appetite were mediated in the brain. This was supported by the emergence that the endocannabinoids appear to be under negative control by leptin, an appetite-curbing hormone produced by adipose tissue. Administration of leptin decreases the levels of endocannabinoids in hypothalamic brain areas, and when leptin signalling is defective, as in the ob/ob mice (which lack leptin), or db/db mice (which lack leptin receptors), hypothalamic concentrations of endocannabinoids increase. It thus appears that chronic activation of the endocannabinoid system is linked to obesity and that leptin and endocannabinoid pathways may interact.

The central affects of the endocannabinoids on appetite appears to be independent of the orexigenic (appetite-stimulating) effects of the arcuate nucleus NPY neurones, as CB1 antagonist will reduce food intake even in mice models where the NPY neurones are non functional. The endocannabinoid system interacts with the mesolimbic dopamine system, which is involved in the motivation to search for food, so endocannabinoids may influence appetite through interactions with this system. This pathway is thought to be strongly involved in addictive behaviours, indeed it is also thought to be involved in gambling and alcohol addictions.

Peripheral effects of Rimonabant

Whilst endocannabinoids have a central mode of action in controlling appetite, they may act peripherally as well . The CB1 receptor is expressed in the gastrointestinal tract on nerve terminals which are involved in satiety signalling in the gut. Food deprivation results in a significant increase in intestinal anandamide levels which are subsequently reduced upon refeeding. The increase in anandamide is not observed in brain tissue and the cause of the rise is unknown but it may be that the rise in anandamide may act as a hunger signal to promote feeding.

Rimonabant acts short term to decrease food intake, but over the long term, fat mass is decreased and there is an improvement in other metabolic parameters that are also typical of obesity, ie decreased plasma levels of insulin, fatty acids and cholesterol. When CB1 null mice are pair fed on a normal diet with a wild type control mouse they have less fat mass and, after eating a high fat diet, the CB1 null mice do not become obese or insensitive to insulin or leptin, as wild type mice may, even though they consumed as much food. This implies that CB1 antagonists not only act to decrease appetite at the central level, but act at the peripheral level by reversing endocannabinoids effects on fat accumulation and lipogenesis The peripheral effects of the endocannabinoids are supported by the discovery of CB1 receptors on white adipocytes where the endocannabinoids appear to activate the enzymes involved in lipogenesis and so by applying a CB1 antagonist, the hormone adiponectin, which is secreted from adipocytes, is upregulated. This hormone is essential for decreasing the expression of enzymes in lipogenesis .