Role of the endocannabinoid system in energy balance regulation and obesity

Obesity, particularly abdominal obesity, and the associated cardiometabolic complications, are critical areas of investigation.

The endocannabinoid system helps to regulate the central control of energy balance and peripheral metabolic processes, both of which may contribute to cardiometabolic risk factors.

Paul E. Szmitko; Subodh Verma

Posted: 03/17/2006; Nat Clin Pract Cardiovasc Med. 2006;3(3):116-117. Ãƒâ€šÃ‚© 2006 Nature Publishing Group

Obesity, particularly visceral adiposity, and its related metabolic and cardiovascular disorders, is a worldwide pandemic. 

The biological properties of one of the most widespread illicit drugs of abuse, marijuana, have been recruited for obesity management. By uncovering the cellular interactions of the cannabinoid tetrahydrocannabinol (THC Delta 9), the major active component of marijuana researchers have identified new molecular pathways for treating cardiometabolic disease.

Studies have demonstrated that modulation of the endocannabinoid system holds great therapeutic promise for the treatment of obesity, dyslipidemia, insulin resistance and atherosclerosis.

The endocannabinoid system contributes to the regulation of food intake, energy balance, inflammation, and lipid and glucose metabolism, and might therefore play a fundamental role in the development of obesity and atherosclerosis. 

To date, two G-protein-coupled cannabinoid receptors that bind tetrahydrocannabinol (THC Delta 9) with equal affinity have been identified: CB₁ and CB₂. The CB₁ receptor, believed to mediate the psychotropic effects of cannabis and to participate in the modulation of food intake and adipogenesis, is expressed at high levels by brain cells and by several peripheral tissues including the gastrointestinal tract, the adrenal gland, the heart and adipose tissue. CB₁ knockout mice exhibit a lean phenotype and appear to be resistant to diet-induced obesity and insulin resistance. 

By contrast, CB₂ receptors are located primarily on blood cells and immune tissues, and stimulation of these receptors with tetrahydrocannabinol (THC Delta 9) results in an immunosuppressive phenotype via the modulation of immune-cell cytokine production This molecular system might have a role in the development of obesity, the metabolic syndrome and atherosclerosis, and its modulation might form the basis of new therapeutic strategies for these pathophysiologically linked conditions.

Using apolipoprotein E knockout mice Steffens et al. demonstrated that tetrahydrocannabinol (THC Delta 9) can protect against the development of atherosclerosis.CB₂ receptors were expressed in both human and mouse atherosclerotic lesions, but were absent in nondiseased arteries.

Apolipoprotein E knockout mice fed a high cholesterol diet developed extensive atherosclerotic lesions in the aortic root; however, when 1 mg/kg tetrahydrocannabinol (THC Delta 9) daily was added to the dieta dose not associated with CB₁ activation and psychotropic effectsa significant reduction in the progression of atherosclerotic lesions was observed. Concomitant CB₂ receptor antagonist treatment abolished this observed anti-atherosclerotic effect.

Even though tetrahydrocannabinol (THC Delta 9)-fed mice continued to have elevated serum lipid levels, fewer inflammatory cells were recruited into atherosclerotic lesions, suggesting that tetrahydrocannabinol (THC Delta 9) treatment had a beneficial effect on the inflammatory milieu. Indeed, Steffens and co-workers demonstrated that the immunosuppressive properties of tetrahydrocannabinol (THC Delta 9) interfered with the adhesion, migration, proliferation and function of immune cells involved in atherosclerotic plaque formation.

These promising results do not imply that smoking marijuana is the key to a healthy heart. Too often there is failure to translate promising results observed in murine models to human patients. The effects of tetrahydrocannabinol (THC Delta 9) on atherogenesis in man have not been studied, so whether this cannabinoid does more cardiovascular harm than good remains to be seen.

The beneficial effects of tetrahydrocannabinol (THC Delta 9) observed by Steffens et al. followed a U-shaped distribution with a very narrow therapeutic window, suggesting that the blood concentrations of tetrahydrocannabinol (THC Delta 9) obtained from smoking marijuana would be too variable to provide sustained clinical benefit.

Furthermore, it is unlikely that purified tetrahydrocannabinol (THC Delta 9) extract or marijuana would be legalized for use as an adjunctive treatment of cardiovascular disease, since both compounds could serve as drugs of abuse. 

In addition, smoking marijuana increases carboxyhemoglobin levels, and tetrahydrocannabinol (THC Delta 9) activation of CB₁ receptors induces a cardiovascular stress response; raising heart rate and blood pressure, decreasing the anginal threshold, and promoting acute coronary syndromes. 

Overall, smoking marijuana probably has a negative effect on the cardiovascular system. For these reasons, therapeutic strategies using the apparent anti-inflammatory properties of tetrahydrocannabinol (THC Delta 9) will probably depend upon developing specific CB₂-receptor agonists, to prevent the onset of psychotropic effects. Once thoroughly tested in animal models, translation to human trials could see the positive effects reported by Steffens et al. clinically realized.

Activation of the endocannabinoid system through the CB₁ receptor plays an important role in central and peripheral regulation of energy balance, body weight and food intake.

Blockade of the CB₁ receptor appears to offer great promise in cardiometabolic risk reduction, and 1-year results from the RIO program are very encouraging.

In this trial, 1,507 patients with a BMI of at least 30 kg/m², or at least 27 kg/m² or more with treated or untreated dyslipidemia, hypertension or both, received double-blind treatment with 5 mg rimonabant, a selective CB₁ receptor blocker daily, 20 mg rimonabant daily, or placebo, in addition to a hypocaloric diet.

Treatment with 20 mg rimonabant for 1 year significantly decreased total body weight and waist circumference, and produced a significant weight-independent effect on lipid parameters and several other cardiovascular risk factors. 

The beneficial changes to the lipid profile remained significant after adjusting for weight loss. Furthermore, treatment resulted in a significant reduction in fasting plasma glucose, fasting plasma insulin, insulin resistance and the proportion of patients who fulfilled the criteria for the metabolic syndrome compared with placebo. 

To explain the observed weight-independent effect on both lipid and glycemic variables, Van Gaal et al. hypothesized that enhanced rimonabant-induced expression of adiponectina cytokine that has a role in the regulation of hyperglycemia, hyperinsulinemia and fatty acid oxidation and is reduced in obese individuals could be responsible. Thus, by improving adipocyte function, rimonabant might contribute to beneficial changes in other adipokines, such as C-reactive protein, reinforcing the link between obesity and atherosclerosis.

Further investigation of in vivo effects of rimonabant are required to fully elucidate this mechanism, especially given the concern that CB₁ antagonists might raise blood pressure. Furthermore, rimonabant appears to be a useful agent for smoking cessation, yet another cardiac risk factor.

Thus, pharmacologic manipulation of cannabinoid-receptor signaling might combat the development of atherosclerosis through the treatment of obesity, the metabolic syndrome, vascular inflammation and smoking. 

The beneficial effects with rimonobant appear to be consistent in over 6,600 patients enrolled in the RIO program. 

Patients administered this drug enjoy sustained reductions in weight, BMI and visceral adiposity, and improvements in insulin sensitivity and dyslipidemia. More importantly, the beneficial effects to counter insulin resistance, improve dyslipidemia and increase adiponectin, are only partly explained by the reduction in weight, indicating a potential direct role for CB₁ in adipogenesis and lipid derangement.

The results of the RIO program and the study by Steffens et al. indicate that modulating the activity of the endocannabinoid system holds promise as an approach to treating obesity, dyslipidemia and atherogenesis. 

The CB₁ and CB₂ receptors might have opposing effects on atherogenesis: whereas central CB₁-receptor blockade offers hope for atherogenic risk reduction, peripheral CB₂-receptor stimulation in animals has powerful anti-atherosclerotic effects.

It is possible that a strategy of CB₁-receptor antagonism and CB₂-receptor agonism might emerge as the most effective treatment across the spectrum of insulin resistance and vascular disease. 

It is paradoxical that studying the effects of cannabis, an illicit drug that provides society with numerous social problems, could serve as the basis for novel therapeutic strategies to reduce cardiometabolic risk.