The Endocannabinoid System as a Mechanism Regulating Appetite and Energy Balance

| June 2, 2007

by Louis J. Aronne, MD, FACP,and Kathy Keenan Isoldi, MS, RD, CDE

Dr. Aronne is Former President of the North American Association for the Study of Obesity and a Fellow of the American College of Physicians. He has authored more than 40 papers and book chapters on obesity, and edited the National Institutes of Health Practical Guide to the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. He is a consultant to the VA Weight Management/ Physical Activity Executive Council. Kathy Keenan Isoldi, MS, RD, CDE, is Coordinator of Nutrition Services at The Comprehensive Weight Control Program, New York, New York. Ms. Isoldi has been counseling adult and pediatric clients seeking weight management for the past 19 years. She is currently a doctoral candidate at New York University.


Treating obesity through lifestyle and behavioral interventions, which focus on reducing food intake and increasing physical activity, has offered only short-term success.[1] To date, the pharmacological treatment of obesity has also resulted in limited efficacy.[2] The search continues for better, long-term treatment options for obese individuals. The endocannabinoid system (ECS) has recently emerged as an exciting target for drug intervention to treat obesity.[3] The approval in Europe of rimonabant, the first drug which impacts the ECS, for the treatment of obesity and cardiometabolic risk, has created great interest in the details of ECS physiology.

The ECS consists of the cannabinoid receptors, their endocannabinoid ligands, and the enzymes for endocannabinoid synthesis and degradation.[4] Cannabinoid receptor sites, along with endogenous ligands, function as a signaling network with multiple central and peripheral actions that regulate a wide spectrum of vital physiological functions, including appetite and energy metabolism.[3,4] The locations and actions of the ECS make it appear to be a “vertical integrator” of energy regulation and cardiometabolic risk. Evidence associating overactivation of the ECS with human obesity and increased intra-abdominal fat suggests that this system is part of the “pathophysiology” of body weight regulation (Figure 1).

Figure 1

Cannabinoid Receptors—CB1 & CB2

In 1988, specific high-affinity cannabinoid-binding sites were discovered in rodent brain cells.[4] To date, two cannabinoid receptors have been cloned in humans. The cannabinoid receptor-1 (CB1), believed to regulate food intake and energy expenditure, was cloned in 1991. The cannabinoid receptor-2 (CB2), the focus of which appears to be the immune system, was cloned in 1993.[4] CB1 receptors are located in the central nervous system, as well as in peripheral sites including adipocytes, hepatocytes, skeletal muscles, endothelial cells, gastrointestinal tract, heart, lungs, and the gonads. CB2 receptors are found in the spleen, thymus, and tonsils. Unlike CB1 receptors, CB2 receptors are not believed to be involved in the regulation of food intake and energy homeostasis.[4]

Endogenous Cannabinoid Ligands

The search for compounds that exert their influence by binding to cannabinoid receptors led to the discovery of endogenous cannabinoid ligands. In 1992, N-arachidonoyl-ethanolamine (AEA or anandamide) was identified and isolated. The identification of 2-arachidonoyl-glycerol (2-AG) soon followed.[4] The endocannabinoids are lipophilic and cannot be stored in vesicles. Thus endocannabinoid signaling is tightly controlled by the process of synthesis, release, uptake, and degradation. Endocannabinoid signaling appears to be limited by degradation of the ligands. AEA is degraded by fatty acid amide hydrolase (FAAH), 2-AG is degraded by monoglycerol lipase,[4,5] and low levels of these enzymes have been associated with increased weight. While both 2-AG and AEA are recognized as important mediators of energy homeostasis,[5,6] the fact that they have distinct synthetic and degradative enzymes suggests they play different roles.

The Endocannabinoid Signaling System and Weight Regulation

The discovery that centrally expressed CB1 receptors signal activity that regulates energy homeostasis sparked much interest in the development of CB1 receptor antagonists to treat obesity.[4,5] Early research on animal models sparked excitement when it became evident that low doses of the cannabinoid ligands enhanced food intake as exogenous administration of 2-AG directly into the nucleus accumbens of rats caused an acute increase in food consumption.[4,7] Further research showed that CB1 receptor antagonists decrease food intake and body weight.[7] Researchers found that even while taking in the same amount of calories, CB1 knockout mice were resistant to diet-induced obesity when compared to wild-type mice.[8] Administration of a CB1 receptor blocker (rimonabant) in genetically obese and leptin-deficient mice protected the rodents from developing characteristic hyperphagia and weight gain.[4]

There appears to be a significant interplay between the adipocyte-expressed, energy-regulating hormone leptin and endogenous cannabinoid production. Leptin appears to act by suppressing production of endocannabinoids in the hypothalamus. Genetically obese mice with defects in the leptin-signaling pathway exhibit elevated levels of both AEA and 2-AG in the hypothalamus.[4] The communication between serum leptin and endocannabinoids may ultimately influence neuropeptide Y (NPY), one of the body’s most potent orexigenic (appetite-stimulating) peptides.[4,9]

CB1 receptor antagonists may also influence weight by increasing energy utilization. In animal trials, obese Zucker rats treated with a CB1 receptor antagonist SR141716 (rimonabant) initially reduced their food intake, but continued to lose and maintain their weight loss throughout the treatment period, even when food intake returned back to that of untreated rats.[9] To test whether a CB1 receptor blocker could increase energy expenditure, Liu and colleagues[9] measured oxygen consumption in genetically obese mice treated with rimonabant. They found that a seven-day treatment with the CB1 receptor antagonist caused a 37-percent increase in basal oxygen consumption, thus supporting the theory that the ECS influences energy expenditure.

Endocannabinoids also modulate gastric emptying time and gastric motility. Endocannabinoids and CB1 receptors are found in the neurons of the gastrointestinal mesentery and the mucosa of the fundus. It is believed that the endocannabinoids cause tonic stimulation of ghrelin release. Ghrelin is a peripheral polypeptide that markedly stimulates hunger.[10]

Recent studies have shown an association between serum concentration of endocannabinoids and body weight in humans. Engeli and colleagues[5] measured circulating levels of endocannabinoids in 20 lean and 20 obese postmenopausal women. Circulating levels of AEA and 2-AG were 35 and 52 percent higher, respectively, in obese versus lean subjects. Elevated serum levels of 2-AG have also been reported in obese men. Cote and colleagues[11] report finding significantly higher circulating levels of 2-AG, but not AEA, in a group of men with higher levels of intra-abdominal adiposity (IAA). Engeli and colleagues also found a strong negative correlation between FAAH expression in adipose tissue and circulating endocannabinoids. This suggests that perhaps obese individuals have higher circulating endogenous endocannabinoid levels due to limited availability of FAAH to degrade endocannabinoids.[5]

The Endocannabinoid Signaling System and Lipid and Glucose Regulation

A growing body of evidence indicates that the ECS is involved in the physiological regulation of glucose and lipid metabolism.[4] The intake of a high-fat diet activates the hepatic ECS, which leads to increased lipogenesis and the subsequent development of hepatic steatosis.[8] The discovery that 2-AG is found in the liver in concentrations two times higher than is found in other peripheral tissues illuminates the influence the endocannabinoid system bears on lipid metabolism.[4] It has been demonstrated that subjects treated with CB1 blockers experience improved insulin sensitivity, reductions in triglycerides, and an elevation in HDL-cholesterol that goes beyond what would be expected given the amount of body fat lost.[12-14] In addition, blocking CB1 receptors on adipocytes produces a significant elevation in adiponectin secretion. Adiponectin serves to regulate both lipid and glucose metabolism and functions as an anti-inflammatory agent,[14,15] providing another possible mechanism influencing the favorable changes in lipid profile and glucose metabolism.

Human Trials with CB1 Antagonist— Rimonabant

Results from human clinical trials investigating the safety and efficacy of a selective CB1 antagonist (rimonabant) for the treatment of obesity reported favorable outcome measurements.[12-14] The Rimonabant in Obesity (RIO) trials are a series of randomized, blind, placebo-controlled trials conducted in North America and Europe to test the efficacy of rimonabant for the management of obesity and cardiometabolic risk. In North America, 64 US and eight Canadian sites studied 3,045 men and women over 18 years of age with a body mass index (BMI) of >30, or with a BMI of >27 with obesity-related comorbidity for up to two years. Subjects were randomized to receive either placebo or rimonabant 5mg or 20mg for year one of the trial. During the second year of the trial, subjects in the placebo group continued to receive placebo, and the treatment groups were re-randomized to receive either the same dose of rimonabant as year one, or to receive placebo. All participants received instructions on a low-calorie diet and were instructed to increase daily physical activity.[12]

Table 1

At the one-year mark, there were statistically significant, favorable outcome measurements in the 20mg rimonabant group compared to the placebo group for body weight, waist measurement, serum triglycerides, fasting glucose, fasting insulin, insulin resistance, and serum HDL-cholesterol levels (Table 1). At the end of the two-year mark, subjects who were randomized from 20mg of rimonabant to placebo experienced weight regain, whereas those who remained on the drug maintained their favorable results. Researchers concluded that 20mg per day of rimonabant plus diet for two years promoted sustained reductions in weight, waist circumference, and changes in cardiometabolic risk factors.[12]

The drug was generally well tolerated by the majority of study participants. Adverse events reported included anxiety, depressed mood, nausea, fatigue, dizziness, upper respiratory tract infection, headaches, diarrhea, and vomiting. The dropout rate over two years was 51 percent despite good weight loss, similar to previous trials of anti-obesity agents.

Using the same study design as RIO-North America, RIO-Europe enrolled 1,507 adult men and women to investigate the potential use of rimonabant for obesity treatment. Researchers reported favorable results after one year with statistically significant reductions in body weight, waist measurement, serum triglycerides, fasting glucose, fasting insulin, and insulin resistance, and increases in serum HDL-cholesterol levels in the 20mg treatment group (Table 2).[13] In the group of study participants who completed the trial, 67.4 percent receiving 20mg rimonabant achieved a weight loss of >5 percent in comparison to 30.5 percent in the placebo group. Over three times as many participants receiving 20mg of rimonabant achieved 10 percent weight loss than the placebo group (39% vs. 12.4%, respectively).[13]

Table 2

The RIO Diabetes trial, a multicenter, randomized, placebo-controlled, one-year study[14] examined the use of rimonabant in participants with type 2 diabetes. Overweight or obese diabetic patients (n=1,045), who were already receiving metformin or sulfonylurea, were randomized to receive rimonabant (5mg or 20mg once daily) or placebo. Rimonabant 20mg was associated with a significant reduction in body weight and waist circumference. Weight and waist circumference decreased by 5.3kg and 5.2cm, respectively, in patients treated with rimonabant 20mg versus 1.4kg and 1.9cm for placebo-treated patients (P< 0.001),[14] similar to those typically observed for diabetics in trials of weight loss agents.
Rimonabant also exerted a beneficial effect on cardiometabolic and glycemic variables. Twice as many patients in the rimonabant 20mg group (43%) achieved the target endpoint of HbA1C below 6.5 percent compared with placebo (21%; P<0.001).[14] More than 50 percent of the improvement in HbA1C attributed to rimonabant was independent of the weight loss achieved. Rimonabant reduced the prevalence of the metabolic syndrome in the 20mg group from 79 percent at baseline to 64 percent at the end of one year.[14]


The ECS presents an intriguing target to modulate obesity, as well as cardiometabolic risk factors. The mechanisms underlying this system are complex and continue to be elucidated. There is still much to learn, though what has been uncovered thus far is very encouraging indeed. Selective CB1 receptor antagonists show promise in the treatment of obesity and related metabolic


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