Could An Anti-Marijuana Compound Hold The Key To Body Weight And Appetite Control?

SR141716 is a potent and selective central cannabinoid receptor antagonist and has been widely used to investigate receptors involved in appetite regulation. Results of a new animal study provide strong evidence for the involvement of SR141716 and the receptors in the regulation of feeding.

(December 6, 2002)  Bethesda, MD – That people are getting fatter is not news. Around the globe,  physically demanding occupations like farming and mining are now carried out by machines.  Western values such as television and automobiles are now encroaching on the most isolated environments.  Finally, a highly processed diet -- along with a sedentary lifestyle -- is the likely culprit in the high rates of obesity seen among indigenous peoples who were originally hunters and foragers.  Now they eat a diet that is "entirely store bought and provided by truck.”  Scientists and anthropologists have observed that in some societies, a high rate of infectious disease seems to be keeping children's weight low or substandard while many of the adults are obese. In effect, very small children evolve very quickly into obese adults.

The aesthetic qualities of obesity are the least of the problems associated with this spike in worldwide weight gain.  The disorder is associated with an increased risk of life threatening conditions such as diabetes, hypertension and heart diseases, and weight loss has been reported to ameliorate these associated conditions.  To prevent these chronic disorders, some try to reduce weight by caloric restriction; however the effort generally fails as most obese patients regain their lost weight thereafter.

Therefore, medicinal treatment becomes a necessity. One facet currently being explored is the central regulators of food intake. This includes the cannabinoid system with its putative endogenous ligands anandamide and 2-arachidonoyl glycerol (2-AG). In addition to its many pharmacological activities, this system has been implicated in food intake regulation.

Stimulation of appetite is one of the most commonly related effects of marijuana in humans and delta-9-tetrahydrocannabinol (Δ-9-THC), the main active component of this drug, has been reported to produce hyperphagia. The endogenous cannabinoids anandamide and 2-AG also stimulate feeding when administered to rats.  SR141716, a potent and selective central cannabinoid (CB1) receptor antagonist, has been widely used to investigate the role of CB1 receptors in appetite regulation. SR141716 antagonizes the hyperphagia (excessive eating) induced by anandamide, 2-AG and Δ-9-THC, primary ingredients in marijuana.  These results provide strong evidence for the involvement of CB1 receptors in the regulation of feeding. In addition to modulating the effects of cannabinoids in animals, SR141716 has been shown to produce changes in ingestive behaviors when administered alone. Several studies have reported that SR141716 selectively attenuates the consumption of palatable food or drink. It decreases sucrose intake in rats, alcohol consumption in mice and sweet diet intake in marmosets while having little effect on bland food consumption.

These results suggest that the blockade of the central cannabinoid system may alter the rewarding value of foods and so reduce eating. As the majority of human obesity is partly due to difficulty in regulating intake in the face of an increased availability of palatable foods, SR141716 may provide a new interesting way for the treatment of this disorder.

Recently, a strong relationship between the endocannabinoid system and leptin, a helical protein secreted by adipose tissue and acting on a receptor site in the ventromedial nucleus of the hypothalamus to curb appetite and increase energy expenditure as body fat stores increase, was reported.  Specifically, a deficiency of leptin has been found in obese animal subjects.

SR141716 has been shown to induce a significant decrease in food intake and body weight gain and reduce the intake of a high fat diet in these obese rats.  Now, a new research effort seeks to assess the effect of SR141716 in a diet-induced obesity (DIO) model.

The Study

The authors of “Anti-Obesity Effect of SR141716, a CB1 Receptor Antagonist, in Diet-Induced Obese Mice,” are Christine Ravinet-Trillou, Michèle Arnone, Claire Delgorge, Nadine Gonalons, Peter Keane, Jean-Pierre Maffrand, and Philippe Soubrié, all from the Central Nervous System Research, Sanofi-Synthélabo, Toulouse, Cedex, France.  Their findings currently appear in the online edition of the American Journal of Physiology -- Regulatory, Integrative and Comparative Physiology.  The publication is one of 14 journals produced monthly by the American Physiological Society (APS).

Methodology

Rodents were fed a high fat diet to develop moderate obesity with an increase in energy intake and in insulin resistance. The objectives were to examine the effect of a chronic SR141716 treatment was investigated in C57BL/6 DIO mice, with emphasis on changes in food intake. The most effective dose tested in the Zucker rat study (10 mg/kg, orally) was used in this first experiment. In a subsequent experiment, which included plasma analyses, the effect of a lower dose (3 mg/kg) on adiposity was also assessed. Finally, to confirm whether the effects of SR141716 were mediated by CB1 receptor blockade, the compound was administered to CB1 receptor knockout mice fed a high fat diet.

Results

This work describes the effect of blockade of CB1 receptors with SR141716 in a non-genetic model of obesity using high palatable diet fed mice. The ability of the compound to reduce food intake in this model was expected, as previous studies have already demonstrated such an effect in rodents and primates.

In this study, SR141716 produced a marked acute lower rate of eating, and it  appears that such an effect tends to diminished over chronic administration.

In contrast, SR141716 induced a sustained effect on body weight, which remained low until the end of the 5-week experiment with 10 mg/kg/d SR141716, up to a 20 percent difference with DIO control mice).

The weight loss was associated with a depletion of fat stores reaching about 50 percent after the dose of 10 mg/kg/d SR141716, as indicated both by the weight of abdominal fat pads and by the total body fat content.

Furthermore, SR141716 corrected the insulin resistance and lowered plasma leptin, insulin and free fatty acid levels. Most of these effects were present but less pronounced at 3 mg/kg/d.

In addition to its hypophagic action, SR141716 may influence metabolic processes as the body weight loss of SR141716-treated mice was significantly higher during 24 hour fasting when compared to vehicle-treated animals, and when a three-day treatment was compared to a pair feeding.

SR141716 had no effect in CB1 receptor knockout mice, which confirmed the implication of CB1 receptors in the activity of the compound.

Discussion and Conclusions

Overall, there are many indications showing that endocannabinoids are key components of systems that regulate both feeding and body weight, and belong to the wide family of orexigenic substances. A further demonstration is the clear anti-obesity effect of the CB1 receptor antagonist SR141716 in a nongenetic model of obesity reported in this research. SR141716 sharply decreased body weight and adiposity of obese mice without sustained lower eating rates, and improved their insulin resistance. These effects were already seen at three mg/kg/d, and appeared more pronounced at 10 mg/kg/d. In contrast, no effect of SR141716 was observed in CB1 receptor knockout mice.

Dietary-obese mice develop the characteristics of the abdominal obesity syndrome found in humans, including marked visceral obesity and diabetes. The high efficacy of SR141716 in this model suggests that CB1 receptor antagonists may constitute a new alternative for the treatment of appetite and body weight disorders in humans.

Source:  American Journal of Physiology -- Regulatory, Integrative and Comparative Physiology, currently published online. The journal is a publication of the American Physiological Society (APS).

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The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

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Editor’s Note: To set up an interview with a member of the research team, please contact Donna Krupa at 703.527.7357 (direct dial), 703.967.2751 (cell) or djkrupa1@aol.com.