Review
The endocannabinoid system: Its roles in energy balance and potential as a target for obesity treatment

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Abstract

Obesity and cardiometabolic risk continue to be major public health concerns. A better understanding of the physiopathological mechanisms leading to obesity may help to identify novel therapeutic targets. The endocannabinoid system discovered in the early 1990s is believed to influence body weight regulation and cardiometabolic risk factors. This article aims to review the literature on the endocannabinoid system including the biological roles of its major components, namely, the cannabinoid receptors, their endogenous ligands the endocannabinoids and the ligand-metabolising enzymes. The review also discusses evidence that the endocannabinoid system constitutes a new physiological pathway occurring in the central nervous system and peripheral tissues that has a key role in the control of food intake and energy expenditure, insulin sensitivity, as well as glucose and lipid metabolism. Based on the important finding that there is a close association between obesity and the hyperactivity of the endocannabinoid system, interest in blocking stimulation of this pathway to aid weight loss and reduce cardiometabolic risk factor development has become an important area of research. Among the pharmacological strategies proposed, the antagonism of the cannabinoid receptors has been particularly investigated and several clinical trials have been conducted. One challenging pharmacological task will be to target the endocannabinoid system in a more selective, and hence, safe way. As the management of obesity also requires lifestyle modifications in terms of healthy eating and physical activity, the targeting of the endocannabinoid system may represent a novel approach for a multifactorial therapeutic strategy.

Introduction

Obesity is defined as an excessive fat accumulation in the body. According to the World Health Organisation, obesity is one of the greatest public health challenges of the 21st century. Once considered a problem only in high income countries, obesity is now dramatically on the rise in low- and middle-income countries, particularly in urban settings. Global increases in obesity are attributable to a number of factors including (i) a global shift in diet towards increased intake of energy-dense foods that are high in fat and sugars but low in vitamins, minerals and other micronutrients such as polyphenols; (ii) a trend towards decreased physical activity due to the increasingly sedentary nature of many forms of work, changing modes of transportation and increasing urbanisation.

Along with alarming rise in obesity to epidemic proportions, associated complications such as insulin resistance, oxidative stress and inflammation constitute a major risk factor for a number of chronic diseases including type 2 diabetes, cardiovascular diseases and cancer (Despres and Lemieux, 2006, Shoelson et al., 2007). Overweight and obese individuals also experience psychosocial burdens as a consequence of excess of fat mass, by increased stigmatisation and being targets of discrimination (Puhl and Brownell, 2001).

The need to manage obesity as a chronic illness is therefore apparent and patients need to learn that there is no quick solution to maintain a healthy weak. The multiple benefits of weight loss appear obvious, yet, the ability to lose and maintain lost weight remains very difficult (Foster, 2006). Different modalities including diet, exercise, pharmacotherapy and surgery can be considered to treat obesity (Aronne, 2002). Among the possible pharmacological strategies, current approaches are based on the investigation of several new targets in order to modulate biological pathways occurring in the central nervous system (CNS) and peripheral tissues and playing roles in food intake regulation, nutrient absorption and metabolism as well as both energy expenditure and storage (Aronne and Thornton-Jones, 2007).

One new physiological pathway of interest is the endocannabinoid system for which there is a growing literature data regarding its impact on the mechanisms involved in appetite regulation, adipose tissue biology, glucose metabolism, lipogenesis and their dysregulations during obesity.

In this review we will discuss:

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    what and where the endocannabinoid system is, by defining cannabinoid receptors, their endogenous ligands called the endocannabinoids and the ligand-metabolising enzymes;

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    what the endocannabinoid system role in energy balance is;

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    and why the endocannabinoid system could be considered as a therapeutic target for obesity treatment.

Section snippets

Definition

The endocannabinoid system includes the cannabinoid receptors, their ligands the endocannabinoids (EC) and EC anabolic and catabolic enzymes. This system was identified in the early 1990s during investigations into the mechanism of action of Delta(9)-tetrahydrocannabinol (THC), the major psychoactive principle of the hemp plant Cannabis sativa (Mechoulam et al., 1998, Pertwee, 2005). The cloning of cannabinoid receptors led to the identification of endogenous molecules capable of binding and

Conclusion

Since the endocannabinoid system was identified in the early 1990s, a growing literature data has helped to better define what this system is and why it could be considered as a target for obesity treatment. Main data that have been reviewed here provide evidence that the endocannabinoid system can be defined as a new physiological pathway occurring in the CNS and peripheral tissues and playing crucial roles in the control of food intake, energy balance and body mass. Based on the important

Acknowledgements

We gratefully acknowledge our colleagues from the Laboratoire de Biochimie et Génétique Moléculaire at the University of La Réunion, for exciting scientific discussions helping us to progress in our research work. We also thank our colleagues from the Endocannabinoid Research Group based in Italy and more particularly Isabelle Matias and Vincenzo Di Marzo for their contribution to our better understanding of the endocannabinoid system. Finally, we thank the European Union, the French Ministry

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