Endocannabinoids and Energy Homeostasis

Stephen C. Woods, PhD, and Daniela Cota, md

Contents

Introduction

The Endocannabinoid System Endocannabinoid Biology

Endocannabinoids and Regulation of Energy Balance

Endocannabinoid System and Peripheral Metabolism

Clinical Use of CB1 Agonists

Conclusion

References

Summary

The body's endogenous endocannabinoid system includes two endogenous agonists for cannabinoid-(CB)-1 receptors, anadamide and 2-arachidonoyl-glycerol (2-AG). Both of these endocannabinoids (ECs) are fatty acid signals derived from cell membranes. They exert a coordinated action at multiple tissues to promote increased food intake, lipogenesis, and storage of fat. Endocannabinoids interact with multiple hypothalamic circuits and transmitter systems to stimulate food intake in general, and they also act in reward areas of the brain to selectively enhance intake of palatable foods. Activation of CB1 receptors increases enzyme activity that causes de novo fatty acids to be formed in the liver and circulating lipids to be taken up by fat cells. All these actions are reversed in animals lacking CB1 receptors, and there is growing evidence that activity of the endocannabinoid system is toni-cally increased in animal and human obesity. Acute or chronic administration of selective synthetic CB1 antagonists to overweight or obese individuals causes weight loss, reduced waist circumference, and an improved lipid and glycemic profile. Developing ligands for endocannabinoid receptors is an important novel therapeutic strategy for the treatment of metabolic dysregulation.

Key Words: Satiety; lipogenesis; obesity; anandamide; 2-arachidonoyl-glycerol; CB1 receptors; food intake; leptin.

INTRODUCTION Energy Homeostasis

Energy homeostasis is a term that encompasses the collective processes whose goal is to provide adequate supplies of energy to the body's organs. This includes stocking fuel storage depots such as fat and liver cells with ample supplies, as well as recruiting

From: Contemporary Endocrinology: Treatment of the Obese Patient Edited by: R. F. Kushner and D. H. Bessesen © Humana Press Inc., Totowa, NJ

the stored energy back from these depots and distributing them to tissues as needed. It also includes procuring new sources of energy, whether by the consumption of food or by the de novo synthesis of utilizable high-energy molecules by liver and other tissues. All these processes are controlled by a complex and highly integrated network of cells in strategic locations in the body that continuously monitor the energy use and anticipated energy needs of each tissue; at the same time, the network continuously monitors energy available in storage depots, what will be entering the blood from ingested food still within the gastrointestinal system, and energy that may be available to eat in the external environment. Myriad neural and hormonal signals participate in this regulation, with the goal of ensuring that active tissues have what they need when they need it.

The previous decades saw tremendous growth in our understanding of many of the signals involved in energy homeostasis. Dozens of neurotransmitters, neuropeptides, and other signals were newly described and found to fit the general model depicted in Fig. 1. Information relevant to the regulation of energy intake and metabolism is detected by sensory cells in strategic organs, and they in turn generate signals that are relayed to other cells, especially to the brain, so that any necessary action can be taken. Most signals transferring information between cells in the body are derived from modified amino acids (e.g., glutamate and y-aminobutyric acid [GABA]) or biogenic amines (e.g., serotonin, acetylcholine, and the catecholamines), or are composed of chains of amino acids formed into biologically active peptides. Lipids in the form of steroids have long been known to be important signaling molecules, and other signaling lipids in the form of modified fatty acids have recently been added to the list. Finally, energy-rich molecules themselves, including glucose and some fatty acids, are also recognized to function as key signals in this system. For a review, see ref. (1).

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