Endocannabinoid System

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A recently characterized physiologic system that plays a major role in modulating energy metabolism is the endocannabinoid-CB1 receptor system (Figure 4.9)31'32. The discovery of this system represents a significant advance in understanding mechanisms contributing to the development of obesity and as such, provides targets for new pharmacological approaches to target abdominal obesity and its related metabolic

Figure 4.8 The development of systemic insulin resistance in obesity-induced inflammation and stress. In obese states, adipose tissue is under a constant state of metabolic stress, resulting in the activation of the stress and inflammatory response, which leads to the accumulation of macrophages. In this state, adipocytes release cytokines, adipokines and free fatty acids, which can act in a paracrine or autocrine fashion to amplify the proinflammatory state within adipose tissue and cause localized insulin resistance. Adipose tissue also serves as an endocrine organ whereby these cytokines, adipokines and free fatty acids travel to liver and muscle and may decrease insulin sensitivity. In addition to the adipose tissue-derived factors, stress and inflammatory signals can arise independently within liver and muscle, and result in local insulin resistance within these organs. From reference 30, with permission

Figure 4.8 The development of systemic insulin resistance in obesity-induced inflammation and stress. In obese states, adipose tissue is under a constant state of metabolic stress, resulting in the activation of the stress and inflammatory response, which leads to the accumulation of macrophages. In this state, adipocytes release cytokines, adipokines and free fatty acids, which can act in a paracrine or autocrine fashion to amplify the proinflammatory state within adipose tissue and cause localized insulin resistance. Adipose tissue also serves as an endocrine organ whereby these cytokines, adipokines and free fatty acids travel to liver and muscle and may decrease insulin sensitivity. In addition to the adipose tissue-derived factors, stress and inflammatory signals can arise independently within liver and muscle, and result in local insulin resistance within these organs. From reference 30, with permission complications. The endocannabinoid system consists of a family of endogenous agonists that are phospholipid derivatives and locally produced (endocannabinoids) and the receptors which they activate, i.e. Gi/O-protein-coupled CBi receptors33-35.

It has been reported that the CB2 receptors are located in key areas of the brain involved in the regulation of appetite/satiety as well as in several tissues/organs such as the autonomic nervous system, the liver, skeletal muscle, gastrointestinal tract and adipose tissue (Figure 4.10)31,36. There appears to be key differences between classic neurotransmitters and the endocannabinoid system as it is now described that endocannabinoids are produced on demand post-synaptically and degraded rapidly (Figure 4.11). There is therefore considerable evidence supporting the notion that the endocannabinoid system has an important role in the regulation of energy balance37. For example, it has been demonstrated that the endo-cannabinoid administration increases energy intake and this effect is not observed in animals lacking the CB1 receptor38,39. Furthermore, animals lacking the

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1

Limbic forebrain

Hypothalamus

Motivation for

Hunger/satiety

palatable food

Energy intake

Ghrelin,

PYY, GLP-Í

I Gastric emptying

lJ GI motility

Digestion, absorption, transport

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