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Introduction/Overview

Appetite regulation and energy homeostasis are complex physiologic processes involving interactions among multiple neuromodulatory systems in the brain.¹ The hypothalamus and hindbrain are the two key areas that regulate food intake, energy homeostasis, and body weight, while the limbic system is believed to contain the neuronal circuitry determining perceptions of food palatability and appetite.^{2, 3} For example, specific populations of neurons in the lateral hypothalamus project to key cortical, limbic, and basal forebrain areas, indicating these neurons may have an important role in determining the hedonic or motivational aspects of feeding behavior.^4-6 Over the last decade, a large body of experimental and clinical evidence has demonstrated the involvement of the endocannabinoid system (ECS) in this regulatory network.

Energy Balance and Metabolic Regulation

Appetite, motivation, satiety, and energy expenditure: Role of the ECS

The orexigenic effects of cannabinoids were recognized as early as 300 AD.⁷ The ECS appears to play a direct role in the central regulation of feeding behavior and energy balance.² The cannabinoid receptor type 1 (CB₁) is among the most abundant G protein-coupled receptors in the brain, where its density is similar to that of γ-aminobutyric acid (GABA)- and glutamate-gated ion channels.^{2, 8} CB₁ receptor protein is expressed in the lateral hypothalamus of the rat⁹ and hypothalamic CB₁ receptor mRNA is co-localized with neuropeptides known to modulate food intake, such as melanin-concentrating hormone, cocaine-amphetamine-regulated transcript, and prepro-orexin.¹⁰ Although the density of CB₁ receptors in the hypothalamus is actually relatively low compared with other areas of the brain, the hypothalamic CB₁ receptors have a high efficiency when activated.²

Administration of the endocannabinoid 2-arachidonoyl glycerol (2-AG) into the shell subregion of the nucleus accumbens (a limbic forebrain area implicated in eating motivation) induced short-term hyperphagia.¹¹ CB₁ receptor blockade reversed this effect, suggesting a CB₁ receptor-mediated effect of 2-AG on feeding.¹¹ Interestingly, endocannabinoid levels are directly modulated by nutritional status. In fact, in the rat limbic forebrain and/or hypothalamus, levels of the endocannabinoids anandamide and 2-AG were elevated with fasting and declined with feeding.^{1, 11} In contrast, endocannabinoid levels in the cerebellum-a region not directly involved in food intake-were unaffected by fasting or feeding (Figure 1).¹¹

As noted earlier, CB₁ receptor protein is co-localized in lateral hypothalamic neurons with neuropeptides that modulate feeding. These neurons, in turn, project to cortical, limbic, and basal forebrain areas implicated in the regulation of arousal and motivated aspects of feeding.¹² In a recent electrophysiological study, depolarization of perifornical lateral hypothalamic neurons resulted in a suppression of inhibitory postsynaptic currents.¹² This depolarization protocol has been shown to cause release of endocannabinoids in other brain areas. The depolarization-induced decrease in inhibitory tone was blocked with a CB₁ receptor antagonist and mimicked the effect of treatment with a CB₁ receptor agonist. These findings provide support for the hypothesis that endocannabinoids are involved in modulating the excitability of hypothalamic circuits involved in the motivational aspects of feeding.

The intestine and associated organs of the gastrointestinal (GI) tract play a well-defined role in the physiology of energy balance, predominately by communicating with centers in the brain through neural and endocrine pathways.¹³ Signals arising from the gut act in concert with central mechanisms to influence eating behavior (Figure 2).² Among the most important of these are a number of gut-derived hormones, such as cholecystokinin (CCK) and gastric leptin, which decrease food intake. Conversely, ghrelin, another gut-derived peptide, exerts an orexigenic effect.² These hormones function as satiety/hunger signals by triggering nerve impulses in sensory nerves traveling to the hindbrain.² However, they are also transported in the blood and are able to cross the blood-brain barrier, providing signals that are integrated in the hindbrain and the hypothalamus.²

The vagus nerve may be another target through which the ECS modulates food intake.¹⁴ The vagus connects the gastrointestinal (GI) tract with medulla and brainstem nuclei that are intimately involved in the control of satiety.¹⁴ The gut hormone CCK is secreted during a meal from cells lining the duodenum, and interacts with specific CCK receptors located on the afferent terminals of the vagus nerve.² From there, information is transmitted via vagal axons and ultimately relayed to the hypothalamus, where it is integrated with other signals to decrease food intake.² Receptors for the hormone leptin have also been located on these same nerve terminals.¹⁵

Recent studies have shown that the expression of CB₁ receptor mRNA on vagal afferent neurons projecting into the duodenum is decreased in rats fed ad libitum, while its expression is increased when rats are food deprived.¹⁵ Importantly, renewed feeding in previously fasted rats or the administration of CCK leads to decreased levels of CB₁ receptor mRNA in the same vagal afferents.¹⁵ Thus, reduced ECS activity may mediate the induction of satiety by CCK.¹⁴

Hypothalamic endocannabinoids appear to be under negative control by leptin, a hormone predominantly produced by the adipose tissue that elicits anorexigenic signaling in the hypothalamus. Di Marzo et al showed that obese mice or rats with disrupted leptin signaling (obese Zucker rats and obese db/db mice) have higher levels of endocannabinoids in the hypothalamus compared with wild-type animals.¹⁶ Moreover, the influence of leptin on endocannabinoids appears to occur specifically in the hypothalamus, as levels of cerebellar endocannabinoids did not differ between db/db mice and controls.¹⁶ When leptin was systemically administered to normal animals or to obese animals lacking the hormone, it decreased hypothalamic endocannabinoid levels. These data thus suggest that leptin exerts negative control over hypothalamic endocannabinoids.¹⁶ Consistent with this possibility, leptin attenuated the CB₁ receptor-mediated suppression of inhibitory postsynaptic currents in perifornical lateral hypothalamic neurons (Figure 3).¹² In addition, leptin-deficient obese mice (ob/ob) showed an increase in steady-state voltage-gated calcium currents in lateral hypothalamic neurons and a 6-times longer depolarization-induced suppression of inhibition than lean littermates.¹² These findings indicate that integration of endocannabinoid and leptin signaling may regulate the excitability of appetite-related neural circuits. Endocannabinoids also appear to be involved in modulating the orexigenic effect of the gastric hormone ghrelin.¹⁷ In rats, infusion of ghrelin into the paraventricular nucleus of the hypothalamus was associated with a near doubling of food intake (Figure 4). This effect was blocked by pretreatment with the CB₁ receptor antagonist SR141716 at a dose that had no effect on feeding when administered alone.¹⁷

Implications

The ECS in the brain appears to be controlled by the anorexigenic hormone leptin and the orexigenic hormone ghrelin. Interactions between the human thrifty genotype, reduced physical activity, and increased food intake have been posited as the root cause of the rising prevalence of obesity and its associated complications.¹⁸ A growing body of data indicate that the ECS may play an important role in human feeding behavior and energy balance. Overall, experimental data indicate that the ECS is activated in obesity. As a result, the role of the peripheral ECS in energy balance and metabolic regulation is now being studied with great interest. Selectively blocking the CB₁ receptor may be a clinically viable treatment for clinical conditions characterized by dysregulated energy balance and metabolism, such as obesity and type 2 diabetes.

Figures

Figure 1. Food deprivation increases endocannabinoid levels in the limbic forebrain and hypothalamus. From Kirkham et al.¹¹

Figure 2. Central and peripheral signals regulate energy balance and metabolism. Adapted from Schwartz 2000.¹⁹

Figure 3. Integration of Central CB₁ Receptor and Leptin Signaling in Appetite Regulation. (Left side) Schematic of lateral hypothalamus (LH) illustrating perifornical LH neurons. Melanocortin-concentrating hormone (MCH) neurons receive GABAergic inputs from diverse brain areas, including the nucleus accumbens/ventral striatum and the arcuate nucleus. The regulation of these GABAergic inhibitory tones to MCH neurons appears to be an important factor for controlling food intake and appetite. (Right top panel) Cartoon of proposed model for mechanisms of endocannabinoid signaling and modulation of GABAergic transmission in the perifornical LH neurons of the LH. The activation of presynaptic CB₁ receptors located on GABA terminal decreases GABA release, thereby enhancing the net excitability of perifornical LH neurons, consistent with increased feeding behavior. The activation of leptin receptors on perifornical LH neurons inhibits voltage-gated calcium currents (VGCC) via activation of janus kinase 2 (JAK2) and mitogen-activated protein kinase (MAPK). The consequent decrease in [Ca]int results in less synthesis and release of endocannabinoids and hence decreases depolarization-induced suppression of inhibition. Perifornical LH neurons in leptin-deficient, obese mice ( ob/ob) have larger VGCC, consistent with upregulated endocannabinoid signaling, enhanced excitability, and consequent hyperphagia. (Right bottom panel) Cartoon of proposed model for mechanisms in which rimonabant, a CB₁ receptor antagonist, decreases body weight and food intake. Rimonabant would inhibit CB₁ receptors, antagonizing the elevated endocannabinoids from the MCH neuron. This would potentially normalize GABA release and inhibit MCH release, leading to decreased appetite. From Jo et al.¹²

Figure 4. CB₁ receptor blockade attenuates ghrelin-induced hyperphagia. From Tucci et al.¹⁷

References

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