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Introduction/Overview

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.¹ In the GI tract, cannabinoid receptor type 1 (CB₁ receptors) are present in neurons of the enteric nervous system and in sensory terminals of vagal and spinal neurons, activation of which has been shown to modulate several important aspects of nutrient processing, including gastric secretion, gastric emptying, and intestinal motility.² Signals arising from the gut act in concert with central mechanisms to influence eating behavior (Figure 1).³ 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.³ These hormones function as satiety/hunger signals by triggering nerve impulses in sensory nerves traveling to the hindbrain.³ 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.³

Energy Balance and Metabolic Regulation

Appetite, Motivation, Satiety, and Energy Expenditure: Role of the ECS

Endocannabinoids are synthesized in the GI tract and their administration, like that of the gastric hormone ghrelin, causes an increase in food intake.³ Moreover, endocannabinoid levels in certain areas of the GI tract appear to be modulated by feeding.⁴ For example, anandamide levels were shown to increase sevenfold in the small intestine of rats in response to 24 hours of food deprivation, whereas levels normalized when feeding was resumed. In addition, systemic, but not central, blockade of the ECS with SR141716 led to a reduction in food intake both in rats deprived of food for 24 hours and in rats that were partially satiated.⁴ This study also showed that chemical destruction of sensory terminals innervating the gut-the same nerves expressing CCK receptors and that mediate CCK-induced satiety-abolished these CB₁ receptor-mediated effects, essentially inhibiting the anorectic action of SR141716A.^{4, 5}

The vagus nerve may be another target through which the ECS modulates food intake.⁵ The vagus connects the gastrointestinal (GI) tract with medulla and brainstem nuclei that are intimately involved in the control of satiety.⁵ 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.³ 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.³ Receptors for the hormone leptin have also been located on these same nerve terminals.⁶

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.⁶ 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.⁶ Thus, reduced ECS activity may mediate the induction of satiety by CCK.⁵

Endocannabinoids also appear to be involved in modulating the orexigenic effect of the gastric hormone ghrelin.⁷ In rats, infusion of ghrelin into the paraventricular nucleus of the hypothalamus was associated with a near doubling of food intake (Figure 2). This effect was blocked by pretreatment with the CB₁ receptor antagonist SR141716 at a dose that had no effect on feeding when administered alone.⁷

Implications

CB₁ receptors are present in neurons associated with the GI tract² and endocannabinoids are synthesized within the GI tract; their levels being responsive to nutritional status.⁴ The induction of satiety by CCK is determined by the decrease in ECS activity.⁵ Fasting appears to overcome satiety by elevating endocannabinoid levels in the small intestine, thereby releasing vagal CB₁ receptors from CCK inhibition.⁵ Other evidence reviewed in this section indicates that the ECS in the brain is controlled by the anorexigenic hormone leptin and the orexigenic hormone ghrelin, both of which are also found in the GI tract. The gut is an important source of signals that control meal size and participate in metabolic regulation.^{3, 4} The ECS appears to be modulated by these gut-derived signals.

Glucose Homeostasis

Glycemic Control: Role of the ECS

In addition to digesting and assimilating ingested nutrients, the GI tract plays a key role in the physiology of glucose homeostasis, predominately by communicating with the central nervous system through both neural and endocrine pathways.¹ Peripheral signals from the GI tract relating to recent nutritional state generally take the form of absorbed nutrients, neural signals, and peptide release. Neuronal pathways relate information about stomach distention and the chemical and hormonal environment of the GI tract to specific areas in the brain that control short-term eating behavior.¹

In the GI tract, CB₁ receptors are present in neurons of the enteric nervous system and in sensory terminals of vagal and spinal neurons.² Endogenous and synthetic cannabinoids have been shown to inhibit electrically evoked contractions in the isolated pig small intestine.² In studies of gastric emptying and intestinal motility in both humans and rodents, administration of a naturally occurring cannabinoid slowed both physiologic processes.² These results were duplicated with the administration of a CB₁ receptor agonist and reversed with the administration of a CB₁ receptor antagonist.

Immplications

The clinical implications of the ECS in the GI tract for glycemic control are under investigation.

Figures

Figure 1. Signals from the gut act in concert with central and other peripheral signals to regulate energy balance and metabolism. Adapted from Schwartz 2000.⁸

Figure 2. CB₁ receptor blockade attenuates ghrelin-induced hyperphagia. From Tucci et al.⁷

References

1. Badman MK, Flier JS. The gut and energy balance: visceral allies in the obesity wars. Science. Mar 25 2005;307(5717):1909-1914.
2. Massa F, Storr M, Lutz B. The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract. J Mol Med. Dec 2005;83(12):944-954.
3. Cota D, Woods S. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12:338-351.
4. Gomez R, Navarro M, Ferrer B, et al. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci. Nov 1 2002;22(21):9612-9617.
5. Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci. May 2005;8(5):585-589.
6. Burdyga G, Lal S, Varro A, Dimaline R, Thompson DG, Dockray GJ. Expression of cannabinoid CB1 receptors by vagal afferent neurons is inhibited by cholecystokinin. J Neurosci. Mar 17 2004;24(11):2708-2715.
7. Tucci SA, Rogers EK, Korbonits M, Kirkham TC. The cannabinoid CB1 receptor antagonist SR141716 blocks the orexigenic effects of intrahypothalamic ghrelin. Br J Pharmacol. Nov 2004;143(5):520-523.
8. Schwartz MW, Woods SC, Porte D, Jr., Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. Apr 6 2000;404(6778):661-671.