Serotonin-3 receptors in gastric mechanisms of cholecystokinin-induced satiety

Abstract

OUR UNDERSTANDING OF THE CONTROLS of food intake has increased substantially during the last 30 years. Important in this has been the recognition of the meal as a controlled, physiologically relevant unit of energy intake. During a meal, ingested nutrients accumulate in the stomach and gradually pass to the small intestine. The gastrointestinal presence of nutrients stimulates the release of peptides and neurotransmitters that coordinate gastrointestinal secretion and motility to facilitate digestion. These events can individually, and in concert, produce signals to the brain that lead to meal termination or satiety (28) and thus determine individual meal size. The gut-brain peptide cholecystokinin (CCK) and the monoamine serotonin (5-HT) are two long-recognized agents of satiation. In this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Hayes et al. (16) present important new information about how CCK and 5-HT systems interact to promote peripheral mechanisms of satiety.Since the original demonstration (14) that systemic administration of CCK inhibits food intake in rats by reducing meal size and duration, CCK has become the best-characterized satiety factor (24). CCK is released from enteroendocrine cells in the proximal small intestine in response to fat and protein. CCK binds to CCK-1 receptors (also known as CCK-A receptors) to promote meal termination (2). CCK activates CCK-1 receptors on mechanoreceptive vagal afferents from the stomach and duodenum, as well as duodenal chemoreceptive vagal afferents, to directly transmit meal-related feedback signals to the brain (29). CCK also activates CCK-1 receptors in the circular muscle layer of the pylorus, causing it to contract. This slows gastric emptying, resulting in gastric distension and the indirect activation of gastric mechanoreceptive vagal afferents (29).The monoamine 5-HT is produced by platelets, endothelial cells, mast cells, serotonergic neurons, and enterochromaffin cells (13). Its wide distribution in the gastrointestinal tract and vasculature have made 5-HT a strong candidate for involvement in peripheral mechanisms of satiety. Parenteral administration of 5-HT reduces food intake by reducing meal size and duration (11). Like CCK, 5-HT is released from intestinal enteroendocrine cells in response to nutrients (21). In addition, 5-HT is also released in response to gastric distension (22). Gastrointestinal release of 5-HT, like CCK, activates vagal afferent fibers (22,27).Given the complex pharmacology of 5-HT receptor subtypes, and the emphasis on central 5-HT in feeding (5, 6), the identification of roles for specific 5-HT receptors in peripheral mechanisms of feeding control has been challenging. The 5-HT type-3 (5-HT3) receptor was long discounted from having an important role in the control of food intake. Systemic administration of antagonists at 5-HT3 receptors usually produced negative results and occasionally decreased food intake (7, 23, 30, 32). For some time, the only consistent data for...

Peripheral neural targets in obesity

“…While parenteral 5‐HT administration has been shown to reduce meal size and duration in rats, vagotomy appears to increase this effect (Fletcher and Burton, 1985; 1986). Additionally, outcomes of studies using 5‐HT 3 receptor antagonists to influence satiety in animals and humans have generally been inconsistent, raising questions for a peripheral role of 5‐HT in food intake regulation (for review, see Aja, 2006). Indeed, most attention has been focussed on central sites of satiety actions of 5‐HT acting on 5‐HT 1 and 5‐HT 2 receptor subtypes (for review, see Atkinson, 2008).…”

Review article: the gastrointestinal tract: neuroendocrine regulation of satiety and food intake

“…Distension of the stomach by a volume load is able to reduce food intake significantly 2, 3 . Exposing the small intestine to nutrients leads to release of gut peptides and neurotransmitters that induce a reduction in hunger levels and food intake 4–7 …”

“…During the process of meal ingestion, some nutrients will already have entered the small intestine and gastric and intestinal satiety signals interact to limit meal size, 5, 8 to increase satiation and to increase satiety between meals.…”

Implication of neurohormonal-coupled mechanisms of gastric emptying and pancreatic secretory function in diabetic gastroparesis

“…In addition, electrophysiological studies have shown that endogenously released and intraluminally perfused 5-HT activated vagal afferent neurons within the nodose ganglion. On the other hand, 5-HT is considered as one of the key factors that regulates food intake and mediates satiety due to its wide distribution within the GI tract[ 82 ].…”