Loss of cholecystokinin and glucagon-like peptide-1-induced satiation in mice lacking serotonin 2C receptors

Abstract

Asarian L. Loss of cholecystokinin and glucagon-like peptide-1-induced satiation in mice lacking serotonin 2C receptors. Am J Physiol Regul Integr Comp Physiol 296: R51-R56, 2009. First published November 12, 2008 doi:10.1152/ajpregu.90655.2008.-To investigate the role of serotonin 2C receptors (2CR), which are expressed only in the central nervous system, in the satiating actions of the gut peptides CCK and glucagon-like peptide 1 (GLP-1), we examined 1) the effect of null mutations of serotonin 2CR (2CR KO) on the eating-inhibitory potencies of dark-onset intraperitoneal injections of 0.9, 1.7, or 3.5 nmol/kg (1, 2, or 4 g/kg) CCK and 100, 200, and 400 nmol/kg (33, 66, or 132 g/kg) GLP-1, and 2) the effects of intraperitoneal injections of 1.7 nmol//kg CCK and 100 nmol/kg GLP-1 on neuronal activation in the brain, as measured by c-Fos expression. All CCK and GLP-1 doses decreased 30-min food intake in wild-type (WT) mice, but none of them did in 2CR KO mice. CCK increased the number of cells expressing c-Fos in the nucleus tractus solitarii (NTS) of WT, but not 2CR KO mice. CCK induced similar degrees of c-Fos expression in the paraventricular (PVN) and arcuate (Arc) nuclei of the hypothalamus of both genotypes. GLP-1, on the other hand, increased c-Fos expression similarly in the NTS of both genotypes and increased c-Fos expression more in the PVN and Arc of 2CR KO mice, but not WT mice. These results indicate that serotonin signaling via serotonin 2CR is necessary for the full satiating effects of CCK and GLP-1. In addition, they suggest that the satiating effects of the two peptides are mediated by different neural mechanisms. endocrine; eating; hormone; neural; immunocytochemistry; 5HT ON THE BASIS OF FULFILLMENT of criteria for endocrine satiation signals initially proposed by Gibbs et al. (20), intestinal CCK and GLP-1 are now considered to be physiological controls of eating (4,10,19,32). Both hormones are released during meals, and premeal administration of doses producing plasma hormone levels that are similar to prandial levels is sufficient to inhibit meal size in the absence of adverse effects in humans. Furthermore, administration of CCK 1 receptor antagonists in humans or rats, or GLP-1 receptor antagonists in rats, increases food intake (Williams D, personal communication); CCK 1 receptor antagonists also block the satiating effects of CCK secretagogues in humans and rats. Although the understanding of the roles of these peptides in physiology of eating has increased tremendously in the last two decades (19,39,41,54), the brain mechanisms underlying their effects are still unclear.Serotonin appears to be a key neurotransmitter in the central mediation of eating, including the control of meal size. Extracellular concentrations of serotonin and its metabolite 5-HIAA increase in rats' brains during spontaneous meals (44). The serotonin agonist fenfluramine, which both releases synaptic serotonin and blocks serotonin reuptake (14, 21), inhibits eating in rats by reducing meal size without affectin...

Serotonin controlling feeding and satiety

“…This would also be in keeping with earlier in vitro experiments demonstrating excitatory effects of CCK on serotonergic neurons in the dorsal raphe nucleus [228]. When CCK is administered peripherally to 5-HT2C receptor knockoutmice it has no hypophagic effect, adding evidence to previous pharmacological studies demonstrating that this 5-HT receptor is involved in the mediation of CCK-induced satiety [229]. Together these indicate that CCK recruits central 5-HT to induce satiety.…”

“…The primary metabolite of GLP-1, GLP-1 (9-39), had an 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 23 antagonistic effect though, as it blocked the effect of GLP-1 on 5-HT release [305]. Similar to the observed loss of CCK-induced satiety, the hypophagic effect of GLP-1 was lost in 5-HT2C receptor knockout mice [229,306]. It cannot be excluded though, that mechanisms downstream to the 5-HT2C receptor, rather than the 5-HT2C receptor itself, are required to mediate the satiating effect of peripheral GLP-1.…”

“…C-fos expression pattern suggest that and GLP-1 and CCK use partially independent mechanisms to exert their satiating effects, as, in contrast to CCK, the NTS is probably not required for GLP-1-induced satiation [229]. This interpretation is supported by the finding that the 5-HT2C agonist mCPP does no activate GLP-1 neurons in the NTS [307].…”

Neuroendocrine control of satiation

“…Studies in mice deficient in 2CR, however, showed that these serotonin receptors are crucial in the mediation of CCK satiation [338]. Furthermore, intraperitoneal injections of doses of GLP-1 that reduced eating in wild-type mice by 50-60% had no reliable effect in 2CR-KO mice [338]. These are the first data that we know implicating serotonin in GLP-1 satiation.…”

“…The pharmacological tools used, however, were not highly selective to 2CR and were not administered locally, which is important because several populations of serotonin receptors in the brain and in the periphery have been implicated in CCK satiation. Studies in mice deficient in 2CR, however, showed that these serotonin receptors are crucial in the mediation of CCK satiation [338]. Furthermore, intraperitoneal injections of doses of GLP-1 that reduced eating in wild-type mice by 50-60% had no reliable effect in 2CR-KO mice [338].…”