Serotonergic Neurons Are Targets for Leptin in the Monkey¹

Abstract

Leptin is a secretory product of adipocytes that has been shown to affect food intake, metabolism, and reproduction. One site of leptin's action is the central nervous system, where the leptin receptor (Ob-R) messenger ribonucleic acid (mRNA) and protein are expressed in discrete areas. In both the rat and monkey, Ob-R mRNA has been localized in the Raphe nuclei of the brainstem. Neurons in the Raphe nuclei are the primary source of serotonin in the brain. Serotonergic pathways influence both feeding and reproduction, and these cells are plausible direct targets for leptin's action. We used double label in situ hybridization and computerized image analysis to determine whether serotonergic neurons in the brainstem of the female pigtailed macaque (Macaca nemestrina) express Ob-R mRNA. We observed that many cells in the Raphe nuclei express serotonin transporter mRNA, a marker of serotonergic cells, and Ob-R mRNA. Based on quantitative analysis, the highest number of cells that express both serotonin transporter and Ob-R mRNAs were found in the caudal dorsal Raphe and median Raphe nuclei; fewer double labeled cells were situated in the caudal linear nucleus and rostral median Raphe, whereas double labeled cells occurred infrequently in the rostral dorsal Raphe. These observations suggest that leptin may act on serotonergic cells to mediate some of its effects on ingestive behavior, metabolism, and reproduction. (J Clin Endocrinol Metab 86: [422][423][424][425][426] 2001) L EPTIN IS A protein product of the obese (ob) gene and is secreted primarily by adipocytes. Leptin regulates body weight and metabolism and may also act as a metabolic signal to the reproductive axis (1, 2). Animals that have mutations in the genes that code for either leptin (e.g. ob/ob mice) or its receptor (Ob-R; e.g. db/db mice and fa/fa rats) are hyperphagic, obese, and infertile (3, 4). These abnormalities are corrected in ob/ob mice by treatment with exogenous leptin (5, 6). In rodents as well as nonhuman primates, central injections of leptin result in decreased food intake (6, 7), suggesting that leptin acts directly on the brain to regulate this physiological process. Fasting results in a decline in circulating leptin levels (8) as well as a reduction in the activity of the neuroendocrine reproductive axis, as evidenced by a decrease in plasma levels of LH (9, 10). Both central and peripheral administration of leptin to fasted animals prevents the suppression of LH secretion (11-13).Although it would appear that leptin acts on the brain to affect feeding and reproduction, the neural circuitry mediating leptin's action in the central nervous system has yet to be fully elucidated. To date, the majority of effort in mapping this circuitry has focused on the hypothalamus, an area of the brain known to be involved in the regulation of ingestive behaviors, metabolism, and reproduction (14). This is due to the abundant expression of Ob-R messenger ribonucleic acid (mRNA) in several hypothalamic nuclei (12,15). Recently, we identifie...

Metabolic and reproductive consequences of the serotonin transporter promoter polymorphism (5-HTTLPR) in adult female rhesus monkeys (Macaca mulatta)

“…However, this result is supported by data showing anovulation is associated with hypoleptinemia [72,73] as well as activation of the LHPA axis [74,75]. The stimulatory effect of leptin on the neuroendocrine axis of monkeys is well-documented [76] and 5HT neurons in the raphe are a target of [77]. Indeed, there is evidence that 5HT may mediate, in part, leptin's effect on reproduction, as estrous cyclicity is rescued in leptin deficient mice with an SSRI [78].…”

Administration of human leptin differentially affects parameters of cortisol secretion in socially housed female rhesus monkeys

“…However, the possibility exists that leptin inhibits ACTH from vesicles in the corticotropes. Leptin receptors are located in many parts of the CNS [69], underscoring the nature of its pleiotropic effects [70][71][72][73][74] including neuroprotection [75] and anxiolytic action [76]. Although the anorexic effects of leptin may, in part, be mediated by an increased expression of CRF in the PVN [77], leptin increases GR expression in areas known to mediate glucocorticoid negative feedback [78][79][80], including the PVN and hippocampus [81].…”

Anomalies de la prise alimentaire chez la souris dépourvue de récepteur 5-HT4

“…7). La localisation des récepteurs de la leptine sur les neurones sérotoninergiques du NRD et du noyau du raphé médian de la souris (Finn et al, 2001) représente un argument supplémentaire en faveur d'une interaction entre la leptine et les neurones sérotoninergiques. Dans le même paradigme expérimental d'utilisation du MDMA, nos résultats indiquent que les taux de leptine sont diminués chez les souris mutantes (Fig.…”