leptin and 1-(3-chlorophenyl)piperazine

Corticosterone plays an important role in feeding behavior. However, its mechanism remains unclear. Therefore, the present study aimed to investigate the effect of corticosterone on feeding behavior. In this study, cumulative food intake was increased by acute corticosterone administration in a dose-dependent manner. Administration of the 5-HT

Topics: Animals; Appetite Depressants; Appetite Regulation; Appetite Stimulants; Behavior, Animal; Corticosterone; Dose-Response Relationship, Drug; Energy Intake; Hyperphagia; Hypothalamus; Leptin; Mice, Inbred ICR; Nerve Tissue Proteins; Neurons; Organ Specificity; Piperazines; Proto-Oncogene Proteins c-fos; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Spiro Compounds; Sulfonamides; Up-Regulation

Most forms of human obesity are characterized by impaired leptin sensitivity and, therefore, the effectiveness of anti-obesity leptin therapy in these leptin-resistant obese patients is marginal. Hence, the development of strategies to increase leptin sensitivity is of high priority in the field of obesity research.. We first examined the effects of co-administration of leptin and meta-chlorophenylpiperazine (mCPP), an agonist of 5-HT2C and 5-HT1B receptors, on energy balance in leptin-resistant diet-induced obese (DIO) mice. We further assessed leptin-induced phosphorylation of the STAT-3 (pSTAT3) in various brain regions of DIO mice pretreated with mCPP or in mice genetically lacking 5-HT2C receptors.. Co-administration of mCPP with leptin had an additive effect on reducing body weight in DIO mice. Furthermore, mCPP pretreatment in DIO mice enhanced leptin-induced pSTAT3 in the arcuate nucleus, the ventromedial hypothalamic nucleus, and the ventral premammillary nucleus. Finally, deletion of 5-HT2C receptors significantly blunted leptin-induced pSTAT3 in these same hypothalamic regions.. Our study provides evidence that drugs, which activate 5-HT2C receptors, could function as leptin sensitizers and be used in combination with leptin to provide additional weight loss in DIO.

Topics: Animals; Body Weight; Diet; Dose-Response Relationship, Drug; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phosphorylation; Piperazines; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; STAT3 Transcription Factor; Structure-Activity Relationship

Serotonin 2C receptors (5-HT(2C)Rs) expressed by pro-opiomelanocortin (POMC) neurons of hypothalamic arcuate nucleus regulate food intake, energy homeostasis and glucose metabolism. However, the cellular mechanisms underlying the effects of 5-HT to regulate POMC neuronal activity via 5-HT(2C)Rs have not yet been identified. In the present study, we found the putative transient receptor potential C (TRPC) channels mediate the activation of a subpopulation of POMC neurons by mCPP (a 5-HT(2C)R agonist). Interestingly, mCPP-activated POMC neurons were found to be a distinct population from those activated by leptin. Together, our data suggest that 5-HT(2C)R and leptin receptors are expressed by distinct subpopulations of arcuate POMC neurons and that both 5-HT and leptin exert their actions in POMC neurons via TRPC channels.

Topics: Animals; Arcuate Nucleus of Hypothalamus; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Leptin; Male; Membrane Potentials; Mice; Mice, Transgenic; Neurons; Patch-Clamp Techniques; Piperazines; Pro-Opiomelanocortin; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin 5-HT2 Receptor Agonists; TRPC Cation Channels

NEFA/nucleobindin2 (NUCB2), a novel satiety molecule, is associated with leptin-independent melanocortin signaling in the central nervous system. Here, we show that systemic administration of m-chlorophenylpiperazine (mCPP), a serotonin 5-HT1B/2C receptor agonist, significantly increased the expression of hypothalamic NUCB2 in wild-type mice. The increases in hypothalamic NUCB2 expression induced by mCPP were attenuated in 5-HT2C receptor mutant mice. Systemic administration of mCPP suppressed food intake in db/db mice with leptin receptor mutation as well as lean control mice. On the other hand, the expression of hypothalamic NUCB2 and proopiomelanocortin (POMC) was significantly decreased in hyperphagic and non-obese 5-HT2C receptor mutants compared with age-matched wild-type mice. Interestingly, despite increased expression of hypothalamic POMC, hypothalamic NUCB2 expression was decreased in 5-HT2C receptor mutant mice with heterozygous mutation of beta-endorphin gene. These findings suggest that 5-HT systems upregulate the expression of hypothalamic NUCB2 via 5-HT2C receptors, and induce anorexia via a leptin-independent pathway in mice.

Topics: Animals; Anorexia; Calcium-Binding Proteins; DNA-Binding Proteins; Eating; Hypothalamus; Leptin; Male; Mice; Mice, Mutant Strains; Nerve Tissue Proteins; Nucleobindins; Piperazines; Pro-Opiomelanocortin; Receptor, Serotonin, 5-HT2C; RNA, Messenger; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists; Up-Regulation