5-HT2CRs Expressed by Pro-Opiomelanocortin Neurons Regulate Energy Homeostasis

Yong Xu,Juli E Jones,Daisuke Kohno,Kevin W Williams,Charlotte E Lee,Michelle J Choi,Jason G Anderson,Lora K Heisler,Jeffrey M Zigman,Bradford B Lowell,Joel K Elmquist

doi:10.1016/j.neuron.2008.09.033

Abstract

SummaryDrugs activating 5-hydroxytryptamine 2C receptors (5-HT2CRs) potently suppress appetite, but the underlying mechanisms for these effects are not fully understood. To tackle this issue, we generated mice with global 5-HT2CR deficiency (2C null) and mice with 5-HT2CRs re-expression only in pro-opiomelanocortin (POMC) neurons (2C/POMC mice). We show that 2C null mice predictably developed hyperphagia, hyperactivity, and obesity and showed attenuated responses to anorexigenic 5-HT drugs. Remarkably, all these deficiencies were normalized in 2C/POMC mice. These results demonstrate that 5-HT2CR expression solely in POMC neurons is sufficient to mediate effects of serotoninergic compounds on food intake. The findings also highlight the physiological relevance of the 5-HT2CR-melanocortin circuitry in the long-term regulation of energy balance.

Highlights

The central 5-hydroxytryptamine (5-HT) system, including the 5-HT2C receptors (5-HT2CRs) plays critical roles in the regulation of energy homeostasis
Using PCR primers specific for 5-HT2CR mRNA, we found that expression of 5-HT2CR mRNA was disrupted in the cerebral cortex, whole hypothalamus, arcuate nucleus of hypothalamus (ARC), and brainstem of 2C null mice
POMC mRNA is expressed in the anterior pituitary gland, we found no endogenous 5-HT2CR mRNA expressed in the pituitary of wild-type (WT) mice

Summary

SUMMARY

Drugs activating 5-hydroxytryptamine 2C receptors (5-HT2CRs) potently suppress appetite, but the underlying mechanisms for these effects are not fully understood. To tackle this issue, we generated mice with global 5-HT2CR deficiency (2C null) and mice with 5-HT2CRs re-expression only in pro-opiomelanocortin (POMC) neurons (2C/POMC mice). We show that 2C null mice predictably developed hyperphagia, hyperactivity, and obesity and showed attenuated responses to anorexigenic 5-HT drugs. All these deficiencies were normalized in 2C/POMC mice. These results demonstrate that 5-HT2CR expression solely in POMC neurons is sufficient to mediate effects of serotoninergic compounds on food intake. The findings highlight the physiological relevance of the 5-HT2CR-melanocortin circuitry in the long-term regulation of energy balance

INTRODUCTION

AND DISCUSSION

EXPERIMENTAL PROCEDURES