Hypothalamic Ahi1 Mediates Feeding Behavior through Interaction with 5-HT2C Receptor

Hao Wang,Zhenbo Huang,Liansha Huang,Shaona Niu,Xiurong Rao,Jing Xu,Hui Kong,Jianzhong Yang,Chuan Yang,Donghai Wu,Shihua Li,Xiao-Jiang Li,Tonghua Liu,Guoqing Sheng

doi:10.1074/jbc.m111.277871

Abstract

It is indicated that there are important molecules interacting with brain nervous systems to regulate feeding and energy balance by influencing the signaling pathways of these systems, but relatively few of the critical players have been identified. In the present study, we provide the evidence for the role of Abelson helper integration site 1 (Ahi1) protein as a mediator of feeding behavior through interaction with serotonin receptor 2C (5-HT(2C)R), known for its critical role in feeding and appetite control. First, we demonstrated the co-localization and interaction between hypothalamic Ahi1 and 5-HT(2C)R. Ahi1 promoted the degradation of 5-HT(2C)R through the lysosomal pathway. Then, we investigated the effects of fasting on the expression of hypothalamic Ahi1 and 5-HT(2C)R. Fasting resulted in an increased Ahi1 expression and a concomitant decreased expression of 5-HT(2C)R. Knockdown of hypothalamic Ahi1 led to a concomitant increased expression of 5-HT(2C)R and a decrease of food intake and body weight. Last, we found that Ahi1 could regulate the expression of neuropeptide Y and proopiomelanocortin. Taken together, our results indicate that Ahi1 mediates feeding behavior by interacting with 5-HT(2C)R to modulate the serotonin signaling pathway.

Highlights

It is indicated that there are important molecules interacting with brain nervous systems to regulate feeding and energy balance by influencing the signaling pathways of these systems, but relatively few of the critical players have been identified
5-HT2CR selectively bound to endogenous Abelson helper integration site 1 (Ahi1), whereas no signal was detected in immunoprecipitates from non-immune rabbit serum control. To confirm this physical interaction, we subsequently expressed them in transfected HEK293 cells; green fluorescent protein (GFP)-5-HT2CR showed an extensive distribution throughout the plasma membrane and cytoplasm of the cell, whereas Ahi1 showed a unique distribution pattern characterized as dot-like structures
We found that the co-localization of Ahi1 and 5-HT2CR was lost in the cells transfected with C terminal-truncated Ahi1 (Fig. 1D)

Summary

Introduction

It is indicated that there are important molecules interacting with brain nervous systems to regulate feeding and energy balance by influencing the signaling pathways of these systems, but relatively few of the critical players have been identified. We provide the evidence for the role of Abelson helper integration site 1 (Ahi1) protein as a mediator of feeding behavior through interaction with serotonin receptor 2C (5-HT2CR), known for its critical role in feeding and appetite control. Our results indicate that Ahi mediates feeding behavior by interacting with 5-HT2CR to modulate the serotonin signaling pathway. The normal neural function of Ahi, remains poorly defined Both protein and mRNA studies have shown that Ahi is distributed in several brain areas implicated in feeding and metabolic regulation such as the hypothalamic. Recent studies [26, 27] show that brain Ahi may play an important role in the regulation of feeding behavior

Methods

Results

Conclusion