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

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.Obesity and its associated ailments such as diabetes have become a worldwide epidemic carrying with them a heavy toll of morbidity and mortality. Over the past decades, it has become evident that neural circuits in the central nervous system play a direct and crucial role in controlling feeding and energy homeostasis (1, 2). Disruptions in the mechanisms of central nervous system energy sensing are able to alter the standard homeostatic responses and are factors that contribute to the pathophysiology of obesity and diabetes. The brain serotonin system has long been implicated in the neural regulation of food intake and energy metabolism, as highlighted by the clinical use of serotonin releasers and reuptake inhibitors as appetite suppressant and weight loss medication (3-5). Depletion of central serotonin using selective neurotoxins has been shown to result in hyperphagia and obesity, whereas the release of serotonin and the inhibition of reuptake by D-fenfluramine potently reduce feeding and body weight (6). More recently, several lines of evidence show that serotonin receptor agonists can significantly improve glucose tolerance and reduce plasma insulin in mouse models of obesity and type 2 diabetes (7-9).Numerous serotonin receptor subtypes have been identified in which serotonin receptor 2C (5-HT 2C R) 4 is recognized specifically as a mediator of serotonin-induced appetite and glucose regulation (10 -13). During the past few years, both pharmacological and genetic evidence has indicated that neuropeptide Y (NPY) and melanocortin systems are the necessary mechanisms by which 5-HT 2C R agonists reduce appetite and improve diabetic conditions (14 -16). Although significant progress has been made in the study of serotonin-mediated regulation of energy metabolism, we ...

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