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CXCL12 promotes development of hypothalamic peptide neurons responsive to fat

CXCL12促进对脂肪敏感的下丘脑肽神经元的发育

基本信息

批准号：
8857108
负责人：
KINNING POON
金额：
$ 5.8万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8857108
关键词：
Adult Affect Animals Architecture Attention Behavior Behavioral Behavioral Paradigm Blood Body Weight Brain Brain region Bromodeoxyuridine CXCL12 gene CXCR4 Receptors CXCR4 gene Cells Chronic Consumption Data Development Diet Dietary Fats Embryo Embryonic Development Enkephalins Epidemic Exposure to Fatty acid glycerol esters Feeding behaviors Fellowship Fluorescence Food Galanin Goals Grant Growth Health Histocytochemistry Hyperphagia Hypothalamic structure Immune Immunofluorescence Immunologic Immunohistochemistry In Vitro Inflammation Inflammation Mediators Inflammatory Ingestion Intake Label Measurement Measures Mediating Messenger RNA Neurons Neuropeptides Novelty-Seeking Behaviors Obesity Operative Surgical Procedures Organogenesis Peptides Physiological Placenta Play Pregnancy Proteins Pump Rattus Role Slice Small Interfering RNA System Testing Weight Gain Western Blotting Woman behavior measurement behavior test cell growth cell motility chemokine cytokine feeding in vivo knock-down mature animal melanin-concentrating hormone migration neurogenesis neuron development novel offspring postnatal prenatal prenatal exposure programs receptor research study response skills

项目摘要

DESCRIPTION (provided by applicant): Global obesity is an epidemic problem that has been steadily increasing over the past several decades, leading to a higher percentage of women overeating and being obese during pregnancy. Many studies have shown that high fat diet (HFD) and obesity during pregnancy produces offspring that are similarly prone to overeating and gaining weight, further exacerbating the obesity problem. Recent evidence suggests that this may be attributed to increased neurogenesis and expression of the orexigenic peptides, enkephalin (ENK), galanin (GAL) and melanin-concentrating hormone (MCH) in the hypothalamus of offspring, with these peptides in this brain region being stimulators of HFD intake. Although the mechanism for this change has not been established, current evidence suggests that inflammatory mediators may be involved. Chemokines are a group of small proteins that have been found to play a role in neuronal modulation, development, migration, and growth. There are studies showing chemokines to be increased with ingestion of a HFD and in dietary obesity, but there is little known about he relationship of chemokines to the orexigenic peptides in the brain. To establish the relationship between chemokines and HFD intake, this grant will investigate, both in adult rats and in offspring prenatally exposed to HFD, the relationship of a specific chemokine, CXCL12, to hypothalamic peptides, HFD consumption and behaviors associated with excess intake. Aim 1 will determine in adult animals whether the receptors, CXCR4 and CXCR7, are co-expressed with ENK, GAL and MCH neurons and if CXCL12 functions through these receptors to stimulate peptide expression and HFD intake, by using immunohistochemistry, mRNA quantification, western blotting, siRNA knockdown and behavioral paradigms. Preliminary results show that HFD stimulates the expression of CXCL12, CXCR4, and CXCR7 in the hypothalamus and that treatment of cultured neurons with CXCL12 increases the expression of ENK, GAL and MCH. Aim 2 will provide a direct test of the possible role of CXCL12 in mediating the neurogenesis and migration of peptide neurons into the hypothalamus and in increasing the propensity for increased HFD intake in the offspring, by using immunofluorescence histochemistry and behavioral tests. Preliminary results show an increase in circulating CXCL12 in dams ingesting the HFD, increased levels of CXCL12 and CXCR4 in the hypothalamus of embryos, and increased migration of cultured neurons in response to CXCL12. The data thus far implicate CXCL12 in mediating the effects of prenatal fat exposure and also reveal an important relationship to the orexigenic peptides. These studies will yield new evidence to support the function of CXCL12 in mediating the behavioral programming induced by dietary fat.

描述（由申请人提供）：全球肥胖是一个流行病，在过去几十年里一直在稳步增长，导致女性在怀孕期间暴饮暴食和肥胖的比例更高。许多研究表明，怀孕期间的高脂肪饮食 (HFD) 和肥胖会导致后代同样容易出现以下问题：暴饮暴食、体重增加，进一步加剧肥胖问题。最近的证据表明，这可能归因于后代下丘脑中促食欲肽、脑啡肽 (ENK)、甘丙肽 (GAL) 和黑色素浓缩激素 (MCH) 的神经发生和表达增加，而该大脑区域中的这些肽是 HFD 摄入的刺激物。尽管这种变化的机制尚未确定，但目前的证据表明炎症介质可能参与其中。趋化因子是一组小蛋白质，已被发现在神经元调节、发育、迁移和生长中发挥作用。有研究表明，摄入 HFD 和饮食肥胖会增加趋化因子，但人们对趋化因子与大脑中促食欲肽的关系知之甚少。为了建立趋化因子和 HFD 摄入量之间的关系，这项资助将在成年大鼠和产前接触 HFD 的后代中研究特定趋化因子 CXCL12 与下丘脑肽、HFD 消耗以及与过量摄入相关的行为的关系。目标 1 将通过使用免疫组织化学、mRNA 定量、蛋白质印迹、siRNA 敲低和行为范例，确定成年动物中的受体 CXCR4 和 CXCR7 是否与 ENK、GAL 和 MCH 神经元共表达，以及 CXCL12 是否通过这些受体发挥作用，刺激肽表达和 HFD 摄入。初步结果表明，HFD 刺激下丘脑中 CXCL12、CXCR4 和 CXCR7 的表达，并且用 CXCL12 处理培养的神经元会增加 ENK、GAL 和 MCH 的表达。目标 2 将通过使用免疫荧光组织化学和行为测试，直接测试 CXCL12 在介导神经发生和肽神经元迁移到下丘脑中以及在增加后代 HFD 摄入量增加的倾向方面的可能作用。初步结果显示，摄入 HFD 的母鼠循环 CXCL12 增加，胚胎下丘脑中 CXCL12 和 CXCR4 水平增加，并且培养的神经元响应 CXCL12 的迁移增加。迄今为止的数据表明 CXCL12 介导了产前脂肪暴露的影响，并且还揭示了与食欲肽的重要关系。这些研究将产生新的证据来支持 CXCL12 在介导膳食脂肪诱导的行为编程中的功能。