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

• 批准号: 8645839
• 负责人: KINNING POON
• 金额: $ 5.39万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 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/8645839
• 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; 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; public health relevance; receptor; research study; response; skills

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）：全球肥胖症是一个流行病问题，在过去几十年中一直在稳步增长，导致怀孕期间妇女暴饮暴食和肥胖的比例较高。许多研究表明，高脂肪饮食（HFD）和肥胖在怀孕期间产生的后代，同样容易 暴饮暴食和体重增加，进一步加剧了肥胖问题。最近的证据表明，这可能是由于后代下丘脑中食欲肽、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，该脑区中的这些肽是HFD摄入的刺激物。虽然这种变化的机制尚未建立，目前的证据表明，炎症介质可能参与。趋化因子是一组小分子蛋白质，已发现其在神经元调节、发育、迁移和生长中起作用。有研究表明趋化因子随着HFD的摄入和饮食性肥胖而增加，但对趋化因子与大脑中的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，该基金将在成年大鼠和产前暴露于HFD的后代中研究特定趋化因子CXCL 12与下丘脑肽、HFD摄入量和与过量摄入相关的行为的关系。目的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，确定在成年动物中受体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功能以刺激肽表达和HFD摄入。初步结果显示，HFD刺激下丘脑中CXCL12、CXCR4和CXCR7的表达，并且用CXCL12处理培养的神经元增加ENK、GAL和MCH的表达。目的2将提供一个直接的测试，CXCL 12在介导的神经发生和迁移的肽神经元进入下丘脑，并在增加的倾向，增加HFD摄入量的后代，通过使用免疫荧光组织化学和行为测试的可能作用。初步结果显示，增加循环CXCL12在母鼠inflammation HFD，增加水平的CXCL12和CXCR4在下丘脑的胚胎，并增加迁移的培养神经元响应CXCL12。迄今为止的数据暗示CXCL12介导产前脂肪暴露的影响，也揭示了与食欲肽的重要关系。这些研究将为CXCL12介导膳食脂肪诱导的行为编程提供新的证据。