FGF21 activates HPA and sympathetics via neuroinflammation and plasticity

FGF21 通过神经炎症和可塑性激活 HPA 和交感神经

• 批准号: 8835993
• 负责人: Amy Elizabeth Bruestle Packard
• 金额: $ 5.33万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835993
• 关键词: Adult; Americas; Anti-Inflammatory Agents; Anti-inflammatory; Atkins Diet; Autonomic nervous system; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Body Weight decreased; Brain; Brain region; CREB1 gene; Carbohydrates; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Chronic; Chronic stress; Clinical; Diabetes Mellitus; Diet; Disease; Event; FGFR1 gene; Fatty Acids; Fatty acid glycerol esters; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Figs - dietary; Future; Glucocorticoids; Glucose; Goals; Health; Heart Hypertrophy; Heart Rate; Hormonal; Hypothalamic structure; Individual; Inflammation; Intervention; Ketone Bodies; Ketoses; Ketosis; Kidney; Link; Lipids; Liver; Mediating; Mediator of activation protein; Medical; Medium chain triglycerides; Metabolic; Metabolism; Microglia; Mus; Nature; Neuroendocrinology; Neurons; Nucleic Acid Regulatory Sequences; Obesity; Pathology; Patients; Phenotype; Process; Rattus; Regulation; Research; Research Personnel; Research Project Grants; Risk; Rodent; Scientist; Signal Pathway; Signal Transduction; Site; Stress; Supplementation; Synapses; Synaptic plasticity; System; Testing; Time; Training; Visceral; Weight; Weight Gain; Wood material; Work; adverse outcome; authority; base; cardiovascular risk factor; career; feeding; fibroblast growth factor 21; hypothalamic-pituitary-adrenal axis; ketogenic diet; mRNA Expression; mortality; neuroimmunology; neuroinflammation; paraventricular nucleus; post-doctoral training; prevent; public health relevance; receptor; research clinical testing

DESCRIPTION (provided by applicant): Obesity is highly prevalent in America (greater than 30% of adults) and predisposes patients to a host of disorders from diabetes to cardiovascular disease. Low-carbohydrate, high-fat diets (e.g., the Atkins diet) is a popular and effective choice to lose weight. The major goal of these diets is to induce ketosis, a process by which the liver converts fatty acids to ketone bodies providing an alternative fuel in the face of limited glucose availability. Enthusiasm for these ketogenic diets (KD) is tempered by recent evidence suggesting an increased risk of mortality from cardiovascular events for individuals consuming these diets. KD may increase cardiovascular risk and other adverse outcomes as it induces excessive, chronic activation of stress regulatory systems, including the hypothalamic pituitary adrenal axis (HPA) and sympathetic branch of the autonomic nervous system, despite decreased body weight gain. KD induces cardiac hypertrophy and kidney pathology as well as increasing neuronal activation in stress regulatory brain regions including the periventricular nucleus of the hypothalamus (PVN). Hormonal fibroblast growth factor 21 (FGF21) is necessary and sufficient for the effects of KD on HPA and cardiovascular endpoints. The liver produces FGF21 during ketosis that can cross the blood-brain barrier and act on its receptor (FGFR1) present in the brain. KD activates PVN microglia that express FGFR1, suggesting that KD-induced FGF21 may increase neuronal activation by inducing neuroinflammation. FGFR1 is also expressed on PVN neurons where it activates pCREB, a signaling pathway that is critical for synaptic remodeling, suggesting that FGF21 may modulate HPA activity by inducing plasticity. Thus, this project will test the hypothesis that FGF21 increases sympathetic and HPA tone by inducing neuroinflammation and/or synaptic remodeling in stress regulatory brain regions. Pharmacological anti-inflammatory intervention and CREB anti-sense ODN will be used to test whether neuroinflammation and pCREB-dependent synaptic remodeling respectively, are necessary for FGF21-mediated effects. The research project has important implications for individuals using KD and suggests they may be at greater risk for stress and cardiovascular diseases, particularly via the actions of FGF21. This project will elucidate the mechanisms by which sympathetic and HPA activity are modulated, specifically identifying the contributions of neuroinflammation and synaptic remodeling. Significantly, after studying inflammation in her dissertation work, Dr. Packard plans to use this postdoctoral training with Dr. Ulrich-Lai (sponsor; expert in stress regulation, stress/diet interactions and synaptic plasticity) and Dr. Woods (co-sponsor; expert in diet, metabolism and obesity) to enable her long term career goal of being an independent, academic researcher at the junction of fields of neuroimmunology, neuroendocrinology and metabolism.

描述（由申请人提供）：在美国（大于30％的成年人）高度普遍存在，使患者患有从糖尿病到心血管疾病的许多疾病。低碳水化合物高脂饮食（例如，阿特金斯饮食）是一种流行有效的选择 减肥。这些饮食的主要目的是诱导酮症，肝脏将脂肪酸转化为酮体，面对有限的葡萄糖可利用性，为酮体提供了替代燃料。这些生酮饮食（KD）的热情通过最近的证据表明，对于食用这些饮食的人而言，心血管事件的死亡风险增加。 KD可能会增加心血管风险和其他不良后果，因为它会诱导压力调节系统过多的长期激活，包括下丘脑垂体肾上腺轴（HPA）和自主神经系统的交感神经分支，尽管体重减轻了。 KD诱导心脏肥大和肾脏病理学，并增加应激调节脑区域的神经元激活，包括下丘脑（PVN）的脑室核。激素成纤维细胞生长因子21（FGF21）对于KD对HPA和心血管终点的影响是必需的，足以满足。肝脏在酮症期间产生FGF21，可以越过血脑屏障并作用于大脑中存在的受体（FGFR1）。 KD激活表达FGFR1的PVN小胶质细胞，表明KD诱导的FGF21可能通过诱导神经炎症来增加神经元激活。 FGFR1也在PVN神经元上表达，该神经元激活PCREB，这是一种对突触重塑至关重要的信号通路，这表明FGF21可能通过诱导可塑性来调节HPA活性。因此，该项目将检验以下假设：FGF21通过在压力调节大脑区域诱导神经炎症和/或突触重塑来增加交感神经和HPA张力。药理学抗炎干预和CREB抗敏感性ODN将用于测试FGF21介导的效应是必需的神经炎症和PCREB依赖性突触重塑是否分别是必需的。 该研究项目对使用KD的个体具有重要意义，并认为他们可能面临更大的压力和心血管疾病风险，尤其是通过FGF21的行为。该项目将阐明调节交感神经和HPA活性的机制，专门识别神经炎症和突触重塑的贡献。值得注意的是，在研究了她的论文工作中的炎症之后，Packard博士计划与Ulrich-Lai博士（赞助商；压力调节，压力/饮食相互作用和突触可塑性专家）和伍兹博士（共同赞助者；饮食，代谢和肥胖症专家）一起成为独立的职业生涯，在独立的学术研究中，在饮食，代谢和肥胖方面的专家神经内分泌学和代谢。