Age-related neuronal regulation of thermogenesis and lipid metabolism

产热和脂质代谢的年龄相关神经元调节

• 批准号: 10513891
• 负责人: Chunmin C. Lo
• 金额: $ 43.53万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513891
• 关键词: Abdomen; Acute; Adipose tissue; Age; Aging; Animals; Attenuated; Biology; Brown Fat; Cardiovascular Diseases; Cholecystokinin; Cholecystokinin A Receptor; Chronic; Consumption; Data; Deposition; Dietary Fats; Down-Regulation; Elderly; Energy Metabolism; Enterocytes; Fatty Acids; Fatty acid glycerol esters; Health; Health Benefit; Hepatic; High Fat Diet; Hormones; Human; Hypertriglyceridemia; Impairment; Infusion procedures; Injections; Insulin; Insulin Resistance; Intestines; Lead; Lipids; Lipolysis; Lipoproteins; Liver; Measures; Mediating; Metabolic Diseases; Molecular Biology; Mus; Myocardium; Neurons; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathway interactions; Patients; Plasma; Production; Regulation; Reporting; Research Personnel; Rodent; Role; Signal Pathway; Skeletal Muscle; Sympathectomy; Sympathetic Nervous System; Testing; Therapeutic; Thermogenesis; Time; Triglycerides; Weight Gain; age related; apolipoprotein A-IV; carcinoembryonic antigen-related cell adhesion molecules; combat; design; hindbrain; innovation; interdisciplinary collaboration; lipid biosynthesis; lipid metabolism; nerve supply; neurophysiology; neuroregulation; neurotransmission; novel; novel therapeutics; obesity prevention; oxidation; relating to nervous system; uptake; young adult

Project Summary Aging is associated with obesity, cardiovascular disease, and type 2 diabetes mellitus. Activating brown adipose tissue (BAT) thermogenesis in humans results in elevation of triglyceride clearance and insulin action, and has great potential to combat obesity, cardiovascular disease, and type 2 diabetes mellitus. We have reported in young adult mice that ACUTE injection of apolipoprotein A-IV(ApoA-IV): 1) elevates thermogenesis and uptake of fatty acid (FA) in BAT and 2) stimulates sympathetic neural activity (SNA) in BAT but reduces SNA in liver of chow-fed mice. However, its effect on lipid metabolism in adipose tissue and liver through alteration of SNA in old mice remains unknown. Chronic consumption of high-fat diet (HFD) suppresses ApoA-IV production normally induced by acute consumption of dietary lipids and attenuates SNA of BAT and thermogenesis. In this regard, we have preliminary evidence in young, HFD-fed mice that CHRONIC infusion of ApoA-IV: 1) elevates thermogenesis in BAT and beige adipose tissue (BeAT) and overall energy expenditure; 2) increases hepatic expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), implying restriction of hepatic lipogenesis; and 3) reduces hepatic and plasma lipid content, fat mass, and body weight gain. These findings suggest that chronic infusion of ApoA-IV alters lipid metabolism in BAT, BeAT and liver through neural or CEACAM1-mediated pathways. Because elderly humans and older rodents have a large decline in BAT activity, we theorize that the lower thermogenesis results in impaired lipid oxidation for energy combustion in BAT/BeAT, insufficient FA uptake into these adipose tissues, and elevated lipogenesis and lipid accumulation in the liver. Thus, we propose the innovative hypothesis that increased levels of ApoA-IV will act through sympathetic innervation to elevate lipid oxidation and uptake in BAT/BeAT and through CEACAM1-mediated reduction of lipogenesis in liver, subsequently reducing hepatic and plasma triglyceride (TG) in old, obese animals. This hypothesis will be tested using comprehensive, innovative, well-designed approaches. Aim 1 will investigate ApoA-IV’s role in sympathetic activation of BAT/BeAT to reverse age-attenuated thermogenesis. Aim 2 will investigate ApoA-IV’s effects on BAT/BeAT and hepatic lipid metabolism through neural or CEACAM1- mediated pathways to lower hepatic and plasma triglycerides. A major strength of this proposal is the interdisciplinary collaboration between Drs. Chunmin Lo (lipid metabolism & neurophysiology) and Haifei Shi (neuroendocrine & adipose biology) with support from Drs. Sonia Najjar (aging & CEACAM1-meidated insulin action), Darlene Berryman (aging & hormones) and Karen Coschigano (molecular biology & signaling pathways). As demonstrated by the strong preliminary data, these investigators have productively collaborated and will delineate the novel mechanism of ApoA-IV in downregulation of age-related obesity and plasma triglycerides, leading to treatments against this health problem in elderly humans.

项目摘要 衰老与肥胖、心血管疾病和2型糖尿病有关。激活褐色脂肪 人体内的组织（BAT）产热导致甘油三酯清除率和胰岛素作用的升高， 治疗肥胖、心血管疾病和2型糖尿病的巨大潜力。我们报道了 急性注射载脂蛋白A-IV（ApoA-IV）的年轻成年小鼠：1）提高产热和摄取 2）刺激BAT中的交感神经活动（SNA），但减少肝脏中的SNA。 喂食的老鼠但其对老年人脂肪组织和肝脏脂质代谢的影响可能是通过SNA的改变而实现的 老鼠仍然未知。长期食用高脂饮食（HFD）可正常抑制ApoA-IV的产生 诱导急性消耗膳食脂质和减弱SNA的BAT和产热。在这方面，委员会认为， 我们有初步证据表明，在年轻的HFD喂养的小鼠中，慢性输注ApoA-IV：1） BAT和米色脂肪组织（BeAT）中的产热和总体能量消耗; 2）增加肝脏 癌胚抗原相关细胞粘附分子1（CEACAM 1）的表达，这意味着 肝脏脂肪生成;和3）降低肝脏和血浆脂质含量、脂肪量和体重增加。这些 研究结果表明，ApoA-IV的慢性输注通过神经系统改变BAT、BeAT和肝脏中的脂质代谢， 或CEACAM 1介导的途径。因为老年人和老年啮齿动物的BAT下降幅度很大 活动，我们推测，较低的产热导致受损的脂质氧化的能量燃烧， BAT/BeAT，这些脂肪组织中FA摄取不足，以及脂肪生成和脂质蓄积增加， 肝脏因此，我们提出了一个创新的假设，即ApoA-IV水平的增加将通过 交感神经支配提高BAT/BeAT中的脂质氧化和摄取，并通过CEACAM 1介导 减少肝脏中的脂肪生成，随后降低老年肥胖者的肝脏和血浆甘油三酯（TG） 动物这一假设将使用全面的、创新的、精心设计的方法进行检验。目标1将 研究ApoA-IV在BAT/BeAT交感神经激活中逆转年龄衰减产热作用。目的 2将研究ApoA-IV通过神经或CEACAM 1 - 1对BAT/BeAT和肝脏脂质代谢的影响。 介导降低肝脏和血浆甘油三酯的途径。这项建议的一个主要优点是 罗春民博士（脂质代谢和神经生理学）和施海飞博士之间的跨学科合作 （神经内分泌和脂肪生物学），由Sonia Najjar博士（衰老和CEACAM 1-meidated胰岛素 行动），达琳贝里曼（衰老与激素）和卡伦Coschigano（分子生物学与信号 路径）。正如强有力的初步数据所证明的那样，这些调查人员进行了富有成效的合作。 并将阐明ApoA-IV在下调年龄相关性肥胖和血浆中的新机制。 甘油三酯，导致治疗老年人的这种健康问题。