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.

项目概要 衰老与肥胖、心血管疾病和 2 型糖尿病有关。 人体组织（BAT）生热作用导致甘油三酯清除率和胰岛素作用升高，并且具有 我们在 2017 年的报告中报道了对抗肥胖、心血管疾病和 2 型糖尿病的巨大潜力。 年轻成年小鼠急性注射载脂蛋白 A-IV (ApoA-IV)：1) 提高产热和吸收 BAT 中的脂肪酸 (FA) 和 2) 刺激 BAT 中的交感神经活动 (SNA)，但减少肝脏中的 SNA 然而，它通过改变老年小鼠的 SNA 对脂肪组织和肝脏的脂质代谢产生影响。 长期食用高脂肪饮食 (HFD) 是否会抑制 ApoA-IV 的正常产生尚不清楚。 饮食中脂质的急剧消耗会导致 BAT 的 SNA 和产热作用减弱。 我们在年轻、高脂饮食喂养的小鼠中获得了初步证据表明，长期输注 ApoA-IV：1) 会升高 BAT 和米色脂肪组织 (BeAT) 的生热作用以及总体能量消耗 2) 增加肝脏； 癌胚抗原相关细胞粘附分子 1 (CEACAM1) 的表达，意味着限制 肝脏脂肪生成；3) 降低肝脏和血浆脂质含量、脂肪量和体重增加。 研究结果表明，长期输注 ApoA-IV 通过神经网络改变 BAT、BeAT 和肝脏的脂质代谢 或 CEACAM1 介导的途径，因为老年人和老年啮齿动物的 BAT 大幅下降。 活性，我们推测较低的生热作用会导致能量燃烧的脂质氧化受损 BAT/BeAT，这些脂肪组织中的 FA 摄取不足，以及脂肪生成和脂质积累增加 因此，我们提出了一个创新的假设：ApoA-IV 水平的增加将通过肝脏发挥作用。 交感神经支配通过 CEACAM1 介导提高 BAT/BeAT 中的脂质氧化和摄取 减少肝脏的脂肪生成，从而降低老年肥胖者的肝脏和血浆甘油三酯 (TG) 该假设将使用全面、创新、精心设计的方法进行测试。 研究 ApoA-IV 在 BAT/BeAT 交感神经激活中的作用，以逆转年龄减弱的生热作用。 2将通过神经或CEACAM1-研究ApoA-IV对BAT/BeAT和肝脏脂质代谢的影响 降低肝脏和血浆甘油三酯的介导途径该提议的主要优点是 Chunmin Lo 博士（脂质代谢和神经生理学）和 Haifei Shi 之间的跨学科合作 （神经内分泌和脂肪生物学）在 Sonia Najjar 博士（衰老和 CEACAM1 介导的胰岛素）的支持下 行动）、Darlene Berryman（衰老与激素）和 Karen Coschigano（分子生物学与信号传导） 正如强有力的初步数据所证明的那样，这些研究人员进行了富有成效的合作。 并将阐明 ApoA-IV 下调年龄相关性肥胖和血浆的新机制 甘油三酯，导致针对老年人这一健康问题的治疗方法。