Age-related neuronal regulation of thermogenesis and lipid metabolism

项目摘要 衰老与肥胖、心血管疾病和2型糖尿病有关。激活棕色脂肪 人体组织(BAT)产热导致甘油三酯清除和胰岛素作用的提高，并具有 与肥胖、心血管疾病和2型糖尿病作斗争的巨大潜力。我们已经在 急性注射载脂蛋白A-IV(ApoA-IV)的幼年小鼠：1)提高产热和摄取 和2)刺激蝙蝠的交感神经活动(SNA)，但降低肝脏的SNA 喂食食物的小鼠。但其通过改变SNA对老年人脂肪组织和肝脏脂代谢的影响 老鼠仍不为人所知。长期食用高脂饮食通常会抑制载脂蛋白A-IV的产生 急性消耗膳食脂肪所致，并可减弱蝙蝠的SNA和生热作用。在这方面， 我们有初步证据表明，在喂食高脂饲料的年轻小鼠中，长期输注载脂蛋白A-IV会升高 蝙蝠和米色脂肪组织的产热作用(BEAT)和总能量消耗；2)增加肝脏 癌胚抗原相关细胞黏附分子1(CEACAM1)的表达 肝脏脂肪生成；以及3)降低肝脏和血浆中的脂肪含量、脂肪质量和体重增加。这些 研究结果表明，长期输注载脂蛋白A-IV通过神经改变蝙蝠、心脏和肝脏的脂代谢 或CEACAM1介导的通路。因为年长的人类和年长的啮齿动物的蝙蝠数量大幅下降 活性，我们的理论是较低的生热作用导致能量燃烧的脂质氧化受损。 BAT/BEAT，这些脂肪组织对FA的摄取不足，并增加了脂肪生成和脂肪积累 肝脏。因此，我们提出了创新的假设，即增加载脂蛋白A-IV的水平将通过 交感神经支配促进BAT/BEAT的脂质氧化和摄取并通过CEACAM1介导 老年肥胖者肝脏脂肪生成减少，进而降低肝脏和血浆甘油三酯(TG) 动物。这一假设将使用全面、创新、精心设计的方法进行检验。目标1将 研究载脂蛋白A-IV在BAT/BAT交感神经激活逆转年龄衰减性产热中的作用。目标 2将通过神经或CEACAM1研究ApoA-IV对BAT/BEAT和肝脂代谢的影响 调节降低肝脏和血浆甘油三酯的途径。这项提议的一个主要优点是 罗春民博士(脂代谢与神经生理学)与史海飞博士的跨学科合作 (神经内分泌和脂肪生物学)由Sonia Najjar博士(衰老和CEACAM1-合并胰岛素)支持 行动)，达琳·贝里曼(衰老与荷尔蒙)和卡伦·科什加诺(分子生物学与信号传递 路径)。正如强有力的初步数据所表明的那样，这些调查人员进行了卓有成效的合作 并将阐明载脂蛋白A-IV下调年龄相关性肥胖和血浆的新机制 甘油三酯，导致治疗这一老年人的健康问题。

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.