Role of HCAR1 in glucose homeostasis

HCAR1 在葡萄糖稳态中的作用

• 批准号: 10046030
• 负责人: YOUNG-HWAN JO
• 金额: $ 16.16万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046030
• 关键词: Acids; Address; Adipocytes; Animal Model; Animals; Antibodies; Bilateral; Blood; Blood Glucose; Brown Fat; CRISPR/Cas technology; Cell model; Coupled; Cytomegalovirus; Data; Development; Diabetes Mellitus; Diet; Dissociation; Energy Metabolism; Exhibits; Fatty acid glycerol esters; Female; GLUT4 gene; Genes; Glucose; Goals; Health; High Fat Diet; Human; Hyperglycemia; Impairment; Individual; Internal Ribosome Entry Site; Lead; Lipolysis; Metabolic; Metabolic dysfunction; Mitochondria; Modeling; Mus; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Organ; Pharmaceutical Preparations; Phenotype; Physiological; Pilot Projects; Play; Production; Proteins; PubMed; Rattus; Receptors, Adrenergic, beta-3; Respiration; Rodent; Role; Signal Transduction; Site; System; Testing; Thermogenesis; Triglycerides; Virus; autocrine; blood glucose regulation; data modeling; feeding; glucose disposal; glucose metabolism; glucose uptake; human study; improved; knock-down; lactate dehydrogenase A; late-onset retinal degeneration; loss of function; male; malignant breast neoplasm; new therapeutic target; optogenetics; overexpression; paracrine; programs; receptor; sex; small molecule; virtual

The hydrocarboxylic acid receptor 1 (HCAR1) acts as a receptor for L-lactate and is coupled to Gi/o proteins. These receptors are found in both rodents and humans and are primarily expressed in white and brown adipocytes. It has been described that activation of HCAR1 by lactate inhibits lipolysis in adipocytes of mice, rats, as well as humans. According to the IDG Development Level Summary, these are targets about which virtually nothing is known. They do not have known drug or small molecule activities and satisfy the following criteria: Pubmed score (32.51), Gene RIFs (12), and antibodies (294). This receptor is also known to be associated with breast cancer and late-onset retinal degeneration. In this pilot studies, we will produce preliminary data to address the lack of cellular and animal model data associated with HCAR1. We will specifically test the hypothesis that HCAR1 in mouse brown adipose tissue plays a critical role in the control of glucose homeostasis in diet-induced obese mice. Interscapular brown adipose tissue (BAT) is a principal site of nonshivering thermogenesis, which results from the uncoupling of mitochondrial oxidative respiration from ATP production to generate heat. Activation of BAT promotes energy expenditure by generating heat and thus, protects against obesity and diabetes in humans. Additionally, BAT possesses great capacity for glucose uptake and metabolism. However, it appears that glucose does not contribute to BAT thermogenesis. Only a small portion of glucose taken up is used for thermogenesis in rodents. Interestingly, lactate production accounts for a large proportion of glucose uptake by BAT. We recently show that optogenetic stimulation of sympathetic nerves exclusively innervating BAT increases expression of the lactate dehydrogenase A (Ldha) gene. Importantly, lactate production appears to be required for glucose uptake by BAT. A recent human study further demonstrates substantial glucose uptake and lactate release from BAT during warm conditions, suggesting that there is an autocrine and/or paracrine release of lactate from BAT. As BAT is a primary organ that expresses lactate receptors, it is highly plausible that HCAR1 in BAT may detect, sense, and respond to changes in circulating and/ or local lactate levels and that activation of HCAR1 in BAT may control glucose uptake and consequently blood glucose levels. Our on-going studies have revealed that high-fat feeding differentially regulates HCAR1 expression in female and male mice. Sex-dependent expression of HCAR1 in BAT appears to contribute to the development of hyperglycemia in male obese animals. In fact, male C57BL/6J mice fed a high-fat diet (HFD) at thermoneutrality show diet-induced obesity (DIO) and hyperglycemia with a significant reduction in HCAR1 expression in BAT. In contrast, female C57BL/6J mice on high-fat feeding do not develop hyperglycemia. These mice exhibit increased HCAR1 expression in BAT. Our preliminary results lead us to hypothesize that HCAR1 in BAT plays a key role in regulating whole-body glucose homeostasis. Aim 1. To determine whether impaired HCAR1 signaling in BAT contributes to the development of hyperglycemia in DIO C57BL/6J mice. As glucose uptake and metabolism in BAT are significantly impaired in individuals with obesity and type 2 diabetes, our findings will improve our understanding of the effects of lactate signaling through HCAR1 on whole-body glucose disposal and lead to the discovery of new therapeutic targets for better treatment of type 2 diabetes. Additionally, data collected by this pilot project will enhance the overall goal of the IDG Program as this project has high potential to impact human health by identifying animal model phenotypes for this understudied HCAR1.

氢羧酸受体1（HCAR1）充当L-乳酸的受体，IS 耦合到GI/O蛋白。这些受体都在啮齿动物和人类中都发现，并且是 主要用白色和棕色脂肪细胞表达。已经描述了激活 乳酸的HCAR1抑制小鼠，大鼠和人类脂肪细胞中的脂解。根据 IDG开发级别的摘要，这些是几乎什么都不知道的目标。 他们没有已知的药物或小分子活性，并且满足以下标准： PubMed评分（32.51），基因RIFS（12）和抗体（294）。该受体也已知是 与乳腺癌和晚期视网膜变性有关。在这项试验研究中，我们将 产生初步数据，以解决与缺乏相关的细胞和动物模型数据 HCAR1。我们将特别检验小鼠棕色脂肪组织中的HCAR1的假设 在饮食引起的肥胖小鼠中控制葡萄糖稳态的控制中起着至关重要的作用。 Xapular Brown脂肪组织（BAT）是非求职者的主要部位 热发生，这是由于线粒体氧化呼吸的解偶联而产生的 ATP生产以产生热量。蝙蝠的激活通过产生促进能量支出 加热，因此可以预防人类的肥胖和糖尿病。此外，蝙蝠拥有 葡萄糖摄取和代谢的强大能力。但是，似乎葡萄糖没有 有助于蝙蝠的热发生。仅使用一小部分葡萄糖。 啮齿动物中的热发生。有趣的是，乳酸生产占很大一部分 蝙蝠吸收葡萄糖。我们最近表明，同情神经的光遗传学刺激 完全支配BAT会增加乳酸脱氢酶A（LDHA）基因的表达。 重要的是，蝙蝠的葡萄糖摄取似乎需要乳酸产生。最近 人类研究进一步证明了大量的葡萄糖摄取和乳酸从蝙蝠释放 在温暖的条件下，表明乳酸有自分泌和/或旁分泌释放 从蝙蝠。由于蝙蝠是表达乳酸受体的主要器官，因此高度合理 蝙蝠中的HCAR1可能检测，感知和响应循环和/或局部乳酸的变化 水平和蝙蝠中HCAR1的激活可能控制葡萄糖摄取，因此血液 葡萄糖水平。 我们正在进行的研究表明，高脂喂养差异化调节HCAR1 在雌性和雄性小鼠中的表达。蝙蝠中HCAR1的性别依赖性表达似乎 有助于雄性肥胖动物中高血糖的发展。实际上，男性C57BL/6J 喂养高脂饮食（HFD）的小鼠表现出饮食诱发的肥胖症（DIO）和 高血糖，蝙蝠中HCAR1表达显着降低。相反，女性 高脂进食的C57BL/6J小鼠不会患高血糖。这些鼠标表现出增加 蝙蝠中的HCAR1表达。我们的初步结果使我们假设HCAR1在BAT中 在调节全身葡萄糖稳态方面起着关键作用。 目的1。确定蝙蝠中的HCAR1信号受损是否有助于开发 DIO C57BL/6J小鼠中的高血糖。 由于蝙蝠中的葡萄糖摄取和代谢的摄取和代谢，患有 肥胖和2型糖尿病，我们的发现将提高我们对乳酸作用的理解 通过HCAR1发出全身葡萄糖处置的信号，并导致发现新的 治疗靶标可更好地治疗2型糖尿病。此外，由此收集的数据 试点项目将增强IDG计划的整体目标，因为该项目具有很高的潜力 通过确定该研究的HCAR1的动物模型表型来影响人类健康。