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-乳酸受体，并且是 与 Gi/o 蛋白偶联。这些受体在啮齿动物和人类中都有发现， 主要表达于白色和棕色脂肪细胞。据描述，激活 乳酸 HCAR1 可抑制小鼠、大鼠以及人类脂肪细胞的脂肪分解。根据 根据 IDG 发展水平摘要，这些目标几乎一无所知。 它们不具有已知的药物或小分子活性，并满足以下标准： Pubmed 评分 (32.51)、基因 RIF (12) 和抗体 (294)。该受体还被认为是 与乳腺癌和迟发性视网膜变性有关。在这项试点研究中，我们将 产生初步数据以解决与相关的细胞和动物模型数据的缺乏 HCAR1。我们将专门检验小鼠棕色脂肪组织中 HCAR1 的假设 在饮食诱导的肥胖小鼠的葡萄糖稳态控制中发挥着关键作用。 肩胛间棕色脂肪组织（BAT）是不颤抖的主要部位 产热作用，是由线粒体氧化呼吸解偶联引起的 产生ATP以产生热量。 BAT 的激活通过产生 热量，从而预防人类肥胖和糖尿病。此外，BAT还拥有 葡萄糖摄取和代谢能力强。然而，葡萄糖似乎并没有 有助于 BAT 生热作用。所摄取的葡萄糖只有一小部分被用于 啮齿动物的产热作用。有趣的是，乳酸产量占了很大比例。 BAT 摄取葡萄糖。我们最近表明，交感神经的光遗传学刺激 专门支配 BAT 会增加乳酸脱氢酶 A (Ldha) 基因的表达。 重要的是，BAT 吸收葡萄糖似乎需要乳酸的产生。最近的一个 人体研究进一步证明 BAT 能大量摄取葡萄糖并释放乳酸 在温暖的条件下，表明存在乳酸的自分泌和/或旁分泌释放 来自英美烟草公司。由于 BAT 是表达乳酸受体的主要器官，因此很有可能 BAT 中的 HCAR1 可以检测、感知和响应循环和/或局部乳酸的变化 BAT 中 HCAR1 的激活可以控制葡萄糖的摄取，从而控制血液 血糖水平。 我们正在进行的研究表明，高脂肪喂养对 HCAR1 有差异性调节 在雌性和雄性小鼠中的表达。 BAT 中 HCAR1 的性别依赖性表达似乎 导致雄性肥胖动物发生高血糖。其实男C57BL/6J 在热中性条件下喂食高脂肪饮食 (HFD) 的小鼠表现出饮食诱导的肥胖 (DIO) 和 高血糖导致 BAT 中 HCAR1 表达显着降低。相比之下，女性 高脂肪喂养的 C57BL/6J 小鼠不会出现高血糖。这些小鼠表现出增加 BAT 中 HCAR1 的表达。我们的初步结果使我们假设 BAT 中的 HCAR1 在调节全身葡萄糖稳态中起着关键作用。 目标 1. 确定 BAT 中 HCAR1 信号传导受损是否有助于发育 DIO C57BL/6J 小鼠高血糖的研究。 由于 BAT 患者的葡萄糖摄取和代谢显着受损 肥胖和 2 型糖尿病，我们的研究结果将提高我们对乳酸影响的理解 通过 HCAR1 发出关于全身葡萄糖处理的信号，并导致新的发现 更好地治疗2型糖尿病的治疗目标。此外，本次收集的数据 试点项目将增强 IDG 计划的总体目标，因为该项目具有很高的潜力 通过识别该尚未充分研究的 HCAR1 的动物模型表型来影响人类健康。