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.

羟基羧酸受体1（HCAR 1）作为L-乳酸的受体， 与Gi/o蛋白偶联。这些受体在啮齿动物和人类中都有发现， 主要在白色和棕色脂肪细胞中表达。已经描述了， HCAR 1通过乳酸盐抑制小鼠、大鼠以及人的脂肪细胞中的脂解。根据 根据IDG的发展水平摘要，这些目标实际上是一无所知的。 它们不具有已知的药物或小分子活性，并符合以下标准： Pubmed评分（32.51）、基因RIF（12）和抗体（294）。这种受体也被认为是 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，以解决缺乏细胞和动物模型数据， HCAR 1。我们将专门检验小鼠棕色脂肪组织中HCAR 1 在控制饮食诱导的肥胖小鼠的葡萄糖稳态中起关键作用。 肩胛间棕色脂肪组织（BAT）是非寒战性的主要部位， 产热，这是由于线粒体氧化呼吸的解偶联， ATP产生热量。BAT的激活通过产生 加热，从而防止人类肥胖和糖尿病。此外，BAT拥有 葡萄糖吸收和代谢能力强。然而，葡萄糖似乎并不 有助于BAT产热。只有一小部分被吸收的葡萄糖用于 啮齿类动物的产热作用有趣的是，乳酸盐的产生占了很大比例， BAT的葡萄糖摄取。我们最近发现交感神经的光遗传学刺激 仅神经支配BAT增加乳酸脱氢酶A（Ldha）基因的表达。 重要的是，乳酸盐的产生似乎是BAT摄取葡萄糖所必需的。最近的一 人体研究进一步证实了BAT的大量葡萄糖摄取和乳酸盐释放 在温暖的条件下，提示存在乳酸的自分泌和/或旁分泌释放 从BAT由于BAT是表达乳酸盐受体的主要器官， BAT中的HCAR 1可以检测、感知和响应循环和/或局部乳酸的变化 BAT中HCAR 1的水平和激活可以控制葡萄糖摄取， 葡萄糖水平 我们正在进行的研究表明，高脂肪喂养差异调节HCAR 1 在雌性和雄性小鼠中表达。BAT中HCAR 1的性别依赖性表达似乎 导致雄性肥胖动物中高血糖症的发展。事实上，雄性C57BL/6J 在热中性下喂食高脂饮食（HFD）的小鼠显示饮食诱导的肥胖（DIO）， BAT中HCAR 1表达显著降低。相比之下，女性 高脂喂养的C57 BL/6J小鼠不发生高血糖症。这些小鼠表现出增加 BAT中的HCAR 1表达。我们的初步结果使我们假设BAT中的HCAR 1 在调节全身葡萄糖稳态中起关键作用。 目标1.为了确定BAT中受损的HCAR 1信号传导是否有助于发展 DIO C57 BL/6J小鼠的高血糖症。 由于BAT中的葡萄糖摄取和代谢在患有 肥胖和2型糖尿病，我们的研究结果将提高我们对乳酸的影响的理解 通过HCAR 1对全身葡萄糖处置的信号传导，并导致发现新的 2型糖尿病的治疗目标。此外，数据收集 试点项目将提高IDG计划的总体目标，因为该项目具有很高的潜力 通过鉴定这种未充分研究的HCAR 1的动物模型表型来影响人类健康。