Glucagon signaling in metabolic homeostasis

代谢稳态中的胰高血糖素信号传导

• 批准号: 10261596
• 负责人: Mehboob A Hussain
• 金额: $ 30.71万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261596
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adult; Binding; Biological Models; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Diabetes Mellitus; Disease; Ensure; Exhibits; Fasting; Fatty Liver; Feeding behaviors; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Genetic Transcription; Glucagon; Glucagon Receptor; Glucose; Glucose Clamp; Glucose Intolerance; Glycogen; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Hepatic; Hepatocyte; High Fat Diet; Homeostasis; Hormonal; Hormones; Hyperinsulinism; Impairment; Individual; Insulin; Insulin Resistance; Insulin Signaling Pathway; Knowledge; Ligand Binding; Lipids; Liver; Measurement; Metabolic; Metabolism; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Organ; Outcome Study; Pathway interactions; Phospholipase C; Protein Biosynthesis; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; RAS Superfamily Proteins; Regulation; Role; Secure; Signal Pathway; Signal Transduction; Structure; Techniques; Testing; Time; Tissues; Tracer; Virus; Whole Organism; arm; base; blood glucose regulation; diet-induced obesity; equilibration disorder; feeding; flexibility; glucose production; hyperglucagonemia; impaired glucose tolerance; improved; inositol 3-phosphate; insight; insulin signaling; knock-down; lipid biosynthesis; liver metabolism; metabolomics; mouse model; new therapeutic target; overexpression; programs; receptor; response; restoration

A hallmark of the bi-hormonal disease diabetes mellitus is a disturbed balance between the gluco- regulatory hormones insulin and glucagon. The liver is the principal organ where the metabolic actions of insulin and glucagon action are borne out. Insulin is the main hormone orchestrating and signaling during the anabolic (fed) state, while glucagon orchestrates a catabolic (fasting) metabolic state ensuring metabolic homeostasis and survival. The transition from the fasting state to the rapid supply of nutrients during a meal (feeding) poses a particular challenge to the liver - whereby insulin action regulates the rapid shift from a catabolic to an anabolic state including a switch from hepatic glucose production to glycogen storage, lipid and protein synthesis. While much is understood about the metabolic effects and signaling pathways of insulin acting via its receptor on hepatocytes, the molecular components of glucagon signaling in the liver are only beginning to be understood. The main signaling pathways activated upon glucagon binding to its receptor in the liver are the phospholipase C (PLC) -inositol-3-phosphate (IP3) pathway and the cyclic AMP (cAMP) pathway. The latter bifurcates into the cAMP – protein kinase A (PKA) pathway and the cAMP-EPAC (exchange protein activated by cAMP) pathway. EPAC2C (a guanine nucleotide exchange factor) is an isoform of EPAC2 that is uniquely expressed only in the liver. Importantly, homeostatic and metabolic role of EPAC2C signaling and its downstream effector Rap1 (Ras-proximate-1 or Ras-related protein 1) in the liver are poorly understood. Surprisingly, liver EPAC2C knockdown results in a disturbed transition from fasting to feeding accompanied by glucose intolerance, insulin resistance, hyperinsulinemia and mild hyperglucagonemia – changes reminiscent of type 2 diabetes mellitus. Based on these observations, we hypothesize that during fasting the hormone glucagon - via EPAC2C-Rap1 signaling - primes the liver for subsequent insulin action in response to feeding and that EPAC2C-Rap1 is an important signaling component to secure liver metabolic flexibility and metabolic homeostasis. Building on these observations, we also find virus transduced over-expression of a constitutively active EPAC2C isoform in the liver ameliorates glucose homeostasis in diet-induced obese mice. The present proposal aims to extend our exciting findings to further elucidate liver EPAC2C-Rap1 signaling in metabolic homeostasis. Our proposed studies will expand our understanding of glucagon action in the liver and also identify a novel therapeutic target for treating diabetes mellitus.

双激素疾病糖尿病的一个标志是血糖与血糖之间的平衡被破坏。 调节激素胰岛素和胰高血糖素肝脏是发挥胰岛素和胰高血糖素代谢作用的主要器官，胰岛素是合成代谢（进食）状态下的主要激素协调和信号传导，而胰高血糖素则协调分解代谢（空腹）代谢。确保代谢稳态和生存的状态从禁食状态到进餐（进食）期间快速供应营养物质的转变对肝脏构成了特殊的挑战 - 因此胰岛素的作用调节着从禁食状态到快速供应营养的状态。分解代谢状态到合成代谢状态，包括从肝葡萄糖生成转变为糖原储存、脂质和蛋白质合成。肝脏中胰高血糖素与其受体结合后激活的主要信号传导途径才刚刚开始被了解。 磷脂酶 C (PLC) -肌醇-3-磷酸 (IP3) 途径和环 AMP (cAMP) 途径，后者分为 cAMP - 蛋白激酶 A (PKA) 途径和 cAMP-EPAC（由 cAMP 激活的交换蛋白）。 EPAC2C（鸟嘌呤核苷酸交换因子）是 EPAC2 的一种亚型，仅在肝脏中表达，重要的是具有稳态和代谢作用。人们对肝脏中的 EPAC2C 信号传导及其下游效应器 Rap1（Ras-proximate-1 或 Ras 相关蛋白 1）知之甚少，令人惊讶的是，肝脏 EPAC2C 敲低会导致从禁食到进食的过渡受到干扰，并伴有葡萄糖不耐受、胰岛素抵抗、高胰岛素血症。和轻度高胰高血糖素血症——这种变化让人想起 2 型糖尿病。根据这些观察，我们在禁食胰高血糖素期间发现了这一点。 EPAC2C-Rap1 信号传导 - 为肝脏随后响应进食而发挥胰岛素作用做好准备，并且 EPAC2C-Rap1 是 确保肝脏代谢灵活性和代谢稳态的重要信号成分。 基于这些观察，我们还发现病毒转导的肝脏中持续活跃的 EPAC2C 同种型的过度表达可改善饮食诱导的肥胖小鼠的葡萄糖稳态。 本提案旨在扩展我们令人兴奋的发现，以进一步阐明代谢稳态中的肝脏 EPAC2C-Rap1 信号传导。我们提出的研究将扩大我们对肝脏中胰高血糖素作用的理解，并确定治疗糖尿病的新治疗靶点。