Role of a lactate-derived signaling metabolite in tissue crosstalk and energy balance

乳酸衍生信号代谢物在组织串扰和能量平衡中的作用

• 批准号: 10714022
• 负责人: Jonathan Z Long
• 金额: $ 52.43万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714022
• 关键词: Ablation; Anabolism; Biochemical; Biochemical Pathway; Biochemistry; Body Weight; Cell Surface Proteins; Cell surface; Cells; Circulation; Complement; Data; Data Set; Eating; Energy Metabolism; Enzymes; Excretory function; Exercise; Exhibits; Foundations; Future; Homeostasis; Kidney; Knockout Mice; Knowledge; Ligands; Liquid substance; LoxP-flanked allele; Macrophage; Mediating; Metabolic; Metabolic Diseases; Metabolism; Molecular; Molecular Target; Mus; Mutagenesis; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathway interactions; Phenotype; Physiological; Physiology; Population; Post-Translational Protein Processing; Production; Publishing; Reagent; Regulation; Reporting; Role; Signal Transduction; Signaling Molecule; Source; Testing; Therapeutic; Tissues; Transfection; Work; candidate identification; cell type; energy balance; feeding; functional group; human subject; in vitro activity; in vivo; insight; interest; metabolomics; new therapeutic target; obesity treatment; pharmacologic; receptor; reconstitution; screening; solute

Project summary The role of lactate in energy metabolism has been of considerable biochemical and physiologic interest. Beyond its classical description as glycolytic end-product, lactate’s more recent emerging roles include inter-organ metabolic fuel, receptor ligand, and protein post-translational modification. Given that some of these roles have only been identified, or further expanded upon, in the past few years suggests that we are still in the early stages of understanding the diversity of lactate functions in energy homeostasis. We have recently reported that lactate metabolism into a downstream metabolite, Lac-Phe, generates a blood-borne signaling molecule that mediates tissue crosstalk and suppresses feeding and obesity (Li et al., Nature 2022). Ablation of Lac-Phe biosynthesis in mice increases food intake and obesity after exercise, demonstrating the physiologic relevance of this pathway. Our data uncover an unexpected and underappreciated aspect of lactate – as a precursor for a circulating lactate-derived signaling metabolite – in energy homeostasis. Because of this fundamentally new insight, here in this proposal we focus entirely on additional biochemical and physiologic studies of Lac-Phe and this downstream pathway of lactate metabolism. Building on a large body of published preliminary data, as well as unpublished studies in cells and in mice, this proposal will test the central hypothesis that Lac-Phe is a tightly regulated, lactate-derived signaling metabolite that engages specific cell surface molecules to regulate energy balance. In Aim 1, we will determine the specific cell populations that produce Lac-Phe in vivo and their contribution to whole-body energy balance. This Aim is enabled by our newly generated conditional, Cndp2 floxed allele which allows for cell type-specific ablation of Lac-Phe biosynthesis. In Aim 2, we will determine the role of a kidney solute carrier in the downstream metabolism of Lac-Phe. Preliminary studies demonstrate this solute carrier exhibits robust Lac-Phe transport activity in cells. Finally in Aim 3, we will determine the structural features and downstream molecular targets that mediate Lac-Phe’s effects on food intake. We have identified candidate cell surface molecules that are engaged by Lac-Phe. Successful completion of this proposal will provide a detailed and molecular understanding of Lac-Phe biochemistry and physiology, thereby establishing a scientific foundation for developing new therapeutics that target the Lac-Phe pathway for obesity, type 2 diabetes, and metabolic diseases.

项目概要 乳酸在能量代谢中的作用引起了广泛的生化和生理学兴趣。 乳酸的经典描述是糖酵解终产物，最近出现的作用包括器官间作用 鉴于其中一些作用具有代谢燃料、受体配体和蛋白质翻译后修饰。 过去几年才被确定或进一步扩展，这表明我们仍处于早期阶段 了解乳酸在能量稳态中功能的多样性我们最近报道了乳酸。 代谢为下游代谢物 Lac-Phe，产生血源性信号分子，介导 组织串扰并抑制进食和肥胖（Li 等人，Nature 2022）。 在小鼠中，运动后食物摄入量增加，肥胖增加，证明了这一点的生理相关性 我们的数据揭示了乳酸的一个意想不到且未被充分重视的方面——作为一种前体。 循环乳酸衍生信号代谢物——在能量稳态中的作用是全新的。 洞察力，在此提案中，我们完全专注于 Lac-Phe 和 这一乳酸代谢的下游途径也建立在大量已发表的初步数据的基础上。 作为未发表的细胞和小鼠研究，该提案将检验 Lac-Phe 是一种紧密结合的中心假设。 受调节的乳酸衍生信号代谢物，与特定细胞表面分子结合来调节能量 在目标 1 中，我们将确定体内产生 Lac-Phe 的特定细胞群及其数量。 对全身能量平衡的贡献是通过我们新生成的条件 Cndp2 实现的。 floxed 等位基因允许 Lac-Phe 生物合成的细胞类型特异性消融。在目标 2 中，我们将确定 初步研究证明了肾脏溶质载体在 Lac-Phe 下游代谢中的作用。 溶质载体在细胞中表现出强大的 Lac-Phe 转运活性 最后，在目标 3 中，我们将确定其结构。 我们已经确定了介导 Lac-Phe 对食物摄入影响的特征和下游分子靶标。 Lac-Phe 参与的候选细胞表面分子将成功完成该提案。 提供对 Lac-Phe 生物化学和生理学的详细分子理解，从而建立 科学基金会开发针对 2 型肥胖 Lac-Phe 途径的新疗法 糖尿病、代谢性疾病。