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

项目总结 乳酸在能量代谢中的作用一直是生物化学和生理学研究的热点。超越 乳酸盐的经典描述是糖酵解的最终产物，它最近出现的作用包括器官间 代谢燃料、受体配体和蛋白质翻译后修饰。鉴于其中一些角色具有 只是在过去几年中才被确定或进一步扩展，这表明我们仍处于早期阶段 了解乳酸在能量平衡中功能的多样性。我们最近报道了乳酸盐 代谢成下游代谢物Lac-Phe会产生一种血液传播的信号分子， 组织串扰并抑制摄食和肥胖(Li等人，《自然》2022)。乳酸-苯丙氨酸生物合成的消融 增加运动后小鼠的食物摄入量和肥胖，证明了这与生理上的相关性 路径。我们的数据揭示了乳酸的一个意想不到和被低估的方面--作为一种 循环中乳酸衍生的信号代谢物--能量平衡。因为这从根本上说是新的 洞察，在这项建议中，我们完全专注于对Lac-Phe和Lac-Phe的额外生化和生理研究 乳酸代谢的这一下游途径。还建立在大量已公布的初步数据基础上 作为尚未发表的细胞和小鼠研究，这一提议将检验Lac-Phe是一种紧密的 受调节的、乳酸衍生的信号代谢物，与特定的细胞表面分子结合来调节能量 平衡。在目标1中，我们将确定体内产生Lac-Phe的特定细胞群体及其 对全身能量平衡的贡献。这个目标是由我们新生成的条件Cndp2实现的 允许特定细胞类型消融Lac-Phe生物合成的花等位基因。在目标2中，我们将确定 肾脏溶质载体在Lac-Phe下游代谢中的作用。初步研究证明了这一点 溶质载体在细胞内表现出很强的Lac-Phe转运活性。最后在目标3中，我们将确定结构 调节Lac-Phe对食物摄入量影响的特征和下游分子靶点。我们已经确定了 Lac-Phe参与的候选细胞表面分子。成功完成这项提案将 提供对Lac-Phe生物化学和生理学的详细和分子理解，从而建立 开发针对Lac-Phe途径治疗2型肥胖症的新疗法的科学基础 糖尿病和代谢性疾病。

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 Building on a large body of published preliminary data, as well as unpublished studies in cells and in mice, this proposal will test the central hypothesis that Lac-Phe is a tightly regulated, lactate-derived signaling metabolite that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.