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

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 Building on a large body of published preliminary data, as well as unpublished studies in cells and in mice, this proposal will test the central hypothesis that Lac-Phe is a tightly regulated, lactate-derived signaling metabolite that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