Gut-derived N-lactoyl phenylalanine regulates energy balance

Project Summary/Abstract The objective of this proposal is to determine the molecular mechanisms by which Lac-Phe, a lactate-derived signaling metabolite, regulate energy balance. Lac-Phe is synthesized from lactate and phenylalanine via CNDP2, and was initially discovered as an exercise-inducible metabolite that suppresses food intake. I recently identified metformin, a widely-used anti-diabetic medicine, as a strong pharmacological inducer of Lac-Phe biosynthesis in both humans and mice (Xiao et al., Nature Metabolism, 2024). Cndp2-KO mice, which are genetically deficient in Lac-Phe biosynthesis, show resistance to the anti-obesity effects of metformin. Additionally, statistical mediation analysis provides evidence for Lac-Phe as a mediator of the metformin- associated weight loss in humans. These preliminary results establish the important role of Lac-Phe in regulation of energy balance. However, critical knowledge gaps remain regarding the locations of Lac-Phe production in vivo and the mechanisms through which Lac-Phe reduces food intake. In preliminary results, I found that gut- specific Cndp2-KO mice phenocopy the global Cndp2-KO mice in terms of both basal and metformin-inducible Lac-Phe production. These results suggest the gut as the primary source of Lac-Phe biosynthesis in vivo. Enteroendocrine cells scatter along the gut and secretes hormones to regulate metabolism. Vagal sensory neurons, which innervate the gut, send signals to the nucleus of the solitary tract (NTS). Considering the gut’s crucial role in feeding control, my central hypothesis is that gut-derived Lac-Phe targets NTS neurons to regulate energy balance. I will test the hypothesis with three specific aims: 1) Determine the contribution of gut-derived Lac-Phe to the anti-obesity effects of metformin and exercise; 2) Determine the crosstalk between Lac-Phe and GLP-1 through a fatty acid receptor, FFAR2; 3) Determine the role of NTS neurons as downstream effectors of Lac-Phe’s effect on food intake. I will pursue these aims using a combination of innovative and interdisciplinary approaches spanning physiology, endocrinology, and neurobiology to reveal the neuronal basis of the anorexigenic effects of Lac-Phe. This proposal is significant and impactful because it will determine the mechanisms by which a lactate-derived metabolite affects energy balance. Successful completion of the proposal will functionally expand our understanding of lactate metabolism in energy homeostasis, and reveal a Lac-Phe-mediated gut-to-brain communication pathway. More importantly, this research provide new opportunities for developing treatments, a similar comparison of Semaglutide and native GLP-1 to combat obesity, diabetes, and other metabolic disorders. My career goal is to become an independent investigator to study the tissue crosstalk in regulation of metabolic homeostasis and energy balance. This K99/R00 award presents an outstanding opportunity: the scientific and career goals will be fulfilled by having a multidisciplinary mentor and advisory team, which possesses extensive experience in areas related to the proposed research and in mentoring trainees towards independence.