2. Academic Validation
  3. Lactate homeostasis is maintained through regulation of glycolysis and lipolysis

Lactate homeostasis is maintained through regulation of glycolysis and lipolysis

  • Cell Metab. 2025 Mar 4;37(3):758-771.e8. doi: 10.1016/j.cmet.2024.12.009.
Won Dong Lee 1,  Daniel R Weilandt 1,  Lingfan Liang 1,  Michael R MacArthur 1,  Natasha Jaiswal 2,  Olivia Ong 2,  Charlotte G Mann 3,  Qingwei Chu 4,  Craig J Hunter 1,  Rolf-Peter Ryseck 1,  Wenyun Lu 1,  Anna M Oschmann 1,  Alexis J Cowan 5,  Tara A TeSlaa 6,  Caroline R Bartman 7,  Cholsoon Jang 8,  Joseph A Baur 4,  Paul M Titchenell 4,  Joshua D Rabinowitz 9
Affiliations

Affiliations

  • 1 Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA.
  • 2 Department of Health and Kinesiology, Purdue University, West Lafayette, IN, USA.
  • 3 Department of Health Sciences and Technology, ETH Zürich, Schwerzenbach, Switzerland.
  • 4 Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • 6 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
  • 7 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 8 Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
  • 9 Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA. Electronic address: joshr@princeton.edu.
PMID: 39889702 DOI: 10.1016/j.cmet.2024.12.009
Abstract

Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, Insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.

Keywords

HCAR1 signaling; TCA cycle; competitive catabolism; diabetes mellitus; insulin resistance; insulin signaling; lactate metabolism; metabolic flux; metabolic homeostasis; quantitative modeling.

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