Is lactate a driver of skin burn-induced adipose browning?

Letter to the EditorTranslational PhysiologyIs lactate a driver of skin burn-induced adipose browning?Jens Lund, Valdemar Brimnes Ingemann Johansen, Christoffer Clemmensen, and Zachary Gerhart-HinesJens LundNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark, Valdemar Brimnes Ingemann JohansenNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark, Christoffer ClemmensenNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark, and Zachary Gerhart-HinesNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DenmarkPublished Online:09 Oct 2023https://doi.org/10.1152/ajpendo.00251.2023MoreSectionsPDF (258 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat to the editor: Browning of white fat following burn injuries is a well-known phenomenon (1). A new article by Barayan et al. (2) suggests that this effect is driven by lactate shuttling. In their study, skin burn-injured patients and mice displayed induction of uncoupling protein 1 (UCP1) in white fat and an elevated lactate concentration in blood (2). Moreover, burn trauma led to increased protein levels of monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase and raised the NADH/NAD+-ratio in white fat (2), suggesting that lactate might mediate skin burn-induced browning.In further studies, Na-l-lactate or saline was administered intraperitoneally to skin-burned mice for seven consecutive days. While skin burning caused a 2.4% reduction in body weight and a 10% mortality rate in saline-treated mice, Na-l-lactate administration increased this to a 5.9% body weight loss and a 25% mortality rate, in addition to potentiating the adipose browning (2). However, the question remains as to whether these effects are driven by lactate. Lactate is often studied by injecting severely hypertonic solutions of Na-l-lactate and, like many other papers in the lactate field (3), Barayan et al. (2) did not state the injection volume used in their studies. This information is essential for evaluating treatment hypertonicity, a potential confounding factor in their study considering that 1) the anorexia caused by subcutaneous administration of Na-l-lactate in diet-induced obese mice can be mimicked by similarly hypertonic solutions of Na-d-lactate, NaCl, and d-mannitol (3) and 2) that intraperitoneal injections of sodium pyruvate (likely in severely hypertonic solutions) can be lethal in genetically obese mice (4). In addition to this, induction of Ucp1 expression after treatment with Na-l-lactate can be largely mimicked by the same doses of NaCl, at least in cell studies (3), and experiments in rats have shown that the thermogenic response to intravenous administration of a hypertonic glucose solution closely correlates with the treatment tonicity and can be mimicked by iso-osmolar NaCl and mannitol (5). This highlights the importance of controlling for treatment hypertonicity and coadministered sodium in studies of Na-l-lactate.In addition to injections of Na-l-lactate, Barayan et al. (2) used phloretin to inhibit cellular lactate transport and thus claim a causal role of lactate shuttling in burn injury-induced browning. Yet, phloretin has been reported to inhibit various cellular transporters, including different MCTs, in addition to having numerous other biological functions (6). Moreover, skin burns not only increase blood lactate (2) but have broader effects on the blood metabolome, as illustrated by increased systemic levels of purines (7) and β-hydroxybutyrate (8). Of note, these metabolites have been linked to the browning of white adipose tissue (9, 10) and β-hydroxybutyrate is also shuttled via MCTs.Given these points and the lack of controls for coadministered sodium and potentially also treatment hypertonicity, additional research is required to conclude that lactate drives adipose browning in response to skin burns.GRANTSThe author’s research on lactate has been supported by a research grant from the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, Grant No. NNF17SA0031406 (PhD scholarship to J.L.) and by a research grant from the European Foundation for the Study of Diabetes (EFSD) and Lilly European Diabetes Research Program 2019. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center, based at the University of Copenhagen, Denmark, and partially funded by an unconditional donation from the Novo Nordisk Foundation (www.cbmr.ku.dk) (Grant No. NNF18CC0034900).DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors. AUTHOR CONTRIBUTIONSJ.L. drafted manuscript; J.L., V.B.I.J., C.C., and Z.G.-H. edited and revised manuscript; J.L., V.B.I.J., C.C., and Z.G.-H. approved final version of manuscript. REFERENCES1. Sidossis LS, Porter C, Saraf MK, Børsheim E, Radhakrishnan RS, Chao T, Ali A, Chondronikola M, Mlcak R, Finnerty CC, Hawkins HK, Toliver-Kinsky T, Herndon DN. Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress. Cell Metab 22: 219–227, 2015. doi:10.1016/j.cmet.2015.06.022. Crossref | PubMed | ISI | Google Scholar2. Barayan D, Abdullahi A, Knuth CM, Khalaf F, Rehou S, Screaton RA, Jeschke MG. 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Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Related ArticlesReply to Lund et al. 09 Oct 2023American Journal of Physiology-Endocrinology and MetabolismCited ByReply to Lund et al.Dalia Barayan, Fadi Khalaf, Carly M. Knuth, Abdikarim Abdullahi, Sarah Rehou, Robert A. Screaton, and Marc G. Jeschke9 October 2023 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 325, No. 4 More from this issue > Volume 325Issue 4October 2023Pages E421-E422 Crossmark Copyright & PermissionsCopyright © 2023 the American Physiological Society.https://doi.org/10.1152/ajpendo.00251.2023PubMed37812086History Received 14 August 2023 Accepted 14 August 2023 Published online 9 October 2023 Published in print 1 October 2023 Keywordsbeige fatcounterionsmetabolitesosmolarityuncoupling protein 1 Metrics