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The anorectic and thermogenic effects of pharmacological lactate in male mice are confounded by treatment osmolarity and co-administered counterions

Nature Metabolism volume 5, pages 677–698 (2023)Cite this article

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Abstract

Lactate is a circulating metabolite and a signalling molecule with pleiotropic physiological effects. Studies suggest that lactate modulates energy balance by lowering food intake, inducing adipose browning and increasing whole-body thermogenesis. Yet, like many other metabolites, lactate is often commercially produced as a counterion-bound salt and typically administered in vivo through hypertonic aqueous solutions of sodium l-lactate. Most studies have not controlled for injection osmolarity and the co-injected sodium ions. Here, we show that the anorectic and thermogenic effects of exogenous sodium l-lactate in male mice are confounded by the hypertonicity of the injected solutions. Our data reveal that this is in contrast to the antiobesity effect of orally administered disodium succinate, which is uncoupled from these confounders. Further, our studies with other counterions indicate that counterions can have confounding effects beyond lactate pharmacology. Together, these findings underscore the importance of controlling for osmotic load and counterions in metabolite research.

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Fig. 1: Na-l-lactate induces a negative energy balance in obese mice.
Fig. 2: Na-d-lactate and NaCl mimics the anorexia of Na-l-lactate.
Fig. 3: Injection hypertonicity drives the anorexia of Na-l-lactate.
Fig. 4: Central Na-l-lactate infusion does not lower food intake.
Fig. 5: Na-l-lactate decreases body weight independently of GPR81.
Fig. 6: Lactate does not stimulate canonical adipose thermogenesis.
Fig. 7: l-lactate does not increase whole-body energy expenditure.
Fig. 8: Effects of succinate and counterion salts on energy balance.

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Acknowledgements

We thank C. S. A. Svendsen, K. Racz, K. Stohlmann, N. Tiutcheva and the Rodent Metabolic Phenotyping Platform for experimental and technical assistance. We also thank members of the Z.G.-H. group and the C.C. group for scientific discussions. This work was supported by a research grant from the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406 (PhD scholarship to J.L.), by a research grant from the European Foundation for the Study of Diabetes (EFSD) and Lilly European Diabetes Research Programme 2019, and by Center for Adipocyte Signaling (NNF15CC0018486 and NNF15SA0018346). M.K. is supported by the Deutsche Forschungsgemeinschaft (KL 3285/2-1) and the Novo Nordisk Foundation (NNF19OC0055192). C.C. is supported by research grants from the Lundbeck Foundation (Fellowship R238-2016-2859) and the Novo Nordisk Foundation (grant number NNF17OC0026114). This project has received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 639382 to Z.G.-H.). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center, based at the University of Copenhagen, and partially funded by an unconditional donation from the Novo Nordisk Foundation (https://cbmr.ku.dk/; grant number NNF18CC0034900). Cartoon illustrations were created with BioRender.com.

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Authors and Affiliations

  1. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Jens Lund, Alberte Wollesen Breum, Cláudia Gil, Sarah Falk, Frederike Sass, Marie Sophie Isidor, Oksana Dmytriyeva, Pablo Ranea-Robles, Cecilie Vad Mathiesen, Astrid Linde Basse, Olivia Sveidahl Johansen, Nicole Fadahunsi, Camilla Lund, Trine Sand Nicolaisen, Anders Bue Klein, Tao Ma, Brice Emanuelli, Zachary Gerhart-Hines & Christoffer Clemmensen

  2. Center for Adipocyte Signaling, University of Southern Denmark, Odense, Denmark

    Frederike Sass, Olivia Sveidahl Johansen & Zachary Gerhart-Hines

  3. The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark

    Trine Sand Nicolaisen & Maximilian Kleinert

  4. Muscle Physiology and Metabolism Group, German Institute of Human Nutrition, Potsdam-Rehbruecke (DIfE), Nuthetal, Germany

    Maximilian Kleinert

  5. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Charlotte Mehlin Sørensen

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Contributions

J.L., Z.G.-H. and C.C. conceptualized the project. J.L., A.W.B., C.G., S.F., P.R.-R., C.V.M., A.L.B., O.S.J., N.F., C.L., T.S.N., A.B.K., T.M. and C.C. performed mouse studies. F.S., M.S.I. and J.L. performed cell studies. All authors contributed to data analysis and/or interpretation. J.L. drafted the manuscript. Z.G.-H. and C.C. edited the manuscript. Other authors provided comments and minor edits to the manuscript.

Corresponding authors

Correspondence to Jens Lund, Zachary Gerhart-Hines or Christoffer Clemmensen.

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Nature Metabolism thanks Joshua Rabinowitz, Evan Rosen and Daniela Cota for their contribution to the peer review of this work. Primary Handling Editor: Alfredo Giménez-Cassina, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Effects of Na-l-lactate on body weight and body composition.

a-e, DIO mice treated daily with injections of 2 g/kg Na-L-lactate or isotonic saline for one week while single-housed in metabolic cages (mouse study 1 in Methods). a, Change in absolute body weight during the study (isotonic saline n = 8 mice, Na-L-lactate n = 8 mice). b, Change in absolute body weight at day 7 (isotonic saline n = 8 mice, Na-L-lactate n = 8 mice). c, Fat mass before (pre = day -3) and after (post = day 7) the study (isotonic saline n = 8 mice, Na-L-lactate n = 8 mice). d, Lean mass before (pre = day -3) and after (post = day 7) the study (isotonic saline n = 8 mice, Na-L-lactate n = 8 mice). e, Absolute change in fat and lean mass at day 7 (isotonic saline n = 8 mice, Na-L-lactate n = 8 mice). Data shown as the mean ± SEM.

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Extended Data Fig. 2 Effects of Na-l-lactate, iso-osmolar Na-D-lactate and iso-osmolar NaCl on body weight.

a-b, DIO mice treated daily with injections of 2 g/kg Na-L-lactate, 2 g/kg Na-D-lactate or isotonic saline for one week while pair/group-housed in standard cages (mouse study 2 in Methods). a, Change in absolute body weight during the study (isotonic saline n = 6 mice, Na-L-lactate n = 5 mice, Na-D-lactate n = 5 mice). b, Change in absolute body weight at day 7 (isotonic saline n = 6 mice, Na-L-lactate n = 5 mice, Na-D-lactate n = 5 mice). c-d, DIO mice treated once with an injection of 2 g/kg Na-L-lactate or PBS while single-housed in standard cages (mouse study 3 in Methods). c, Absolute body weight before (pre = 0 hours) and after (post = 24 hours) the injection (PBS n = 8 mice, Na-L-lactate n = 8 mice). d, Absolute change in body weight after 24 hours (PBS n = 8 mice, Na-L-lactate n = 8 mice). e-f, DIO mice treated once with an injection of NaCl (iso-osmolar to Na-L-lactate in mouse study 3) or PBS while single-housed in standard cages (mouse study 4 in Methods). e, Absolute body weight before (pre = 0 hours) and after (post = 24 hours) the injection (PBS n = 6 mice, NaCl n = 8 mice). f, Absolute change in body weight after 24 hours (PBS n = 6 mice, NaCl n = 8 mice). g, L-lactate levels in Dulbecco’s Modified Eagle Media measured by Statstrip Lactate-meter after addition of Na-L-lactate (20 mM) or Na-D-lactate (20 mM) (Na-L-lactate n = 3 independent solutions, Na-D-lactate n = 3 independent solutions). h, L-lactate levels in DMEM measured by Statstrip lactate-meter after addition of Na-L-lactate at concentrations of 5, 10, 15 and 20 mM (5 mM Na-L-lactate n = 2 independent solutions, 10 mM Na-L-lactate n = 2 independent solutions, 15 mM Na-L-lactate n = 2 independent solutions, 20 mM Na-L-lactate n = 2 independent solutions). Data shown as the mean ± SEM.

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Extended Data Fig. 3 Effects of injection volume and treatment hypertonicity on food intake and body weight.

a-e, Lean mice injected with PBS at a volume of 5 or 40 µL per g body weight or isotonic saline at a volume of 40 µL per g body weight (mouse study 11 in Methods). a, Cumulative food intake during the study (5 µL/g PBS n = 8 mice, 40 µL/g PBS n = 8 mice, isotonic saline n = 8 mice). Dark phase is indicated by grey-shaded area. b, Total food intake after 24 hours (5 µL/g PBS n = 8 mice, 40 µL/g PBS n = 8 mice, isotonic saline n = 8 mice). c, Percentage change in body weight after 24 hours (5 µL/g PBS n = 8 mice, 40 µL/g PBS n = 8 mice, isotonic saline n = 8 mice). d, Change in absolute body weight after 24 hours (5 µL/g PBS n = 8 mice, 40 µL/g PBS n = 8 mice, isotonic saline n = 8 mice). e, Body weight before (pre = 0 hour) and after (post = 24 hours) the injections (5 µL/g PBS n = 8 mice, 40 µL/g PBS n = 8 mice, isotonic saline n = 8 mice). f-i, DIO mice treated daily for 21 days with injections of 1 g/kg Na-L-lactate or PBS (mouse study 12 in Methods). f, Percentage change in body weight during the study (PBS n = 8 mice, Na-L-lactate n = 8 mice). g, Percentage change in body weight at day 21 (PBS n = 8 mice, Na-L-lactate n = 8 mice, PBS versus Na-L-lactate p = 0.0676). h, Change in absolute body weight during the study (PBS n = 8 mice, Na-L-lactate n = 8 mice). i, Change in absolute body weight at day 21 (PBS n = 8 mice, Na-L-lactate n = 8 mice). j-k, DIO mice treated daily for 16 days with injections of 1 g/kg Na-L-lactate, iso-osmolar NaCl or PBS (mouse study 9 in Methods). j, Change in absolute body weight during the study (PBS n = 8 mice, Na-L-lactate n = 12 mice, NaCl n = 8 mice). k, Change in absolute body weight at day 16 (PBS n = 8 mice, Na-L-lactate n = 12 mice, NaCl n = 8 mice). l-m, DIO mice treated daily for 14 days with injections of 1 g/kg Na-L-lactate, iso-osmolar D-mannitol or PBS (mouse study 10 in Methods). l, Change in absolute body weight during the study (PBS n = 5 mice, Na-L-lactate n = 5 mice, D-mannitol n = 5 mice). m, Change in absolute body weight at day 14 (PBS n = 5 mice, Na-L-lactate n = 5 mice, D-mannitol n = 5 mice). n-q, DIO mice treated daily for 14 days with injections of 1 g/kg Na-L-lactate, iso-osmolar D-mannitol or PBS (mouse study 13 in Methods). n, Percentage change in body weight during the study (PBS n = 9 mice, Na-L-lactate n = 11 mice, D-mannitol n = 11 mice). o, Percentage change in body weight at day 14 (PBS n = 9 mice, Na-L-lactate n = 11 mice, D-mannitol n = 11 mice). p, Change in absolute body weight during the study (PBS n = 9 mice, Na-L-lactate n = 11 mice, D-mannitol n = 11 mice). q, Change in absolute body weight at day 14 (PBS n = 9 mice, Na-L-lactate n = 11 mice, D-mannitol n = 11 mice). r, Plasma osmolarity in lean mice in response to injection of 1 g/kg Na-L-lactate (mouse study 14, pilot experiment, in Methods) (0 min n = 2 mice, 8 min n = 3 mice, 14 min n = 3 mice, 25 min n = 3 mice, 35 min n = 3 mice, 45 min n = 2 mice). s, Plasma osmolarity in lean mice measured 25 minutes after sham injections or injections with PBS, 1 g/kg Na-L-lactate, iso-osmolar NaCl or iso-osmolar D-mannitol (mouse study 14, main experiment, in Methods) (sham n = 6 mice, PBS n = 8 mice, Na-L-lactate n = 8 mice, NaCl n = 8 mice, D-mannitol n = 8 mice, sham versus Na-L-lactate p = 0.0031, sham versus NaCl p = 0.0025, sham versus D-mannitol p = 0.0001, PBS versus Na-L-lactate p = 0.0007, PBS versus NaCl p = 0.0005, PBS versus D-mannitol p < 0.0001). t-u, DIO mice treated daily for 21 days with injections of 1 g/kg Na-L-lactate or PBS (mouse study 12 in Methods). t, Cumulative food intake during the study (PBS n = 4 cages, Na-L-lactate n = 4 cages). u, Total food intake after 21 days (PBS n = 4 cages, Na-L-lactate n = 4 cages). v-w, DIO mice treated daily for 14 days with injections of 1 g/kg Na-L-lactate, iso-osmolar D-mannitol or PBS (mouse study 13 in Methods). v, Cumulative food intake during the study (PBS n = 9 mice, Na-L-lactate n = 11 mice, D-mannitol n = 11 mice). w, Total food intake after 14 days (PBS n = 9 mice, Na-L-lactate n = 11 mice, D-mannitol n = 11 mice). Data were analysed by one-way ANOVA with a Bonferroni post hoc test (b-d, o, s and w) and unpaired two-tailed t-test (g and u). Data shown as the mean ± SEM; ** p < 0.01, *** p < 0.001, **** p < 0.0001.

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Extended Data Fig. 4 Food intake after central infusion of Na-l-lactate.

a, Cumulative food intake in lean mice after intracerebroventricular (ICV) administration of 10 nmoles of Na-L-lactate or an identical volume of isotonic saline (mouse study 15, experiment 2, in Methods) (isotonic saline n = 4 mice, Na-L-lactate n = 4 mice, treatment p = 0.9395, time x treatment p = 0.9828). Dark phase is indicated by grey-shaded area. b, Cumulative food intake in lean mice after ICV administration of 500 nmoles Na-L-lactate or an identical volume of isotonic saline (mouse study 15, experiment 3, in Methods) (isotonic saline n = 3 mice, Na-L-lactate n = 3 mice, treatment p = 0.6620, time x treatment p = 0.9743). Dark phase is indicated by grey-shaded area. c, Cumulative food intake in lean mice after ICV administration of a GLP1-R agonist or an identical volume of PBS (mouse study 15, experiment 4, in Methods) (PBS n = 3 mice, GLP1-R agonist n = 3 mice, treatment p = 0.0579, time x treatment p = 0.0117). Dark phase is indicated by grey-shaded area. Data analyzed by two-way ANOVA with a Bonferroni post hoc test (a, b, and c). Data shown as the mean ± SEM.

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Extended Data Fig. 5 Effect of Na-L-lactate on body weight in GPR81 knockout and wild-type mice.

a-d, DIO GPR81 knockout mice (GPR81-KO) and wild-type control mice (GPR81-WT) treated daily with injections of 2 g/kg Na-L-lactate or iso-osmolar NaCl for 15 days while single-housed in standard cages (mouse study 16 in Methods). a, Change in absolute body weight in GPR81-KO mice during the study (Na-L-lactate n = 6 mice, NaCl n = 6 mice). b, Change in absolute body weight in GPR81-KO mice after 15 days (Na-L-lactate n = 6 mice, NaCl n = 6 mice). c, Change in absolute body weight in GPR81-WT mice during the study (Na-L-lactate n = 7 mice, NaCl n = 6 mice). d, Change in absolute body weight in GPR81-WT mice after 15 days (Na-L-lactate n = 7 mice, NaCl n = 6 mice). Data shown as the mean ± SEM.

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Extended Data Fig. 6 Effects of Na-l-lactate on adipose browning and thermogenesis.

a-d, Young and lean mice treated daily with injections of 2 g/kg Na-L-lactate, iso-osmolar NaCl or PBS for 9 days (mouse study 18 in Methods). a, Hematoxylin and eosin staining of inguinal white adipose tissue. Multilocular adipocytes are indicated by black arrows. Each column in the three groups correspond to one mouse (PBS n = 6 mice, Na-L-lactate n = 7 mice, NaCl n = 7 mice). b, Whole-body oxygen consumption in anaesthetized mice before and after administration of norepinephrine (NE) (PBS n = 6 mice, Na-L-lactate n = 7 mice, NaCl n = 7 mice). c, Body weight at the day of the experiment shown in Extended Data Fig. 6b (PBS n = 6 mice, Na-L-lactate n = 7 mice, NaCl n = 7 mice). d, Whole-body oxygen consumption normalized to body weight in anaesthetized mice before and after administration of NE (PBS n = 6 mice, Na-L-lactate n = 7 mice, NaCl n = 7 mice). e, Whole-body oxygen consumption in lean anaesthetized mice placed in metabolic cages and treated first with either 2 g/kg Na-L-lactate or PBS, as indicated by the left black arrow, and subsequently with NE, as indicated by the right black arrow (mouse study 19 in Methods) (PBS n = 6 mice, Na-L-lactate n = 6 mice). f, Ucp1 expression in immortalized mouse brown adipocytes (BMC line) after 24 hours of stimulation with 25, 50 and 100 mM Na-L-lactate (data from a single experiment, data points represent technical replicates). g, Ucp1 expression in immortalized mouse brown adipocytes (BMC line) after stimulation with 25, 50 and 100 mM Na-L-lactate or similar concentrations of NaCl for 24 hours (data from a single experiment, data points represent technical replicates). h, Ucp1 expression in immortalized mouse brown adipocytes (BMC line) after stimulation with 25, 50 and 100 mM Na-L-lactate or similar concentrations of NaCl for 24 hours (data from a single experiment, data points represent technical replicates). i, Ucp1 expression in immortalized mouse brown adipocytes (WT-1 line) after stimulation with 25, 50 and 100 mM Na-L-lactate for 6 hours (data from a single experiment, data points represent technical replicates). j, Ucp1 expression in immortalized mouse brown adipocytes (WT-1 line) after stimulation with 25, 50 and 100 mM Na-L-lactate or similar concentrations of NaCl for 6 hours (data from a single experiment, data points represent technical replicates). k, Ucp1 expression in immortalized mouse brown adipocytes (WT-1 line) after stimulation with 25, 50 and 100 mM Na-L-lactate or similar concentrations of NaCl for 6 hours (data from a single experiment, data points represent technical replicates). Data analyzed by one-way ANOVA with a Bonferroni post hoc test (c) and two-way ANOVA with a Bonferroni post hoc test (b, d, e). Statistical analyses on data based on technical replicates are not shown (f-k). Data shown as the mean ± SEM.

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Extended Data Fig. 7 Effects of Na-l-lactate on tissue gene expression, body weight and food intake.

a-e, Gene expression in gastrocnemius muscle and liver from DIO mice treated daily for 16 days with injections of 1 g/kg Na-L-lactate, iso-osmolar NaCl or PBS (mouse study 9 in Methods). a, Expression of selected metabolic genes in gastrocnemius (PBS n = 8 mice, Na-L-lactate n = 12 mice, NaCl n = 8 mice, Mt2 PBS versus Na-L-lactate p = 0.0208, Mt2 Na-L-lactate versus NaCl p = 0.0187). b, Expression of genes involved in hepatic glycogen synthesis (PBS n = 8 mice, Na-L-lactate n = 12 mice, NaCl n = 8 mice). c, Expression of genes involved in hepatic glycogenolysis (PBS n = 8 mice, Na-L-lactate n = 12 mice, NaCl n = 8 mice). d, Expression of genes involved in hepatic glucose transport (Glut1, Glut2) and glycolysis (Hk1, Hk2, Gck, Pfkl, Pgk1, Pkm1, and Pkm2) (PBS n = 8 mice, Na-L-lactate n = 12 mice, NaCl n = 8 mice). e, Expression of genes involved in hepatic gluconeogenesis (PBS n = 8 mice, Na-L-lactate n = 12 mice, NaCl n = 8 mice, Pck1 PBS versus Na-L-lactate p = 0.0230). f-i, Changes in body weight in DIO mice treated with daily injections of 1 g/kg Na-L-lactate or PBS for one week while single-housed in metabolic cages (mouse study 20 in Methods). f, Percentage change in body weight during the study (PBS n = 8 mice, Na-L-lactate n = 8 mice). g, Percentage change in body weight at day 7 (PBS n = 8 mice, Na-L-lactate n = 8 mice, PBS versus Na-L-lactate p = 0.0008). h, Change in absolute body weight during the study (PBS n = 8 mice, Na-L-lactate n = 8 mice). i, Change in absolute body weight at day 7 (PBS n = 8 mice, Na-L-lactate n = 8 mice). j-m, Changes in body weight in DIO mice treated with daily injections of 1 g/kg Na-L-lactate or iso-osmolar NaCl for one week while single-housed in metabolic cages (mouse study 21 in Methods). j, Percentage change in body weight during the study (NaCl n = 8 mice, Na-L-lactate n = 8 mice). k, Percentage change in body weight at day 7 (NaCl n = 8 mice, Na-L-lactate n = 8 mice). l, Change in absolute body weight during the study (NaCl n = 8 mice, Na-L-lactate n = 8 mice). m, Change in absolute body weight at day 7 (NaCl n = 8 mice, Na-L-lactate n = 8 mice). n, Cumulative food intake in response to 1 g/kg Na-L-lactate or PBS (mouse study 20 in Methods) (PBS n = 8 mice, Na-L-lactate n = 8 mice). o, Total food intake after 190 hours (mouse study 20 in Methods) (PBS n = 8 mice, Na-L-lactate n = 8 mice, PBS versus Na-L-lactate p = 0.0116). p, Cumulative food intake in response to 1 g/kg Na-L-lactate or iso-osmolar NaCl (mouse study 21 in Methods) (NaCl n = 8 mice, Na-L-lactate n = 8 mice). q, Total food intake after 190 hours (mouse study 21 in Methods) (NaCl n = 8 mice, Na-L-lactate n = 7 mice). Dashed vertical lines indicate time of injection (n and p). Dark phases are indicated by grey-shaded areas (n and p). Data analyzed by two-way ANOVA with Bonferroni post hoc test (a-e) and by unpaired two-tailed t-test (g, k, o, and q). Data shown as the mean ± SEM; * p < 0.05,*** p < 0.001.

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Extended Data Fig. 8 Effects of succinate and counterion salts on body weight.

a-b, Lean mice shifted from chow to high-fat diet and with ad libitum access to either tap water, tap water with NaCl, tap water with disodium succinate or tap water with disodium fumarate for 28 days (mouse study 22 in Methods). a, Change in absolute body weight during the study (Tap water n = 10 mice, NaCl n = 10 mice, disodium succinate n = 11 mice, disodium fumarate n = 11 mice). b, Change in absolute body weight at day 28 (Tap water n = 10 mice, NaCl n = 10 mice, disodium succinate n = 11 mice, disodium fumarate n = 11 mice). c-d, DIO mice treated once with an injection of 210 mg/kg MgCl2 or PBS (mouse study 23 in Methods). c, Absolute body weight before (pre = 0 hours) and after (post = 24 hours) the injection (PBS n = 6 mice, MgCl2 n = 6 mice). d, Change in absolute body weight after 24 hours (PBS n = 6 mice, MgCl2 n = 6 mice). e-f, DIO mice treated once with an injection of 60 mg/kg LiCl or PBS (mouse study 24 in Methods). e, Absolute body weight before (pre = 0 hours) and after (post = 24 hours) the injection (PBS n = 6 mice, LiCl n = 6 mice). f, Change in absolute body weight after 24 hours (PBS n = 6 mice, LiCl n = 6 mice). g-h, DIO mice treated once with an injection of 40 mg/kg CaCl2 or isotonic saline (mouse study 25 in Methods). g, Absolute body weight before (pre = 0 hours) and after (post = 24 hours) the injection (isotonic saline n = 7 mice, CaCl2 n = 7 mice). h, Change in absolute body weight after 24 hours (isotonic saline n = 7 mice, CaCl2 n = 7 mice). Data shown as the mean ± SEM.

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Supplementary information

Reporting Summary

Supplementary Tables 1–3

Supplementary Table 1: Overview of representative studies. Table 2: Data on experimental solutions (inclusive theoretical osmolarities and measured osmolalities). Table 3: Primer list.

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Source Data Figs. 1–8

Source data for Figs. 1–8.

Source Data Extended Data Figs. 1–8

Source data for Extended Data Figs. 1–8.

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Lund, J., Breum, A.W., Gil, C. et al. The anorectic and thermogenic effects of pharmacological lactate in male mice are confounded by treatment osmolarity and co-administered counterions. Nat Metab 5, 677–698 (2023). https://doi.org/10.1038/s42255-023-00780-4

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