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Early-life ketone body signalling promotes beige fat biogenesis through changes in histone acetylome and β-hydroxybutyrylome

Nature Metabolism (2025)Cite this article

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Abstract

Infants undergo distinct ketogenesis during the preweaning period, yet its physiological implications remain unclear. Here, we show that preweaning ketosis promotes beige fat biogenesis and improves health outcomes in adulthood. Loss of ketogenesis in neonatal mice by early weaning or ablation of Hmgcs2 hinders beige adipogenesis, subsequently exacerbating metabolic dysregulation in high-fat diet-induced obesity. Enhanced ketogenesis during lactation through exogenous ketone supplements enhances energy expenditure, beige fat formation, and mitochondrial biogenesis and respiration. Using single-cell RNA sequencing, we identified a subset of β-hydroxybutyrate-responsive adipocyte progenitor cells (APCs) expressing Cd81 that showed high beige adipogenic potential. Enhanced ketogenesis promotes the recruitment of beige APCs and their differentiation into beige adipocytes. Mechanistically, ketogenesis-derived βHB induces a switch in the histone acetylome and β-hydroxybutyrylome for transcriptional activation of beige fat biogenesis genes. Notably, enhanced ketogenesis during lactation alleviates adverse metabolic effects predisposed by parental obesity. Our study highlights that targeting preweaning ketosis to drive beige adipogenesis may offer a therapeutic approach to combat obesity and metabolic diseases in adulthood.

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Fig. 1: EW exacerbates DIO and insulin resistance in adulthood, which are mitigated by MCT supplementation.
Fig. 2: Loss of endogenous ketogenesis in Hmgcs2-deficient mice impairs cold-induced beige fat formation.
Fig. 3: Enhanced ketogenesis during lactation promotes beige adipocyte accumulation in iWAT upon cold exposure.
Fig. 4: Enhanced ketogenesis during lactation induces transcriptional changes in adipose stromal cells and expands CD81high beige progenitors.
Fig. 5: scRNA-seq of iWAT SVF reveals an increase in a subset of preadipocytes upon 1,3BD treatment.
Fig. 6: Enhanced ketogenesis during lactation increases H3K9/14ac and H3K9bhb occupancies at promoters of beige fat biogenesis genes in adipose stromal cells.
Fig. 7: Enhanced ketogenesis during lactation mitigates parental obesity-induced metabolic alterations under HFD challenge.

Data availability

The next-generation sequencing data generated in this study have been deposited in the Gene Expression Omnibus (GEO) under the following accession numbers: GSE267314 (bulk RNA-seq of iWAT and SVF), GSE267320 (ChIP–seq), GSE268811 (scRNA-seq) and GSE267285 (bulk RNA-seq of SVF from the PO model). Previously published ChIP–seq datasets (GSE175654 and GSE193463) were used to identify H3K27ac-enriched enhancer regions in iWAT and iWAT SVF. Source data are provided with this paper.

Code availability

The code used in this study is available on GitHub at https://github.com/FJLinLab/2025_ketone_biege.

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Acknowledgements

This work was supported by the National Science and Technology Council, Taiwan (NSTC 111-2320-B-002-037-MY3 and 114-2320-B-002-015 to F.-J.L.), NTU (113L894803 and 114L893003 to F.-J.L.) and Ministry of Education Higher Education Sprout Project (NTU 112L7131 to F.-J.L.). We thank the Technology Commons, College of Life Science, NTU, for providing access to the cell analyzer and Seahorse analyzer services. We thank W.-S. Yao at the Technology Commons in the College of Life Science, and the Instrumentation Center sponsored by the National Science and Technology Council, NTU, for technical support with the FACSAria III Cell Sorter. We also thank the Animal Resource Center and the Consortium of Integrative Biomedical Science Key Technology at NTU for their technical assistance with the single-cell experiment. We are grateful to the Taiwan Mouse Clinic, Academia Sinica and Taiwan Animal Consortium for support with body composition measurements and indirect calorimetry. We acknowledge the National Center for Biomodels (NCB), National Institute of Applied Research (NIAR), Taiwan, for providing the C57BL/6-Tg(Adipoq-FusRed,-cre/ERT2)13Narl/Narl mice (RMRC13297) and for technical support in assisted reproductive technology, contract breeding and testing services. We gratefully acknowledge Y.-C. Lee, C.-T. Chen and H.-M. Su for providing mouse cell lines, including 3T3-L1 fibroblasts, CT26.WT colon carcinoma cells and C2C12 myoblasts. We thank S.-H. Wang for the rederivation of Albumin-cre mice and H.-C. Tsai and Y.-J. Huang for assistance with the ChIP experiments. We are also grateful to C.-H. Lee and L.-J. Juan for their valuable discussions and critical reading of the manuscript. Finally, we thank all members of our laboratory for expert mouse husbandry and technical support throughout the study.

Author information

Authors and Affiliations

  1. Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan

    Chung-Lin Jiang, Pei-Hsiang Lai, Chia-Jung Lien, Jian-Da Lin & Fu-Jung Lin

  2. Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan

    Po-Cheng Yang & Hsueh-Ping Catherine Chu

  3. Center for Advanced Computing and Imaging in Biomedicine, National Taiwan University, Taipei, Taiwan

    Jian-Da Lin

  4. Center for Computational and Systems Biology, National Taiwan University, Taipei, Taiwan

    Jian-Da Lin

  5. Department of Biomedical Engineering, National Taiwan University, Taipei, Taiwan

    Sung-Jan Lin

  6. Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan

    Sung-Jan Lin

  7. Department of Dermatology, National Taiwan University, Taipei, Taiwan

    Sung-Jan Lin

  8. Research Center for Development Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan

    Sung-Jan Lin & Fu-Jung Lin

  9. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    Sung-Jan Lin

  10. Laboratory Animal Center, College of Medicine, National Taiwan University, Taipei, Taiwan

    I-Shing Yu

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  1. Chung-Lin Jiang
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Contributions

C.-L.J. and F.-J.L. conceived the project, designed and performed the experiments, interpreted the data, prepared the figures and wrote the manuscript. P.-H.L. conducted experiments, performed the bioinformatics analysis of the scRNA-seq data and prepared figures. P.-C.Y. carried out library construction for ChIP–seq experiments, analysed ChIP–seq data, and prepared figures. C.-J.L. analysed the scRNA-seq data. H.-P.C.C. supervised the ChIP–seq experiments and contributed to data interpretation. J.-D.L. interpreted the scRNA-seq results. S.-J.L. and I.-S.Y. provided reagents. F.-J.L. supervised the project, designed experiments, interpreted data and generated figures with assistance from C.-L.J., P.-H.L. and P.-C.Y. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Fu-Jung Lin.

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Nature Metabolism thanks Yuichiro Arima, Da Jia, Yu-Hua Tseng and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Revati Dewal, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Loss of endogenous ketogenesis in Hmgcs2-deficient mice impairs cold-induced beige fat formation and mitochondrial biogenesis.

a. Hepatic Hmgcs2 mRNA in control (CTL) and Hmgcs2 knockout (KO, Hmgcs2−/−) male mice at P0, P7, P14, and P21. b. Serum βHB levels in CTL and KO mice at P0, P4, P7, P14, and P21. c. Survival rate of Hmgcs2 heterozygous (HET) and KO mice (n = 42, 16). d. Ucp1 mRNA in iWAT of wild-type mice after 1, 2, 5, or 7 days at 4 °C (n = 3/group). e. Hmgcs2 mRNA in iWAT of wild-type mice after 7 days at 4 °C (n = 5/group). f. iWAT weights of CTL and KO mice housed at room temperature (RT) or 4 °C (Cold) for 7 days. g. Quantification of white and beige adipocytes from iWAT sections in Fig. 2c (n = 3/group). h–j. Transcriptomic analysis of iWAT SVF: pie charts (top) and volcano plots (bottom) of differentially expressed genes for (h) CTL Cold vs. RT; (i) KO Cold vs. RT, and (j) KO vs. CTL under Cold conditions. k. Ucp1 and Cidea mRNA in iWAT of mice from (f). l. iBAT weights in mice from (f). m. Ucp1 mRNA in iBAT from mice in (f). n. Fatty acid oxidation (FAO) stress test in SVF-derived adipocytes from CTL and KO mice using palmitic acid (PA)-BSA as substrate, followed by etomoxir (Eto) treatment. Real-time oxygen consumption rate (OCR) shown (n = 3 for CTL; 4 for KO). o. Quantification of basal and maximal FAO responses following Eto treatment (n = 3 for CTL; 4 for KO). p. Mitochondrial DNA (mtDNA) copy number in iWAT, expressed as the ratio of Nd1 to Lpl gene expression (n = 6/group). q. mRNA levels of mitochondrial biogenesis genes in iWAT. Data are expressed as mean ± SD. n = 4/group in a–b, f, k–m, q. Statistical analyses: two-sided Student’s t-test (a, b, d, e, o–q) and two-way ANOVA with Tukey’s post hoc test for multiple comparisons (f, k–m) and. P values in (d) are versus day 0.

Source data

Extended Data Fig. 2 Global and liver-specific deletion of Hmgcs2 impairs cold-induced beige fat formation in male mice.

a. Hmgcs2 mRNA in liver, iWAT, eWAT, and iBAT of P14 control mice (n = 3/group). b. Intracellular βHB concentrations in liver, iWAT, eWAT, and iBAT of P14 control mice (n = 4/group). c. Expression of Hmgcs2 (left) and Fabp4 (right) during adipogenic differentiation of SVF (n = 3/group). d. Schematic of global and conditional Hmgcs2 knockout models and experimental design. Eight-week-old male control (CTL), global knockout (KO, mediated by Sox2-Cre), liver-specific knockout (LiKO, mediated by Albumin-Cre), and adipocyte-specific knockout (AdKO, mediated by Adipoq-CreERT2) mice were maintained on chow and housed at room temperature (RT) or 4 °C (Cold) for 7 days. Rectal temperature was measured after 2 days; iWAT was collected after 7 days. e. Representative western blot of HMGCS2 protein in liver and iWAT. β-actin as loading control. f. Serum βHB levels at P14 in male mice (n = 6 for CTL; 5 for KO; 4 for LiKO; 4 for AdKO). g. Intracellular βHB in iWAT at P14 (n = 3/group). h. Serum βHB levels at P14 in female mice (n = 8 for CTL; 7 for KO; 6 for LiKO; 6 for AdKO). i. Changes in rectal temperature after 2 days at 4 °C in male mice. Delta rectal temperature = temperature at indicated time – baseline temperature (n = 8 for CTL RT; 8 for CTL Cold; 6 for KO; 6 for LiKO; 5 for AdKO). j. Gross morphology and representative H&E-stained iWAT sections. Grid:1 cm×1 cm. Scale bar, 100 µm. k. Quantification of white and beige adipocyte in (j) (n = 4/group). l. mRNA levels of thermogenic genes in iWAT (n = 6 for CTL RT; 6 for CTL Cold; 4 for KO; 4 for LiKO; 4 for AdKO). Data are expressed as means ± SD. Statistical analyses: one-way ANOVA with Tukey’s post hoc test for multiple comparisons (a–b, f–i, l) and two-sided Student’s t-test (c). P values in (c) are versus day 0 (c). Illustrations in d created in BioRender.com, https://biorender.com/hjq5y60.

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Extended Data Fig. 3 Global deletion of Hmgcs2 impairs cold-induced beige fat formation in female mice.

a. Serum βHB levels in P14 male and female mice (n = 4 for males; 6 for females). b. Schematic of the Hmgcs2 KO mouse model and experimental design. Eight-week-old female control (CTL-F) and knockout (KO-F) mice were maintained on chow and housed at room temperature (RT) or 4 °C (Cold) for 7 days. Rectal temperature was measured after 2 days of cold exposure; iWAT was collected after 7 days of cold exposure. c. Gross morphology and representative H&E-stained iWAT sections. Grid:1 cm×1 cm. Scale bar, 100 µm. d. Quantification of white and beige adipocyte numbers in iWAT sections (n = 3/group). e. mRNA expression of thermogenic and white adipocyte-selective genes in iWAT (n = 4/group). f. Changes in rectal temperature after 2 days of cold exposure. Delta rectal temperature = temperature at indicated time – baseline temperature (n = 4/group). g. Representative H&E-stained iBAT sections. Scale bar, 100 µm. h. mRNA expression of Hmgcs2 and Ucp1 in iBAT (n = 4/group). Data are expressed as means ± SD. Statistical analyses: one-way ANOVA with Tukey’s post hoc test for multiple comparisons (e, f, h) and two-sided Student’s t-test (a). Illustrations in b created in BioRender.com, https://biorender.com/oql9znl.

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Extended Data Fig. 4 Enhanced ketogenesis during lactation promotes mitochondrial biogenesis and Ucp1 expression in iWAT.

a. Serum βHB concentrations in 3-week-old C57BL/6 J male mice orally administrated water or 1,3-butanediol (1,3BD; 5 g/kg BW) (n = 3/group). b. Serum βHB levels in P14 mice orally administrated water or 1,3BD starting at P2 (n = 4, 6). c. Intracellular βHB concentrations in P14 mice described in (b) (n = 4, 6). d. Body weight of mice from Fig. 3a (n = 4/group). e. iWAT weight of mice from Fig. 3a (n = 4/group). f. Dio2 and Elovl3 mRNA expression in iWAT of mice from Fig. 3a (n = 4/group). g. Adrb1, Adrb2 and Adrb3 mRNA expression in iWAT of mice from Fig. 3a (n = 4/group). h. Gross morphology of iBAT from mice in Fig. 3a. i. iBAT weight of mice from Fig. 3a (n = 4/group). j. Ucp1 mRNA expression in iWAT and iBAT of mice from Fig. 3a (n = 5, 4, 3, 3). k. Dio2 and Elovl3 mRNA expression in iBAT of control, Hmgcs2 KO, and 1,3BD-treated mice (n = 4, 4, 3). l. Temporal changes and quantification of oxygen consumption rate (VO2) in mice from Fig. 3m, housed at thermoneutrality (30 °C) and cold exposure (4 °C) (n = 5/group). m. Temporal changes and quantification of carbon dioxide production rate (VCO2) in mice from Fig. 3m, housed at 30 °C and 4 °C (n = 5/group). Data are expressed as means ± SD. Statistical analyses: two-sided Student’s t-test (a–c, g, j, l–m), one-way ANOVA with Tukey’s post hoc test (k) and two-way ANOVA with Tukey’s post hoc test for multiple comparisons (d–f, i).

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Extended Data Fig. 5 Enhanced ketogenesis during lactation induces transcriptomic and cellular changes in iWAT SVF.

a. Pie chart of differentially expressed genes in 1,3BD SVF vs. Water SVF. Water SVF and 1,3B -SVF were isolated from iWAT of P21 male mice orally administrated water or 1,3BD from P2–P21 (n = 3/group; each sample pools 3-5 animals). b. Pie chart of differentially expressed transcription factor genes in SVF samples in (a). c. Immunofluorescence staining of UCP1 in SVF samples from (a). d. Western blot analysis of PGC1α, PPARγ1/2, CD81, CD137, and β-actin in SVF from (a). β-actin as loading control. e. Densitometry analysis of (d) (n = 3/group). f. Proportion of CD34−:CD81+ cells in SVF (see Fig. 4i) (n = 3/group). g. Gating strategy for isolating CD81low and CD81high cells from SVF of iBAT in P21 CTL, Hmgcs2 KO and 1,3BD-treated mice. h. Quantification of CD81+ cell populations from (g) (n = 7 for CTL, 6 for KO, 7 for 1,3BD). i. Mean fluorescence intensity (MFI) of CD81 in cells from (g) (n = 7 for CTL, 6 for KO, 7 for 1,3BD). j. Proportions of CD81high and CD81low cells within the CD81⁺ population from (g) (n = 7 for CTL, 6 for KO, 7 for 1,3BD). k. Histogram of BrdU incorporation (left) and quantification of BrdU+ cells in CD81low, CD81high, CD81low cells treated with 2 mM βHB for 2 days (CD81low + βHB cells), and CD81high cells treated with 2 mM βHB for 2 days (CD81high + βHB cells) (n = 3/group). l. Oil Red O staining of differentiated CD81low, CD81high, CD81low + βHB, and CD81high + βHB cells. Cells were isolated from CTL iWAT and cultured under adipogenic conditions for 6 days. Data are expressed as means ± SD. Statistical analyses: two-sided Student’s t-test (e), one-way ANOVA with Tukey’s post hoc test for multiple comparisons (f, h–j) and two-way ANOVA with Tukey’s post hoc test for multiple comparisons (k).

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Extended Data Fig. 6 Marker gene expression patterns across cell clusters from iWAT SVF.

a. Heatmap showing representative gene expression across identified cell clusters from iWAT SVF from P21 male mice (n = 1/group; each sample pools 3–5 animals). b. Violin plots depicting mRNA expression levels of indicated genes across cell clusters. c. UMAP plots and corresponding violin plots illustrating Pdgfra and Ly6a expression in each cluster. d. UMAP visualization of Pparg, Rreb1, Cd81, Tfam, Klf9, and Vdr expression in each cluster of adults (P56) condition. e. Venn diagram showing upregulated differentially expressed genes (DEGs) in ASC1 populations under KO vs. CTL and 1,3BD vs. CTL conditions. Data were obtained from scRNA-seq analysis and are presented as log-normalized gene expression values (a–d).

Extended Data Fig. 7 ChIP-seq analysis of H3K9ac, H3K14ac, and H3K9bhb in iWAT SVF.

a. Representative immunoblot of total lysine acetylation (Kac) in SVF from iWAT of P21 control (CTL), Hmgcs2 knockout (KO) and 1,3BD-treated mice. β-actin as loading control. b. Densitometry analysis of Fig. 6a (n = 4/group). c. Heatmap of Pearson’s correlation coefficients for genome-wide occupancy of H3K9ac, H3K14ac, and H3K9bhb between biological replicates of Water SVF and 1,3BD SVF. d. Co-localization of consensus enrichment peaks for H3K9ac, H3K14ac, and H3K9bhb in Water SVF and 1,3BD SVF. e. Metagene profiles of H3K9ac, H3K14ac and, H3K9bhb coverage around the transcription starts sites (TSS) ( ± 3 kb) of gene involved in cell differentiation, cell fate commitment, cold-induced thermogenesis, and fat cell differentiation in Water SVF and 1,3BD SVF. f–h. ChIP-qPCR validation of H3K9ac, H3K14ac, and H3K9bhb occupancy at the promoters of Ppargc1a (f), Klf9 (g), and Vdr (h) in Water SVF and 1,3BD SVF (n = 3/group). i. Genome browser view of H3K9ac, H3K14ac, and H3K9bhb occupancy at regulatory regions of indicated genes in Water SVF, KO SVF, and 1,3BD SVF. j. ChIP-qPCR validation of H3K9ac occupancy at Cd81 (left) and Ppargc1a (right) promoters in Water SVF and 1,3BD SVF (n = 3/group). k. H3K27ac ChIP-seq profiles from whole iWAT and SVF (GSE175654 and GSE193463) upstream regions of Cd81 (top) and Ppargc1a (bottom) TSS. Red boxes indicate regions targeted by ChIP-qPCR primers. H3K27ac signals are shown in dark blue peaks (GSE175654) and light blue boxes (GSE193463). l–m. ChIP-qPCR validation of H3K27ac occupancy at enhancers of Cd81 (l) and Ppargc1a (m) in Water SVF and 1,3BD SVF (n = 3/group). Data are expressed as means ± SD. n = 3/group in (f–h, l–m). Statistical analyses: one-way ANOVA with Tukey’s post hoc test for multiple comparisons (b) and two-sided Student’s t-test (f–h, j, l–m).

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Extended Data Fig. 8 Exogenous ketone body supplementation induces enrichments of H3K9/14ac and H3K9bhb and gene expression in MEFs.

a. Schematic of the experimental design. b. Representative immunoblot of global H3K9ac, H3K14ac, H3K9bhb, and total histone H3 in wild-type mouse embryonic fibroblasts (MEFs) treated with or without βHB for 2 days. Histone H3 as loading control. c. Densitometry analysis of (b). d. ChIP-qPCR validation of H3K9ac, H3K14ac, and H3K9bhb occupancy at the promoter region of Ppargc1a in control (CTL) and βHB-treated MEFs. e. ChIP-qPCR validation of H3K9ac, H3K14ac, and H3K9bhb occupancy at the promoter region of Klf9 in CTL and βHB-treated MEFs. f. ChIP-qPCR validation of H3K9ac, H3K14ac, and H3K9bhb occupancy at the promoter region of Vdr in CTL and βHB-treated MEFs. g. mRNA expression of Ppargc1a, Klf9 and Vdr in CTL and βHB-treated MEFs. h. mRNA expression of beige progenitor markers Cd81 and Tmem26 in CTL and βHB-treated MEFs. Data are expressed as means ± SD. Sample sizes in b–h were n = 3 per group. Statistical analyses: one-way ANOVA with Tukey’s post hoc test for multiple comparisons (c) and two-sided Student’s t-test (d–h). Illustrations in a created in BioRender.com, https://biorender.com/nmszrfi.

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Extended Data Fig. 9 Ppargc1a is required for βHB-induced beige adipogenesis.

a. Schematic of experimental design. Ppargc1a control (Ppargc1+/+) and knockout (Ppargc1a−/−) mice were orally administered water or 1,3-butanediol (1,3BD) during the preweaning period (P2-P21). SVF were isolated from iWAT of P21 mice and subjected to adipogenic induction. b. Ppargc1a mRNA expression in Ppargc1+/+ and Ppargc1a−/− SVF samples (n = 3/group; 3 animals/group). c. Representative Oil Red O (ORO) staining of differentiated SVF-derived adipocytes from (a). d. Ucp1 mRNA levels in isoproterenol-treated or untreated SVF-derived adipocytes from (a) (n = 3/group; 3 animals/group). e. Oxygen consumption rate (OCR) profiles from mitochondrial stress tests in SVF-derived adipocytes from (a). f. Quantification of basal respiration, maximal respiration, and spare respiratory capacity from data in (e) (n = 3/group; 3 animals/group). g. Mitochondrial DNA (mtDNA) content in SVF-derived adipocytes from (a) (n = 3/group). h. mRNA levels of mitochondrial genes in SVF-derived adipocytes from (a) (n = 3/group). Data are expressed as means ± SD. Statistical analyses: two-sided Student’s t-test (b) and two-way ANOVA with Tukey’s post hoc test for multiple comparisons (d, f–h). Illustrations in a created in BioRender.com, https://biorender.com/czow54b.

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Extended Data Fig. 10 Enhanced ketogenesis during lactation protects against parental obesity-linked metabolic dysfunction.

a. Blood glucose levels in male offspring from lean (Ln-F1) and obese (Ob-F1) parents at P0, P7, P14, and P21 under ad libitum feeding (Ln-F1, n = 3, 3, 5, 4; Ob-F1, n = 4, 4, 4, 5). b. Serum βHB levels in the same mice as (a) (Ln-F1, n = 3, 5, 3, 4; Ob-F1, n = 4, 4, 4, 5). c. Hepatic Hmgcs2 mRNA expression in mice from (a) (Ln-F1, n = 3, 4, 5, 3; Ob-F1, n = 3, 5, 4, 4). d. Pie chart (left) and volcano plot (right) showing differentially expressed genes in SVF from P21 Ob-F1 vs. Ln-F1 mice (n = 1/group). e. Expression of ketone utilization genes in SVF from (d) (n = 3/group). f. Gross morphology (top) and weights (bottom) of eWAT and iBAT in 20-week-old mice (n = 12, 12, 6, 5). g. Serum glucose and systolic/diastolic blood pressure in mice from (f) (glucose: n = 12, 12, 6, 5; blood pressure: n = 5, 5, 3, 3 for blood pressure). h. Oral glucose tolerance test (OGTT) at 16 weeks (left) and AUC (right) in mice from (f) (n = 7, 6, 6, 6). i. Intraperitoneal insulin tolerance test (ipITT) at 18 weeks (left) and AUC (right) in mice from (f) (n = 7, 6, 6, 6). j. Representative western blot of total AKT (t-AKT) and phosphorylated AKT (p-AKT at S473) in iWAT of mice from (f). β-actin as loading control. W, Water; 1,3, 1,3BD. k. Densitometry analysis of (j) (n = 4 for untreated; n = 5 for insulin-treated). l. Gross morphology of iWAT from mice in Fig. 7o; Grid:1 cm×1 cm. m. Cidea and Cox8b mRNA expression in iWAT from Fig. 7o (n = 4/group). n. Representative western blot of UCP1 and β-actin in iWAT from Fig. 7o, with quantification (n = 4/group). β-actin as loading control. Data are means ± SD. Statistical analysis: two-sided Student’s t-test (a–c, e); two-way ANOVA with Tukey’s post hoc test for multiple comparisons (f–i, k, m–n). PO, parental obesity.

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Jiang, CL., Lai, PH., Yang, PC. et al. Early-life ketone body signalling promotes beige fat biogenesis through changes in histone acetylome and β-hydroxybutyrylome. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01378-8

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