Obesity is a worldwide epidemic that predisposes individuals to many age-associated diseases, but its exact effects on organ dysfunction are largely unknown1. Hair follicles—mini-epithelial organs that grow hair—are miniaturized by ageing to cause hair loss through the depletion of hair follicle stem cells (HFSCs)2. Here we report that obesity-induced stress, such as that induced by a high-fat diet (HFD), targets HFSCs to accelerate hair thinning. Chronological gene expression analysis revealed that HFD feeding for four consecutive days in young mice directed activated HFSCs towards epidermal keratinization by generating excess reactive oxygen species, but did not reduce the pool of HFSCs. Integrative analysis using stem cell fate tracing, epigenetics and reverse genetics showed that further feeding with an HFD subsequently induced lipid droplets and NF-κB activation within HFSCs via autocrine and/or paracrine IL-1R signalling. These integrated factors converge on the marked inhibition of Sonic hedgehog (SHH) signal transduction in HFSCs, thereby further depleting lipid-laden HFSCs through their aberrant differentiation and inducing hair follicle miniaturization and eventual hair loss. Conversely, transgenic or pharmacological activation of SHH rescued HFD-induced hair loss. These data collectively demonstrate that stem cell inflammatory signals induced by obesity robustly represses organ regeneration signals to accelerate the miniaturization of mini-organs, and suggests the importance of daily prevention of organ dysfunction.
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Microarray data have been deposited in the GEO database (accession number GSE131958). RNA-seq data have been deposited in the GEO public database (accession number GSE169173). All ATAC data have been deposited in the DNA Databank of Japan (DDBJ) database (https://www.ddbj.nig.ac.jp; accession number DRA008515) Source data are provided with this paper.
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We thank R. Yajima, H. Katagiri, I. Manabe, S. Wakana and Y. Nabeshima for technical support, and DASS Manuscript for editing. E.K.N. is supported by an AMED Project for Elucidating and Controlling Mechanisms of Ageing and Longevity (JP17gm5010002–JP21gm5010002), Scientific Research on Innovative Areas ‘Stem Cell Aging and Disease’ (26115003) and by Aderans Co Ltd. H. Morinaga is supported by a JSPS Grant-in-Aid for Young Scientists (B) (17K15663). A.A.D is supported by an NIH grant (R01 AR045973) and Cancer Center Support grant (P30 CA046592).
E.K.N. is an inventor on a patent application (in preparation) related to this manuscript, which will be filed by the Tokyo Medical and Dental University. The other authors declare no competing interests.
Peer review information Nature thanks Ömer Yilmaz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Extended data figures and tables
a, Experimental design for a, f, g, and representative images of mice fed an ND or an HFD as indicated (n = 4). b, Experimental design for c–e, h. c–e, Representative images of genetically obese mice fed an ND with hair cycle induction at the indicated times (n = 4 mice each for control and obese). f, Representative images of C57BL/6J mice fed an ND or an HFD (n = 3). g, Representative images of female mice fed an ND or an HFD (n = 4). h–j, Representative images (h), fasting blood glucose levels (i) and body weights (j) of streptozocin-induced diabetic mice (ND, n = 4; HFD, n = 4; STZ-treated mice, n = 8; two-tailed Dunnett’s test, **P < 0.05; for exact P values see Source Data). k, Representative images of mice fed an ND or a high-sucrose diet (HSD; n = 4). l, Representative cross-section images of hair follicles from three ND-fed and three HFD-fed mice. Bulge and basal layer stained with COL17A1 and K14, respectively. m–o, Whole-mount images and bulge numbers for ob/ob mice (n = 3, two-tailed unpaired t-test) or HFD-fed female mice (n = 4, two-tailed unpaired t-test). Scale bars, 60 μm. p, Correlation between the degree of obesity and hair follicle number or the number of hair follicles without a bulge (sebaceous gland only) after five months’ treatment with HFD or ND with monthly hair depilation by plucking. Two-tailed Pearson’s correlation coefficient. ns, not significant; wo, without. Data shown as mean ± s.d.
a, Representative images of zigzag hairs (left) and maximum hair diameters of zigzag and awl hairs (right) from 6-month-old mice (4 months of treatment with ND or HFD). n = 4, two-tailed unpaired t-test. b, Lengths of hairs of 6-month-old mice (n = 4, two-tailed unpaired t-test). c, HE staining (left) and interfollicular epidermis (IFE) thickness (right) of skin from ND- or HFD-fed 6-month-old mice (n = 3, two-tailed unpaired t-test). Scale bar, 100 μm. d, Assay of anagen induction of HFD-fed mice; the HFD was started from 4 weeks of age and hair was shaved at 6 weeks of age. Anagen onset was judged by skin colour change (n = 4). e, HE staining of hair follicles from telogen to catagen of 5-month-old mice (3 months of treatment with ND or HFD). Representative images from three mice at each hair stage. Hair depilation by hair plucking was conducted at telogen and samples were observed on the indicated days after depilation. Scale bar, 100 μm. f, Proportions of catagen and telogen hair follicles 20 days after anagen induction. g, h, Whole-mount imaging (g) and section imaging (h) of endothelial cells (CD31+) and neural cells (TUJ1+). Representative images from three mice. Anagen induction was performed by hair depilation using hair plucking. Scale bar, 30 μm. Data shown as mean ± s.d.
a, The locations of GFP+ cells in K15CrePR;Rosa-H2BGFP mice after recombination (n = 2). K15CrePR:Rosa-H2BGFP mice were treated or not treated with Ru486 (representative images, left) and the locations of GFP+ cells were recorded in Ru486-treated mice (right). Scale bar, 50 μm. b, Representative immunostaining for GFP and the suprabasal marker K1 from three mice. Some GFP+ cells, which had been HFSCs at the timing of Ru486 treatment, expressed K1 when they moved up to the epidermis. Anagen induction was performed by hair depilation using hair plucking. Scale bar, 50 μm (left), 30 μm (bottom right). Top right, timing of experiment. c, Representative whole-mount staining for K14 and K1 of hair follicles from three mice. K1 expression was higher in anagen hair follicles of HFD-fed mice than in anagen hair follicles of ND-fed mice. Scale bar, 60 μm. d, FACS analysis of dorsal skin; the CD34highITGA6highSCA1− population was used as HFSCs for qPCR, microarray analyses and ATAC–sec analysis. e, qPCR analysis for Krt1 in HFSCs from ND- or HFD-fed mice. n = 4 mice, two-tailed unpaired t-test. f, Left, immunostaining for activated CASP3, a marker for apoptosis, and K15 in dorsal skin after hair plucking (pk) or hair removal cream. Right, quantification of hair follicles (HF). n = 3 mice, two-tailed unpaired t-test. g, Whole-mount staining of physiological anagen hair follicles (without any experimental treatment to induce anagen) for K1 and K14. Scale bar, 60 μm. Images are representative of mice aged 25 d (P25; n = 3), 10 m (n = 2) or 24 m (n = 1). Dotted lines show bulge regions. h, Representative cross-section staining of anagen hair follicles from three HFD-fed K15crePR;Rosa-H2B-GFP mice for K1 and GFP. Anagen induction was performed by hair depilation using hair plucking. Scale bar, 50 μm. Arrows in g, h indicate ectopic expression of K1. Data shown as mean ± s.d.
a, Col17a1 mRNA expression in telogen HFSCs from young, old, ND-fed and HFD-fed mice without depilation (3-month feeding, n = 3, two-tailed unpaired t-test) derived from microarray data. b, Motif analysis of ATAC–seq data with binomial P values. TF, transcription factor. c–e, RNA-seq analysis of anagen HFSCs from 6-month-old HFD-fed (4 months) and ND-fed mice (n = 2). c, Pathways downregulated in anagen HFSCs from HFD-fed mice were analysed with GSEA by choosing c2.cp.biocarta.v7.2 (curated gene sets) as the gene set correlation. All pathways with GSEA P < 0.05 are shown. d, Enrichment plot for the SHH pathway Biocarta gene set. e, Heatmap of the Biocarta SHH pathway gene set core signature (red to dark blue, high to low expression in the space of the analysed gene set). f, qPCR analysis for Gli1and Ptch1 of HFSCs from 7-week-old ob/ob and db/db mice (n = 4, two-tailed unpaired t-test). ctrl, control t, telogen; a, anagen. Data shown as mean ± s.d.
a, Study design and all images of male Gli2ΔC mice (control, n = 5; Gli2ΔC, n = 6). b, Images of female Gli2ΔC and control mice (n = 2). c, Representative HE staining of the dorsal skin from two control or Gli2ΔC mice. Scale bar, 100 μm. d, Representative images of whole-mount staining from one K15crePR;Rosa-H2BEGFP (ctrl) mice and one K15crePR;Rosa-rtTA;TetO-Gli2ΔC;Rosa-H2BEGFP mouse 5 days after hair depilation. Seven-week-old mice were treated with Ru486 five times and Dox treatment was started in 8-week-old mice simultaneously with hair cycle induction by a hair depilation cream. Scale bar, 60 μm.
Extended Data Fig. 6 Intrafollicular inflammatory milieu in HFSCs from HFD-fed mice coordinately inhibits the SHH pathway and promotes the epidermal commitment of HFSCs.
a, Pathways upregulated in telogen HFSCs from HFD-fed mice (n = 3) analysed with GSEA by choosing C2 (curated gene sets) as the gene set correlation. All pathways with GSEA P < 0.1 are shown. b, GSEA profiles for telogen HFSCs from HFD-fed mice (n = 3) compared with ND-fed mice. c, Left, immunostaining for NFκB and ITGA6. Scale bar, 10 μm. Right, the relative intensity of NFκB translocation was calculated in the nuclei of HFSCs from 6-month-old mice fed an HFD for 4 months (n = 3, two-tailed unpaired t-test). d, qPCR analysis for Il1b using whole skin cells from 7-week-old ob/ob or db/db mice (n = 4, two-tailed unpaired t-test). e, Representative images of 8-oxoguanine (8G) and K15 staining of skin from three mice after 3 months of ND or HFD. f, Representative images of neutral lipid staining by lipidtox in telogen HFSCs from 2-month-old or 5-month-old mice (n = 3 mice). mo, months old. Scale bar, 30 μm. g, Representative images of neutral lipid staining of anagen HFSCs from 6-month-old K15crePR;RosaH2BGFP mice fed ND or HFD (n = 3 mice). Scale bar, 20 μm. h, Immunostaining for Lipidtox, survivin and COL17A1 in the hair follicle bulge and germ on anagen day 3. Representative images from three mice are shown. Five-month-old mice were depilated by plucking to induce anagen. Scale bar, 20 μm. i, qPCR analysis of Gli1, Gli2 and Ptch1 after treatment of mouse neonatal skin with IL6 or TNF (n = 4, one-way ANOVA followed by two-tailed Dunnett’s test). j, Local administration of recombinant IL-1β activates IL-1R signalling and inhibits SHH signalling, especially in aged mice. Left, an atelocollagen sponge impregnated with 1 μg IL-1β or PBS was implanted subcutaneously; qPCR analysis of HFSCs was conducted 1 day after implantation. n = 4 or n = 2 for 7-week- or 17-month-old mice, respectively. Middle, right, relative expression (two-tailed unpaired t-test; see Methods). k, Representative images of 6-month-old Il1ra knockout mice. l, Representative whole-mount staining of skin from three control or Il1ra knockout mice. Scale bar, 60 μm. m, Hair follicle numbers for 6-month-old control or Il1ra knockout mice (n = 3, two-tailed unpaired t-test). Data shown as mean ± s.d.; for exact P values, see Source Data.
Extended Data Fig. 7 Low-grade inflammatory milieu in HFD-fed mice stimulates IL-1β signalling in HFSCs.
a, Ratio of total immune cells (CD45+), macrophages (CD45+CD11b+F4/80+), T cells (CD45+CD3+) and MHC2+ cells (CD45+MHC2+) in the dermis analysed by FACS for 6-month-old mice fed ND or HFD. Ratio of total immune cells (CD45+), T cells (CD45+CD3+) and MHC2+ cells (CD45+MHC2+) in the epidermis analysed by FACS for the same mice (n = 3 mice, two-tailed unpaired t-test; for exact P values see Source Data). b, c, Immunostaining (left) and quantification (right) of MHC2 (b) and CD3 (c) (n = 3, two-tailed unpaired t-test) in hair follicles from 6-month-old mice fed ND or HFD. Scale bars, 30 μm. d, qPCR analysis of Il1b in the indicated populations (n = 3). ND, not detected. e, qPCR analysis of Il1b in anagen HFSCs from ND-fed or HFD-fed mice. Representative results from four mice. Nt, normal diet telogen; Ht, high fat diet telogen; Na, normal diet anagen; Ha, high fat diet anagen. Data shown as mean ± s.d.
Extended Data Fig. 8 Short-term HFD feeding promotes epidermal commitment of HFSCs through the generation of ROS.
a, Total intracellular ROS contents and mitochondrial superoxide production were analysed using DCFDA and MitoSOX, respectively, in telogen or anagen HFSCs from 7-week-old ND- or HFD-fed mice (dorsal skin collected 4 days after treatment; n = 4). MFI, mean fluorescence intensity. b, Representative images (left) and quantification (right) of 8G in skin from ND-fed or HFD-fed mice (n = 3, two-tailed unpaired t-test). Scale bar, 30 μm. c, OCR of total epidermis measured using lipid mixture or palmitate and sequential injection of oligomycin, FCCP and rotenone/antimycin (left). Basal and maximum OCR levels are shown on the right. LM, lipid mixture. PA, palmitic acid (n = 6, one-way ANOVA followed by two-tailed Dunnett’s test). d, Immunostaining for Tom20, a mitochondria marker, in hair follicles from 8-week-old mice with or without short-term exposure to HFD. Representative images from two mice. e, Principal component (PC) analysis of HFSCs after short-term (4 days) or long-term (3 months) treatment with HFD. f, BioCarta pathway enrichment analysis by DAVID using anagen HFSCs after short-term (4 days) treatment with HFD (fold change ≥ 2.0 or < 0.5, n = 1). g, Immunostaining showed that three days of treatment of mouse dorsal skin with 1% H2O2 or one treatment with 5% H2O2 increased the expression of K1 in anagen HFSCs. Scale bar, 50 μm. h, qPCR showed that three days of treatment with H2O2 increased the expression of K1 (n = 3, two-tailed unpaired t-test) but not Gli1 or Ptch1 in anagen HFSCs. Anagen induction was performed by hair depilation using hair plucking. Data shown as mean ± s.d.
a, Experimental design. b, c, Representative images of Tnf knockout (n = 3) and Il1a Il1b double-knockout mice (n = 3). d, Representative images of HFD-fed mice treated with α-lipoic acid (n = 4, see Methods). e, Representative images of HFD-fed Nrf2 knockout mice (n = 3). f, Representative images of HFD-fed COL17A1 transgenic (Tg) mice (Tg, n = 4; control, n = 3). g, Ki67 staining of hair follicles from Gli2ΔN mice. Three days after onset of the hair cycle, the number of proliferating HFSCs in Gli2ΔN mice was higher than in control mice. Anagen induction was performed by hair depilation (dp) using hair plucking. Scale bar, 30 μm. h, Hair width of zigzag hairs in ND-fed, HFD-fed or SAG-treated HFD-fed mice (n = 4, one-way ANOVA followed by two-tailed Tukey’s test). i, A single treatment with SAG after three months (top) did not rescue HFD-induced hair loss (bottom; n = 3). j, Treatment with SAG every week after hair depilation (top) rescued HFD-induced hair loss (bottom; n = 7, one-way ANOVA followed by two-tailed Tukey’s test; for exact P values see Source Data). k, Treatment of aged mice with SAG for one week did not rescue age-associated hair loss. Top left, timeline; bottom left, representative images of mice; middle, whole-mount images of hair follicles; right, quantification of bulges (n = 4, two-tailed unpaired t-test). Data shown as means ± s.d.
Extended Data Fig. 10 Similarities and differences between ageing-induced and obesity-induced hair loss.
Chronological ageing and obesity induce or accelerate hair follicle miniaturization through stem cell depletion that is based on distinct molecular mechanisms. Age-associated repetition of hair cycles causes a sustained DNA damage response in HFSCs to reduce their expression of COL17A1; this results in hemidesmosomal instability, which causes the repetition of atypical stem cell divisions that induce the epidermal differentiation of HFSCs and eventually detach HFSCs from the basement membrane. By sharp contrast, short-term exposure of HFSCs to an HFD causes the accumulation of ROS, and long-term exposure causes lipid droplets in HFSCs, activates IL-1R signalling and inhibits SHH signalling, which induces epidermal and sebocyte differentiation and elimination of lipid-laden HFSCs upon hair cycle-coupled activation. In both cases, those aberrant fate changes occur in a small population of HFSCs upon their activation at early anagen, thereby diminishing the pool of HFSCs in those particular follicles and causing hair follicle miniaturization and hair thinning in a stepwise manner. Because the skin contains a densely arranged hair follicle bulge (niche) that contains abundant HFSC pools, and the expression of the hair thinning phenotype appears with a time delay because of the long duration of the hair cycle, HFSC depletion proceeds in a latent manner and manifests the hair thinning and loss phenotype only after several rounds of hair cycles.
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Morinaga, H., Mohri, Y., Grachtchouk, M. et al. Obesity accelerates hair thinning by stem cell-centric converging mechanisms. Nature 595, 266–271 (2021). https://doi.org/10.1038/s41586-021-03624-x