Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Obesity accelerates hair thinning by stem cell-centric converging mechanisms


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Obesity accelerates hair loss through fate switching and depletion of HFSCs.
Fig. 2: An HFD inhibits the SHH pathway to promote fate switching of HFSCs towards epidermal differentiation.
Fig. 3: HFD-induced stem cell inflammageing with oxidative stress accelerates HFSC depletion and resultant hair loss through inhibition of SHH signalling.
Fig. 4: SHH activation in HFSCs prevents HFD-induced hair loss by targeting the converging roots of HFSCs.

Data availability

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 (; accession number DRA008515) Source data are provided with this paper.


  1. 1.

    Novak, J. S. S., Baksh, S. C. & Fuchs, E. Dietary interventions as regulators of stem cell behavior in homeostasis and disease. Genes Dev. 35, 199–211 (2021).

    CAS  Article  Google Scholar 

  2. 2.

    Matsumura, H. et al. Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. Science 351, aad4395 (2016).

    Article  Google Scholar 

  3. 3.

    Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 348, 1625–1638 (2003).

    Article  Google Scholar 

  4. 4.

    Sakaue, S. et al. Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan. Nat. Med. 26, 542–548 (2020).

    CAS  Article  Google Scholar 

  5. 5.

    Aune, D. et al. BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants. Br. Med. J. 353, i2156 (2016).

    Article  Google Scholar 

  6. 6.

    Ambrosi, T. H. et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell 20, 771–784.e6 (2017).

    CAS  Article  Google Scholar 

  7. 7.

    Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).

    CAS  Article  ADS  Google Scholar 

  8. 8.

    Inomata, K. et al. Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell 137, 1088–1099 (2009).

    CAS  Article  Google Scholar 

  9. 9.

    Oh, J., Lee, Y. D. & Wagers, A. J. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat. Med. 20, 870–880 (2014).

    CAS  Article  Google Scholar 

  10. 10.

    Flach, J. et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512, 198–202 (2014).

    CAS  Article  ADS  Google Scholar 

  11. 11.

    Matsumura, H. et al. Distinct types of stem cell divisions determine organ regeneration and aging in hair follicles. Nat. Aging 1, 190–204 (2021).

    Article  Google Scholar 

  12. 12.

    Matilainen, V., Koskela, P. & Keinänen-Kiukaanniemi, S. Early androgenetic alopecia as a marker of insulin resistance. Lancet 356, 1165–1166 (2000).

    CAS  Article  Google Scholar 

  13. 13.

    Driskell, R. R. et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504, 277–281 (2013).

    CAS  Article  ADS  Google Scholar 

  14. 14.

    Salzer, M. C. et al. Identity noise and adipogenic traits characterize dermal fibroblast aging. Cell 175, 1575–1590.e22 (2018).

    CAS  Article  Google Scholar 

  15. 15.

    Chen, C. C., Plikus, M. V., Tang, P. C., Widelitz, R. B. & Chuong, C. M. The modulatable stem cell niche: tissue interactions during hair and feather follicle regeneration. J. Mol. Biol. 428, 1423–1440 (2016).

    CAS  Article  Google Scholar 

  16. 16.

    Festa, E. et al. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell 146, 761–771 (2011).

    CAS  Article  Google Scholar 

  17. 17.

    Rompolas, P. & Greco, V. Stem cell dynamics in the hair follicle niche. Semin. Cell Dev. Biol. 25-26, 34–42 (2014).

    Article  Google Scholar 

  18. 18.

    Nakajima, T. et al. Roles of MED1 in quiescence of hair follicle stem cells and maintenance of normal hair cycling. J. Invest. Dermatol. 133, 354–360 (2013).

    CAS  Article  Google Scholar 

  19. 19.

    Greco, V. et al. A two-step mechanism for stem cell activation during hair regeneration. Cell Stem Cell 4, 155–169 (2009).

    CAS  Article  Google Scholar 

  20. 20.

    Xing, L. et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat. Med. 20, 1043–1049 (2014).

    CAS  Article  Google Scholar 

  21. 21.

    St-Jacques, B. et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058–1068 (1998).

    CAS  Article  Google Scholar 

  22. 22.

    Ouspenskaia, T., Matos, I., Mertz, A. F., Fiore, V. F. & Fuchs, E. WNT-SHH antagonism specifies and expands stem cells prior to niche formation. Cell 164, 156–169 (2016).

    CAS  Article  Google Scholar 

  23. 23.

    Hsu, Y. C., Li, L. & Fuchs, E. Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157, 935–949 (2014).

    CAS  Article  Google Scholar 

  24. 24.

    Ermilov, A. N. et al. Maintenance of taste organs is strictly dependent on epithelial hedgehog/GLI signaling. PLoS Genet. 12, e1006442 (2016).

    Article  Google Scholar 

  25. 25.

    Furukawa, S. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Invest. 114, 1752–1761 (2004).

    CAS  Article  Google Scholar 

  26. 26.

    Lichti, U., Anders, J. & Yuspa, S. H. Isolation and short-term culture of primary keratinocytes, hair follicle populations and dermal cells from newborn mice and keratinocytes from adult mice for in vitro analysis and for grafting to immunodeficient mice. Nat. Protocols 3, 799–810 (2008).

    CAS  Article  Google Scholar 

  27. 27.

    Wang, Y. et al. Interleukin-1β induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes. PLoS ONE 9, e110024 (2014).

    Article  ADS  Google Scholar 

  28. 28.

    Horai, R. et al. Production of mice deficient in genes for interleukin (IL)-1α, IL-1β, IL-1 α/β, and IL-1 receptor antagonist shows that IL-1β is crucial in turpentine-induced fever development and glucocorticoid secretion. J. Exp. Med. 187, 1463–1475 (1998).

    CAS  Article  Google Scholar 

  29. 29.

    Tanaka, Y. et al. NF-E2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet. J. Pharmacol. Exp. Ther. 325, 655–664 (2008).

    CAS  Article  Google Scholar 

  30. 30.

    Grachtchouk, M. et al. Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations. J. Clin. Invest. 121, 1768–1781 (2011).

    CAS  Article  Google Scholar 

  31. 31.

    Ito, M. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat. Med. 11, 1351–1354 (2005).

    CAS  Article  Google Scholar 

  32. 32.

    Taniyama, Y. et al. Beneficial effect of intracoronary verapamil on microvascular and myocardial salvage in patients with acute myocardial infarction. J. Am. Coll. Cardiol. 30, 1193–1199 (1997).

    CAS  Article  Google Scholar 

  33. 33.

    Itoh, K. et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236, 313–322 (1997).

    CAS  Article  Google Scholar 

  34. 34.

    Nishie, W. et al. Humanization of autoantigen. Nat. Med. 13, 378–383 (2007).

    CAS  Article  Google Scholar 

  35. 35.

    Yang, R. L., Li, W., Shi, Y. H. & Le, G. W. Lipoic acid prevents high-fat diet-induced dyslipidemia and oxidative stress: a microarray analysis. Nutrition 24, 582–588 (2008).

    Article  Google Scholar 

  36. 36.

    Fujiwara, H. et al. The basement membrane of hair follicle stem cells is a muscle cell niche. Cell 144, 577–589 (2011).

    CAS  Article  Google Scholar 

  37. 37.

    Jensen, K. B., Driskell, R. R. & Watt, F. M. Assaying proliferation and differentiation capacity of stem cells using disaggregated adult mouse epidermis. Nat. Protocols 5, 898–911 (2010).

    CAS  Article  Google Scholar 

  38. 38.

    Ba, X. & Boldogh, I. 8-Oxoguanine DNA glycosylase 1: beyond repair of the oxidatively modified base lesions. Redox Biol. 14, 669–678 (2018).

    CAS  Article  Google Scholar 

  39. 39.

    Solanas, G. et al. Aged stem cells reprogram their daily rhythmic functions to adapt to stress. Cell 170, 678–692.e20 (2017).

    CAS  Article  Google Scholar 

Download references


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).

Author information




H. Morinaga performed the majority of experiments with support from Y.M., K.A., H. Matsumura, Y.N., T.S., T.K. and A.I. M.G. and A.A.D. prepared Gli2ΔC and Gli2ΔN mice. M.O., N.T. and A.I. performed and analysed ATAC–seq. Y.I. prepared Il1ra knockout and Il1a;Il1b knockout mice. Y.S. and K.T. helped to perform the OCR assay. H. Morinaga and E.K.N designed the study and wrote the manuscript.

Corresponding author

Correspondence to Emi K. Nishimura.

Ethics declarations

Competing interests

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.

Additional information

Peer review information Nature thanks Ömer Yilmaz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Obesity accelerates hair loss with repeated hair cycle induction.

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 ce, h. ce, 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). hj, 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. mo, 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.

Source data

Extended Data Fig. 2 An HFD prematurely accelerates hair cycle progression.

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.

Source data

Extended Data Fig. 3 HFD feeding causes HFSCs to prematurely commit to epidermal differentiation.

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.

Source data

Extended Data Fig. 4 SHH signalling is inhibited specifically in HFSCs from HFD-fed mice.

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. ce, 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.

Source data

Extended Data Fig. 5 SHH inhibition causes hair loss after one hair cycle.

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.

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.

Source data

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.

Source data

Extended Data Fig. 9 SHH signal activation partially rescues HFD-induced hair thinning.

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.

Source data

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.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-4.

Reporting Summary

Source data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Morinaga, H., Mohri, Y., Grachtchouk, M. et al. Obesity accelerates hair thinning by stem cell-centric converging mechanisms. Nature 595, 266–271 (2021).

Download citation


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing