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Age-associated telomere attrition in adipocyte progenitors predisposes to metabolic disease

Nature Metabolism volume 2, pages 1482–1497 (2020)Cite this article

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Abstract

White and beige adipocytes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are maintained by proliferation and differentiation of adipose progenitor cells (APCs). Here we use mice with tissue-specific telomerase reverse transcriptase (TERT) gene knockout (KO), which undergo premature telomere shortening and proliferative senescence in APCs, to investigate the effect of over-nutrition on APC exhaustion and metabolic dysfunction. We find that TERT KO in the Pdgfra+ cell lineage results in adipocyte hypertrophy, inflammation and fibrosis in SAT, while TERT KO in the Pdgfrb+ lineage leads to adipocyte hypertrophy in both SAT and VAT. Systemic insulin resistance is observed in both KO models and is aggravated by a high-fat diet. Analysis of human biopsies demonstrates that telomere shortening in SAT is associated with metabolic disease progression after bariatric surgery. Our data indicate that over-nutrition can promote APC senescence and provide a mechanistic link between ageing, obesity and diabetes.

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Fig. 1: Telomere attrition and cell senescence in WAT of Pdgfra-TERT-KO mice.
Fig. 2: Transient AT browning in young Pdgfra-TERT-KO mice.
Fig. 3: Metabolism impairment in aged Pdgfra-TERT-KO mice raised on chow.
Fig. 4: HFD exacerbates metabolism impairment in male Pdgfra-TERT-KO mice.
Fig. 5: Pdgfra-TERT-KO females are protected from metabolism impairment.
Fig. 6: Impaired metabolism in male Pdgfrb-TERT-KO mice.
Fig. 7: Changes in AT stroma resulting from senescence of Pdgfra and Pdgfrb lineages.
Fig. 8: Consequences of adipocyte progenitor depletion in mice and humans.

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Data availability

The data that support the findings of this study are available from the corresponding author on request. There are no restrictions on data availability. Raw scRNA-seq data are available from the Gene Expression Omnibus under accession GSE157815. Source data are provided with this paper.

References

  1. Rosen, E. D. & Spiegelman, B. M. What we talk about when we talk about fat. Cell 156, 20–44 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chau, Y. Y. et al. Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. Nat. Cell Biol. 16, 367–375 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Porter, C. et al. Human and mouse brown adipose tissue mitochondria have comparable UCP1 function. Cell Metab. 24, 246–255 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kajimura, S., Spiegelman, B. M. & Seale, P. Brown and beige fat: physiological roles beyond heat generation. Cell Metab. 22, 546–559 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gray, S. L. & Vidal-Puig, A. J. Adipose tissue expandability in the maintenance of metabolic homeostasis. Nutr. Rev. 65, S7–S12 (2007).

    Article  PubMed  Google Scholar 

  8. Ghaben, A. L. & Scherer, P. E. Adipogenesis and metabolic health. Nat. Rev. Mol. Cell. Biol. 20, 242–258 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Orci, L. et al. Rapid transformation of white adipocytes into fat-oxidizing machines. Proc. Natl Acad. Sci. USA 101, 2058–2063 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim, S. M. et al. Loss of white adipose hyperplastic potential is associated with enhanced susceptibility to insulin resistance. Cell Metab. 20, 1049–1058 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hammarstedt, A., Gogg, S., Hedjazifar, S., Nerstedt, A. & Smith, U. Impaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity. Physiol. Rev. 98, 1911–1941 (2018).

    Article  CAS  PubMed  Google Scholar 

  12. Kusminski, C. M. et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat. Med. 18, 1539–1549 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Frazier, T. et al. Gender and age-related cell compositional differences in C57BL/6 murine adipose tissue stromal vascular fraction. Adipocyte 7, 183–189 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Berry, D. C., Jiang, Y. & Graff, J. M. Emerging roles of adipose progenitor cells in tissue development, homeostasis, expansion and thermogenesis. Trends Endoc. Metab. 27, 574–585 (2016).

    Article  CAS  Google Scholar 

  15. Wang, Q. A., Tao, C., Gupta, R. K. & Scherer, P. E. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat. Med. 19, 1338–1344 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Lee, Y. H., Petkova, A. P., Mottillo, E. P. & Granneman, J. G. In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding. Cell Metab. 15, 480–491 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gawronska-Kozak, B., Staszkiewicz, J., Gimble, J. M. & Kirk-Ballard, H. Recruitment of fat cell precursors during high-fat diet in C57BL/6J mice is fat depot specific. Obesity 22, 1091–1102 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Klyde, B. J. & Hirsch, J. Increased cellular proliferation in adipose tissue of adult rats fed a high-fat diet. J. Lipid Res. 20, 705–715 (1979).

    Article  CAS  PubMed  Google Scholar 

  19. Maumus, M. et al. Evidence of in situ proliferation of adult adipose tissue-derived progenitor cells: influence of fat mass microenvironment and growth. J. Clin. Endocrinol. Metab. 93, 4098–4106 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Jeffery, E., Church, C. D., Holtrup, B., Colman, L. & Rodeheffer, M. S. Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. Nat. Cell Biol. 17, 376–385 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kras, K. M., Hausman, D. B., Hausman, G. J. & Martin, R. J. Adipocyte development is dependent upon stem cell recruitment and proliferation of preadipocytes. Obes. Res. 7, 491–447 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Merrick, D. et al. Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science 364, eaav2501 (2019).

  23. Tang, W. et al. White fat progenitor cells reside in the adipose vasculature. Science 322, 583–586 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Berry, R., Jeffery, E. & Rodeheffer, M. S. Weighing in on adipocyte precursors. Cell Metab. 19, 8–20 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Rodeheffer, M. S., Birsoy, K. & Friedman, J. M. Identification of white adipocyte progenitor cells in vivo. Cell 135, 240–249 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Hepler, C. et al. Identification of functionally distinct fibro-inflammatory and adipogenic stromal sub-populations in visceral adipose tissue of adult mice. eLife 7, e39636 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Traktuev, D. et al. A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ. Res. 102, 77–85 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Vishvanath, L. et al. Pdgfrβ+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice. Cell Metab. 23, 350–359 (2016).

    Article  CAS  PubMed  Google Scholar 

  29. Berry, R. & Rodeheffer, M. S. Characterization of the adipocyte cellular lineage in vivo. Nat. Cell Biol. 15, 302–308 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Raajendiran, A. et al. Identification of metabolically distinct adipocyte progenitor cells in human adipose tissues. Cell Rep. 27, 1528–1540 (2019).

    Article  CAS  PubMed  Google Scholar 

  31. Daquinag, A. C., Salameh, A., Zhang, Y., Tong, Q. & Kolonin, M. G. Depletion of white adipocyte progenitors induces beige adipocyte differentiation and suppresses obesity development. Cell Death Differ. 22, 351–363 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Gao, Z., Daquinag, A. C., Su, F., Snyder, B. & Kolonin, M. G. PDGFRα/PDGFRβ signaling balance modulates progenitor cell differentiation into white and beige adipocytes. Development 145, 1–13 (2018).

    Article  CAS  Google Scholar 

  33. Henninger, A. M., Eliasson, B., Jenndahl, L. E. & Hammarstedt, A. Adipocyte hypertrophy, inflammation and fibrosis characterize subcutaneous adipose tissue of healthy, non-obese subjects predisposed to type 2 diabetes. PLoS ONE 9, e105262 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Xu, M. et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife 4, e12997 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Palmer, A. K. et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 18, e12950 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Berry, D. C. et al. Cellular aging contributes to failure of cold-induced beige adipocyte formation in old mice and humans. Cell Metab. 25, 166–181 (2017).

    Article  CAS  PubMed  Google Scholar 

  37. Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019).

    Article  CAS  PubMed  Google Scholar 

  38. Whittemore, K., Vera, E., Martinez-Nevado, E., Sanpera, C. & Blasco, M. A. Telomere shortening rate predicts species life span. Proc. Natl Acad. Sci. USA 116, 15122–15127 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Calado, R. T. & Dumitriu, B. Telomere dynamics in mice and humans. Semin. Hematol. 50, 165–174 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Blasco, M. A. Telomere length, stem cells and aging. Nat. Chem. Biol. 3, 640–649 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Blackburn, E. H., Greider, C. W. & Szostak, J. W. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat. Med. 12, 1133–1138 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Welendorf, C. et al. Obesity, weight loss and influence on telomere length: new insights for personalized nutrition. Nutrition 66, 115–121 (2019).

    Article  CAS  PubMed  Google Scholar 

  43. Kipling, D. & Cooke, H. J. Hypervariable ultra-long telomeres in mice. Nature 347, 400–402 (1990).

    Article  CAS  PubMed  Google Scholar 

  44. Sacco, A. et al. Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mTR mice. Cell 143, 1059–1071 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu, T. et al. Conditional knockout of telomerase reverse transcriptase in mesenchymal cells impairs mouse pulmonary fibrosis. PLoS ONE 10, e0142547 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Sahin, E. & Depinho, R. A. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464, 520–528 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mender, I. & Shay, J. W. Telomere restriction fragment (TRF) analysis. Bio. Protoc. 5, e1658 (2015).

    PubMed  Google Scholar 

  50. O’Callaghan, N. J. & Fenech, M. A quantitative PCR method for measuring absolute telomere length. Biol. Proced. Online 13, 3 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Randle, D. H., Zindy, F., Sherr, C. J. & Roussel, M. F. Differential effects of p19Arf and p16Ink4a loss on senescence of murine bone marrow-derived preB cells and macrophages. Proc. Natl Acad. Sci. USA 98, 9654–9659 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Capparelli, C. et al. CDK inhibitors (p16/p19/p21) induce senescence and autophagy in cancer-associated fibroblasts, ‘fueling’ tumor growth via paracrine interactions, without an increase in neo-angiogenesis. Cell Cycle 11, 3599–3610 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Burl, R. B. et al. Deconstructing adipogenesis induced by β3-adrenergic receptor activation with single-cell expression profiling. Cell Metab. 28, 300–309 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Daquinag, A. C., Zhang, Y., Amaya-Manzanares, F., Simmons, P. J. & Kolonin, M. G. An isoform of decorin is a resistin receptor on the surface of adipose progenitor cells. Cell Stem Cell 9, 74–86 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Patel, P. & Abate, N. Role of subcutaneous adipose tissue in the pathogenesis of insulin resistance. J. Obes. 2013, 489187 (2013).

    PubMed  PubMed Central  Google Scholar 

  57. Iwayama, T. et al. PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity. Genes Dev. 29, 1106–1119 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sun, K., Gao, Z. & Kolonin, M. G. Transient inflammatory signaling promotes beige adipogenesis. Sci. Signal. 11, eaat3192 (2018).

  59. Romaniuk, A. et al. The non-canonical functions of telomerase: to turn off or not to turn off. Mol. Biol. Rep. 46, 1401–1411 (2019).

    Article  CAS  PubMed  Google Scholar 

  60. Stewart, S. A. et al. Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc. Natl Acad. Sci. USA 99, 12606–12611 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Muñoz-Lorente, M. A., Cano-Martin, A. C. & Blasco, M. A. Mice with hyper-long telomeres show less metabolic aging and longer lifespans. Nat. Commun. 10, 4723 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Karastergiou, K. & Fried, S. K. Cellular mechanisms driving sex differences in adipose tissue biology and body shape in humans and mouse models. Adv. Exp. Med. Biol. 1043, 29–51 (2017).

    Article  CAS  PubMed  Google Scholar 

  63. Nordstrom, A., Hadrevi, J., Olsson, T., Franks, P. W. & Nordstrom, P. Higher prevalence of type 2 diabetes in men than in women is associated with differences in visceral fat mass. J. Clin. Endoc. Metab. 101, 3740–3746 (2016).

    Article  CAS  Google Scholar 

  64. Cherif, H., Tarry, J. L., Ozanne, S. E. & Hales, C. N. Ageing and telomeres: a study into organ- and gender-specific telomere shortening. Nuc. Acids Res. 31, 1576–1583 (2003).

    Article  CAS  Google Scholar 

  65. Wang, J. et al. Association between telomere length and diabetes mellitus: a meta-analysis. J. Int. Med. Res. 44, 1156–1173 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Elks, C. E. & Scott, R. A. The long and short of telomere length and diabetes. Diabetes 63, 65–67 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Mundstock, E. et al. Effect of obesity on telomere length: systematic review and meta-analysis. Obesity 23, 2165–2174 (2015).

    Article  PubMed  Google Scholar 

  68. Kirchner, H. et al. The telomeric complex and metabolic disease. Genes 8, 176 (2017).

  69. Gielen, M. et al. Body mass index is negatively associated with telomere length: a collaborative cross-sectional meta-analysis of 87 observational studies. Am. J. Clin. Nutr. 108, 453–475 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Lakowa, N. et al. Telomere length differences between subcutaneous and visceral adipose tissue in humans. Biochem. Biophys. Res. Commun. 457, 426–432 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Gustafson, B., Nerstedt, A. & Smith, U. Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells. Nat. Commun. 10, 2757 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Joe, A. W., Yi, L., Even, Y., Vogl, A. W. & Rossi, F. M. Depot-specific differences in adipogenic progenitor abundance and proliferative response to high-fat diet. Stem Cells 27, 2563–2570 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Cuttler, A. S. et al. Characterization of Pdgfrb-Cre transgenic mice reveals reduction of ROSA26 reporter activity in remodeling arteries. Genesis 49, 673–680 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    CAS  PubMed  Google Scholar 

  75. Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies and species. Nat. Biotechnol. 36, 411–420 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank S. H. Pan for the TERT floxed mice and V. Lindner for Pdgfrb-Cre mice. We thank Z. Mao for help with microscopy. We also thank ‪A. Ribas-Latre‬ and E. Sahin for expert advice. This work was supported by the Harry E. Bovay, Jr. Foundation. Z.Z. and Y.D. were partially supported by the Cancer Genomics Core funded by the Cancer Prevention and Research Institute of Texas (CPRIT) (RP180734) and National Institutes of Health grant (R01LM012806).

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Authors and Affiliations

  1. Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX, USA

    Zhanguo Gao, Alexes C. Daquinag, Cale Fussell, Kristin L. Eckel-Mahan & Mikhail G. Kolonin

  2. Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Zhongming Zhao & Yulin Dai

  3. Memorial Hermann Texas Medical Center, Houston, TX, USA

    Angielyn Rivera & Brad E. Snyder

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M.G.K. and Z.G. conceived/designed experiments; Z.G., A.C.D., C.F., K.M., Z.Z. and Y.D. performed experiments and analysed data. M.G.K., Z.G. and K.L.E.-M. wrote and edited the manuscript.

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Correspondence to Mikhail G. Kolonin.

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Extended data

Extended Data Fig. 1 Telomere attrition / cell senescence in WAT of a-KO mice.

a, TRF assay reveals advanced telomere shortening in SAT of both a-KO males (M) and females (F) at 8 months of age. b, Telo-FISH staining (red) on sections from Pdgfra-Cre;mTmG;TERTfl/fl (WT) and Pdgfra-Cre;mTmG;TERTfl/fl male mice reveals normal telomeres in mG+ cells of brain and muscle. c, Telo-FISH staining on culture-plated cells from VAT and SAT of control Pdgfra-Cre; mTmG and Pdgfra-Cre; mTmG; TERTfl/fl mice reveals advanced telomere shortening (less red signal) in SAT mG+ cells of a-KO mice. d, Telo-FISH staining on SAT sections from mice in c reveals telomere shortening and nuclear p16 IF signal in mG+ cells of a-KO mice. e, q-PCR reveals telomere shortening in SAT of 8-month old WT mice compared to 3-month old WT mice. Evident is more advanced telomere shortening in SAT of 8-month old α-KO males (M) and females (F), compared to 8-month old WT males and females, respectively. f, Quantitative RT-PCR analysis reveals higher p16 and p21 mRNA expression in VAT and SAT of a-KO mice, compared to WT mice, at 6 months of age. Data are normalized to 18S RNA. N = 3 mice / group. Scale bar=50 µm in all panels. P: Student’s t-test (2-sided).

Extended Data Fig. 2 Transient AT browning in young Pdgfra-TERT-KO (a-KO) mice.

a, Quantitative RT-PCR demonstrates higher Pdgfa mRNA expression in VAT and SAT of 6 month old KO males, compared to 6 month old WT males. Data are normalized to 18S RNA. b, Quantitative RT-PCR demonstrates higher Pdgfa mRNA expression in SVF from SAT of 3 month-old KO males, which is not accompanied by increased p16 and p21 expression at that age. In contrast, in SVF from SAT of 7 month-old KO males, higher Pdgfa expression is accompanied by increased p16 and p21 mRNA expression. Data are normalized to 18S RNA. N = 3 mice / group. P: Student’s t-test (2-sided).

Extended Data Fig. 3 Metabolism impairment in old Pdgfra-TERT-KO (a-KO) mice raised on chow.

a, qPCR analysis of DNA from whole tissue reveals telomere shortening in SAT but not in VAT of a-KO mice at 8 months of age, compared to WT mice at 8 months of age. Real-time PCR data are normalized to data for a single copy gene. b, Quantitative RT-PCR demonstrates higher p16 and TNFa mRNA expression, normalized to 18S RNA, in cultured MEFs of a-KO mice, compared to WT mice. c, EdU incorporation measurement by flow cytometry in control mTmG;TERTfl/fl and a-KO Pdgfra-Cre;mTmG; TERTfl/fl males (2-month-old, HFD-fed) and females (20-month-old, chow-fed). 4 h after EdU injection, mG+ and mT+ SVF cells were gated and EdU incorporation was compared for SAT. EdU fluorescence: 647 nm channel, side scatter (SSC) is used for separation. d, IF analysis of SAT from 12-month-old mice reveals increased infiltration of CD68+ CD206- (M1) macrophages and increased phosphorylation of NFkB subunit p65 in PDGFRα+ cells of a-KO mice, compared to WT mice. Adipocytes are positive for perilipin1 (PLN1). Nuclei are blue. e, Masson’s trichrome staining reveals increased fibrosis in livers of 12-month-old a-KO males compared to WT males. In all panels, N = 3 mice / group; P: Student’s t-test (2-sided). Scale bar=50 µm in all panels.

Extended Data Fig. 4 HFD exacerbates metabolism impairment in male Pdgfra-TERT-KO (a-KO) mice.

a, Echo MRI data demonstrating comparable fat mass in a-KO and WT males raised on HFD for indicated number of months. N = 5-6 mice / group. b, Comparable food intake by a-KO and WT males raised on HFD. N = 5-6 mice / group. c, Comparable spontaneous locomotor activity of a-KO and WT males raised on HFD. N = 5-6 mice / group. d, Comparable physical endurance, reflected by Joules of work performed, by a-KO and WT males. N = 5-6 mice / group. e, Indirect calorimetry based on oxygen consumption (VO2) and carbon dioxide production (VCO2) indicates decreased energy expenditure in a-KO males pre-fed HFD for 8 months. N = 5-6 mice / group. f, Masson’s trichrome staining of VAT from a-KO and WT males raised on HFD for 8 months. g, Telo-FISH staining (red) on SAT and VAT sections from Pdgfra-Cre;mTmG mice raised on chow or HFD revealing a higher degree of telomere shortening (less red signal) induced by DIO in mG+ cells. a-g, N = 5-6 mice / group. Scale bar=50 µm in all panels. P: Student’s t-test (2-sided).

Extended Data Fig. 5 Pdgfra-TERT-KO (a-KO) females are protected from metabolism impairment.

a, Echo MRI data demonstrating lower fat mass in a-KO females raised on HFD for indicated number of months. N = 5-6 mice / group. b, H&E staining demonstrates smaller BAT adipocytes and normal liver and muscle anatomy in a-KO females raised on HFD. Scale bar=50 µm. c, Quantitative RT-PCR demonstrates a lack of p16 induction, despite higher Pdgfa mRNA expression, in SAT of 4-month old a-KO females, compared to 4 month old WT females. Data normalized to 18S RNA. N = 5-6 mice / group. P: Student’s t-test (2-sided).

Extended Data Fig. 6 Senescence and metabolism in Pdgfrb-TERT-KO (b-KO) mice.

a, Quantitative RT-PCR demonstrates higher senescence marker and pdgfa induction in VAT than in SAT of 8-month old b-KO males compared to WT males. Data normalized to 18S RNA. N = 5 mice / group. b, Comparable food intake by b-KO and WT males. c, Comparable spontaneous locomotor activity of b-KO and WT males. d, RER in males calculated based on oxygen consumption (VO2) and carbon dioxide production (VCO2). e, Indirect calorimetry-based measurement of energy expenditure in b-KO and WT males at 8 months of age. f, Comparable cold tolerance in b-KO and WT males placed at 4 °C. g, H&E staining does not reveal abnormality in BAT and liver of b-KO males at 8 months of age. Scale bar=50 µm. h, Echo MRI data: no body composition abnormality in b-KO females at 8 months of age. i, ITT: no insulin resistance in 8-month-old b-KO females. j, Comparable cold tolerance in b-KO and WT females placed at 4 °C. N = 6 mice / group. P: Student’s t-test (2-sided).

Extended Data Fig. 7 Gene expression in ASC of Pdgfra-TERT-KO (a-KO) mice.

a, ScRNAseq data violin plots showing that Pdgfra is expressed in both Dpp4+ and Cd142+ cells, while Pdgfrb is mainly expressed in Cd142+ cells. b, UMAPs of WT, a-KO and b-KO SAT CD45- SVF cells from Fig. 7c were overlapped to identify cells expressing genes assigned in Fig. 7d. N = 4 mice / group (combined). c, Expression of Cdkn1a and Pdgfa determined by scRNAseq for combined Dpp4+ and Cd142+ ASC compared for WT, a-KO, and b-KO mice.

Extended Data Fig. 8 Changes in AT stroma resulting from senescence of Pdgfra and Pdgfrb lineages.

a, IF analysis of SAT reveals increased infiltration of PDGFRα+ (orange, anti-rat Cy5 secondary antibody) and PDGFRb+ (red, anti-rabbit Cy3 secondary antibody) cells in a-KO and b-KO 1-year-old males raised on chow compared to WT male littermates. Isolectin B4 (green) stains endothelium. Nuclei are blue. Scale bar=50 µm. Graph: the ratio of positive cells / total nucleated cells in 4-5 view fields / sample. Plotted are mean +/- SEM. P: Student’s t-test (2-sided). Analysis of tissues from 3 mice / genotype showed similar results. b, Changes in AT stroma resulting from senescence of Pdgfra and Pdgfrb lineages in VAT. UMAP clusters of cells identified by scRNAseq in VAT of TERT a-KO and b-KO mice. Shown are ASC, EC and PA only, CD45+ leukocytes are not shown. Note selective accumulation of Cd142+ ASC in VAT of b-KO mice. Note high expression of Cdkn1a and IL-6 and low expression on Ki67 in ASC.

Extended Data Fig. 9 Consequences of pharmacological adipocyte progenitor depletion in mice treated with D-WAT.

WT males pre-treated with D-WAT or PBS (control) at 4 months of age were subsequently maintained on HFD and analyzed 9 months later. a, Echo MRI data reveals higher adiposity in old mice pre-treated with D-WAT. b, H&E staining reveals larger adipocytes and fibrosis (arrow) in SAT of old mice pre-treated with D-WAT. Scale bar=50 µm. c, GTT reveals lower glucose tolerance of old mice pre-treated with D-WAT. N = 4 mice / group. *P < 0.05 (Student’s t-test, 2-sided).

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Supplementary Tables 1 and 2 and Supplementary Fig. 1.

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Uncropped gel for Fig. 1c.

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Uncropped immunoblots for Fig. 3h.

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Gao, Z., Daquinag, A.C., Fussell, C. et al. Age-associated telomere attrition in adipocyte progenitors predisposes to metabolic disease. Nat Metab 2, 1482–1497 (2020). https://doi.org/10.1038/s42255-020-00320-4

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