Skip to main content

Thank you for visiting nature.com. 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.

  • Review Article
  • Published:

The evolving functions of the vasculature in regulating adipose tissue biology in health and obesity

Nature Reviews Endocrinology volume 19, pages 691–707 (2023)Cite this article

Subjects

Abstract

Adipose tissue is an endocrine organ and a crucial regulator of energy storage and systemic metabolic homeostasis. Additionally, adipose tissue is a pivotal regulator of cardiovascular health and disease, mediated in part by the endocrine and paracrine secretion of several bioactive products, such as adipokines. Adipose vasculature has an instrumental role in the modulation of adipose tissue expansion, homeostasis and metabolism. The role of the adipose vasculature has been extensively explored in the context of obesity, which is recognized as a global health problem. Obesity-induced accumulation of fat, in combination with vascular rarefaction, promotes adipocyte dysfunction and induces oxidative stress, hypoxia and inflammation. It is now recognized that obesity-associated endothelial dysfunction often precedes the development of cardiovascular diseases. Investigations have revealed heterogeneity within the vascular niche and dynamic reciprocity between vascular and adipose cells, which can become dysregulated in obesity. Here we provide a comprehensive overview of the evolving functions of the vasculature in regulating adipose tissue biology in health and obesity.

Key points

  • Advances in technology have uncovered the heterogeneity of the adipose tissue endothelium, revealing that it consists of canonical (venous, capillary, arterial, lymphatic) and adipose tissue-specific (pre-adipocytes, early progenitor endothelial cells, and immunomodulatory endothelial cells) vascular subpopulations.

  • Adipose tissue endothelial phenotypes and gene transcription are governed by a plethora of transcription factors (and their post-translational modifications) and non-coding RNAs. Further investigation into transcriptional and epigenetic factors modulating adipose tissue endothelial phenotypes is warranted.

  • The vasculature of adipose tissue serves as a bidirectional channel for lipids, immune cells, and adipokines. Furthermore, endothelial cells within this tissue maintain active communication with adjacent adipocytes, particularly through paracrine signals such as extracellular vesicles.

  • Obesity correlates with disrupted blood flow in adipose tissue, endothelial dysfunction and reduced vascular density. These changes collectively lead to tissue hypoxia, inflammation and fibrosis.

  • Vascular ageing and obesity-associated vascular malfunction exhibit several common characteristics. Rejuvenating the vasculature might hold the potential to counteract the metabolic deterioration associated with obesity.

  • Obesity correlates with disturbances in the circadian rhythm of adipose tissue, which can trigger metabolic disorders; however, the chronobiology of adipose tissue endothelial cells is still largely unexplored.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Transcriptional heterogeneity of adipose tissue endothelial cells.
Fig. 2: Adipose tissue endothelial cell (inter)communication.
Fig. 3: Bidirectional mechanisms promoting endothelial and adipose dysfunction.
Fig. 4: Ageing and its impact on the vasculature of the adipose tissue.

Similar content being viewed by others

References

  1. Wolfrum, C. & Gerhart-Hines, Z. Fueling the fire of adipose thermogenesis. Science 375, 1229–1231 (2022).

    Article  CAS  PubMed  Google Scholar 

  2. Chew, N. W. S. et al. The global burden of metabolic disease: data from 2000 to 2019. Cell Metab. 35, 414–428.e3 (2023).

    Article  CAS  PubMed  Google Scholar 

  3. Herold, J. & Kalucka, J. Angiogenesis in adipose tissue: the interplay between adipose and endothelial cells. Front. Physiol. 11, 624903 (2020).

    Article  PubMed  Google Scholar 

  4. Li, M., Qian, M. & Xu, J. Vascular endothelial regulation of obesity-associated insulin resistance. Front. Cardiovasc. Med. 4, 51 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  5. Kalucka, J. et al. Single-cell transcriptome atlas of murine endothelial cells. Cell 180, 764–779.e20 (2020).

    Article  CAS  PubMed  Google Scholar 

  6. Emont, M. P. et al. A single-cell atlas of human and mouse white adipose tissue. Nature 603, 926–933 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Strieder-Barboza, C. et al. Single-nuclei transcriptome of human AT reveals metabolically distinct depot-specific adipose progenitor subpopulations. Preprint at bioRxiv https://doi.org/10.1101/2022.06.29.496888 (2022).

  8. Whytock, K. L. et al. Single cell full-length transcriptome of human subcutaneous adipose tissue reveals unique and heterogeneous cell populations. iScience 25, 104772 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Crewe, C. et al. An endothelial-to-adipocyte extracellular vesicle axis governed by metabolic state. Cell 175, 695–708.e13 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Bondareva, O. & Sheikh, B. N. Vascular homeostasis and inflammation in health and disease-lessons from single cell technologies. Int. J. Mol. Sci. 21, 4688 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Vijay, J. et al. Single-cell analysis of human adipose tissue identifies depot and disease specific cell types. Nat. Metab. 2, 97–109 (2020).

    Article  PubMed  Google Scholar 

  12. Bondareva, O. et al. Single-cell profiling of vascular endothelial cells reveals progressive organ-specific vulnerabilities during obesity. Nat. Metab. 4, 1591–1610 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. AlZaim, I., Festa, J. & Kalucka, J. Adipose tissue lymphatic endothelial cells: revisited functions in the modulation of adipose biology. Curr. Opin. Physiol. 34, 100675 (2023).

    Article  CAS  Google Scholar 

  14. Corvera, S., Solivan-Rivera, J. & Yang Loureiro, Z. Angiogenesis in adipose tissue and obesity. Angiogenesis 25, 439–453 (2022).

    Article  PubMed Central  PubMed  Google Scholar 

  15. Tabula Sapiens, C. et al. The tabula sapiens: a multiple-organ, single-cell transcriptomic atlas of humans. Science 376, eabl4896 (2022).

    Article  Google Scholar 

  16. Abumrad, N. A. et al. Endothelial cell receptors in tissue lipid uptake and metabolism. Circ. Res. 128, 433–450 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Pi, X., Xie, L. & Patterson, C. Emerging roles of vascular endothelium in metabolic homeostasis. Circ. Res. 123, 477–494 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Ioannidou, A., Fisher, R. M. & Hagberg, C. E. The multifaceted roles of the adipose tissue vasculature. Obes. Rev. 23, e13403 (2022).

    Article  PubMed  Google Scholar 

  19. Massier, L. et al. An integrated single cell and spatial transcriptomic map of human white adipose tissue. Nat. Commun. 14, 1438 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Amersfoort, J., Eelen, G. & Carmeliet, P. Immunomodulation by endothelial cells – partnering up with the immune system? Nat. Rev. Immunol. 22, 576–588 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Haynes, B. A. et al. Endothelial-to-mesenchymal transition in human adipose tissue vasculature alters the particulate secretome and induces endothelial dysfunction. Arterioscler. Thromb. Vasc. Biol. 39, 2168–2191 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Johnston, E. K. & Abbott, R. D. Adipose tissue paracrine-, autocrine-, and matrix-dependent signaling during the development and progression of obesity. Cells 12, 407 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Cano, A. et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol. 2, 76–83 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Villarejo, A., Cortes-Cabrera, A., Molina-Ortiz, P., Portillo, F. & Cano, A. Differential role of Snail1 and Snail2 zinc fingers in E-cadherin repression and epithelial to mesenchymal transition. J. Biol. Chem. 289, 930–941 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Wilhelm, K. et al. FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature 529, 216–220 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Ibrahim, A. et al. Insulin-stimulated adipocytes secrete lactate to promote endothelial fatty acid uptake and transport. J. Cell Sci. 135, jcs258964 (2022).

    Article  CAS  PubMed  Google Scholar 

  27. Fan, M. et al. Lactate promotes endothelial-to-mesenchymal transition via Snail1 lactylation after myocardial infarction. Sci. Adv. 9, eadc9465 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Zhu, X. et al. Acetate controls endothelial-to-mesenchymal transition. Cell Metab. 35, 1163–1178.e10 (2023).

    Article  CAS  PubMed  Google Scholar 

  29. Zhang, H. et al. LncRNA MEG3 induces endothelial differentiation of mouse derived adipose-derived stem cells by targeting MiR-145-5p/KLF4. Mol. Biol. Rep. 49, 8495–8505 (2022).

    Article  CAS  PubMed  Google Scholar 

  30. Sun, X. et al. MicroRNA-181b improves glucose homeostasis and insulin sensitivity by regulating endothelial function in white adipose tissue. Circ. Res. 118, 810–821 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Liang, X. X. et al. Phosphorylation of Akt at Thr308 regulates p-eNOS Ser1177 during physiological conditions. FEBS Open Bio 11, 1953–1964 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Becker-Greene, D. et al. MiR-409-3p targets a MAP4K3-ZEB1-PLGF signaling axis and controls brown adipose tissue angiogenesis and insulin resistance. Cell Mol. Life Sci. 78, 7663–7679 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Tang, X. et al. Suppression of endothelial AGO1 promotes adipose tissue browning and improves metabolic dysfunction. Circulation 142, 365–379 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Mitić, T. & Caporali, A. Emerging roles of non-coding RNAs in endothelial cell function. Curr. Opin. Physiol. 34, 100672 (2023).

    Article  Google Scholar 

  35. Mattick, J. S. et al. Long non-coding RNAs: definitions, functions, challenges and recommendations. Nat. Rev. Mol. Cell Biol. 24, 430–447 (2023).

    Article  CAS  PubMed  Google Scholar 

  36. Graupera, M. & Claret, M. Endothelial cells: new players in obesity and related metabolic disorders. Trends Endocrinol. Metab. 29, 781–794 (2018).

    Article  CAS  PubMed  Google Scholar 

  37. Vliora, M. et al. The impact of adipokines on vascular networks in adipose tissue. Cytokine Growth Factor Rev. 69, 61–72 (2023).

    Article  CAS  PubMed  Google Scholar 

  38. Vaiopoulos, A. G., Marinou, K., Christodoulides, C. & Koutsilieris, M. The role of adiponectin in human vascular physiology. Int. J. Cardiol. 155, 188–193 (2012).

    Article  PubMed  Google Scholar 

  39. Obata, Y. et al. Adiponectin/T-cadherin system enhances exosome biogenesis and decreases cellular ceramides by exosomal release. JCI Insight 3, e99680 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  40. Parker-Duffen, J. L. et al. T-cadherin is essential for adiponectin-mediated revascularization. J. Biol. Chem. 288, 24886–24897 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Rubina, K. A. et al. Revisiting the multiple roles of T-cadherin in health and disease. Eur. J. Cell Biol. 100, 151183 (2021).

    Article  CAS  PubMed  Google Scholar 

  42. Henning, R. J. Obesity and obesity-induced inflammatory disease contribute to atherosclerosis: a review of the pathophysiology and treatment of obesity. Am. J. Cardiovasc. Dis. 11, 504–529 (2021).

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Bruder-Nascimento, T. et al. Leptin restores endothelial function via endothelial PPARγ-Nox1-mediated mechanisms in a mouse model of congenital generalized lipodystrophy. Hypertension 74, 1399–1408 (2019).

    Article  CAS  PubMed  Google Scholar 

  44. Sturzebecher, P. E. et al. Leptin treatment has vasculo-protective effects in lipodystrophic mice. Proc. Natl Acad. Sci. USA 119, e2110374119 (2022).

    Article  PubMed Central  PubMed  Google Scholar 

  45. Fischer, A. W. et al. Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation. Cell Metab. 33, 547–564.e7 (2021).

    Article  CAS  PubMed  Google Scholar 

  46. Thiemann, E. et al. Role of endothelial cell lipoprotein lipase for brown adipose tissue lipid and glucose handling. Front. Physiol. 13, 859671 (2022).

    Article  PubMed Central  PubMed  Google Scholar 

  47. Davies, B. S. et al. The expression of GPIHBP1, an endothelial cell binding site for lipoprotein lipase and chylomicrons, is induced by peroxisome proliferator-activated receptor-γ. Mol. Endocrinol. 22, 2496–2504 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Surendran, R. P. et al. Decreased GPIHBP1 protein levels in visceral adipose tissue partly underlie the hypertriglyceridemic phenotype in insulin resistance. PLoS ONE 13, e0205858 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  49. Son, N.-H. et al. Endothelial cell CD36 optimizes tissue fatty acid uptake. J. Clin. Invest. 128, 4329–4342 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  50. Peche, V. et al. Endothelial cell CD36 regulates membrane ceramide formation, exosome fatty acid transfer and circulating fatty acid levels. Nat. Commun. 14, 4029 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Daquinag, A. C. et al. Fatty acid mobilization from adipose tissue is mediated by CD36 posttranslational modifications and intracellular trafficking. JCI Insight 6, e147057 (2021).

    Article  PubMed Central  PubMed  Google Scholar 

  52. Salameh, A. et al. Prohibitin/annexin 2 interaction regulates fatty acid transport in adipose tissue. JCI Insight 1, e86351 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  53. Gao, Z., Daquinag, A. C., Yu, Y. & Kolonin, M. G. Endothelial prohibitin mediates bidirectional long-chain fatty acid transport in white and brown adipose tissues. Diabetes 71, 1400–1409 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Wyne, K. L., Pathak, R. K., Seabra, M. C. & Hobbs, H. H. Expression of the VLDL receptor in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 16, 407–415 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Goudriaan, J. R. et al. The VLDL receptor plays a major role in chylomicron metabolism by enhancing LPL-mediated triglyceride hydrolysis. J. Lipid Res. 45, 1475–1481 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Kanda, T. et al. PPARγ in the endothelium regulates metabolic responses to high-fat diet in mice. J. Clin. Invest. 119, 110–124 (2008).

    PubMed Central  PubMed  Google Scholar 

  57. Gogg, S., Nerstedt, A., Boren, J. & Smith, U. Human adipose tissue microvascular endothelial cells secrete PPARγ ligands and regulate adipose tissue lipid uptake. JCI Insight 4, e125914 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  58. Briot, A. et al. Senescence alters PPARγ (peroxisome proliferator-activated receptor gamma)-dependent fatty acid handling in human adipose tissue microvascular endothelial cells and favors inflammation. Arterioscler. Thromb. Vasc. Biol. 38, 1134–1146 (2018).

    Article  CAS  PubMed  Google Scholar 

  59. Wang, C. et al. Smad4-mediated angiogenesis facilitates the beiging of white adipose tissue in mice. iScience 26, 106272 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Kalucka, J. et al. Quiescent endothelial cells upregulate fatty acid β-oxidation for vasculoprotection via redox homeostasis. Cell Metab. 28, 881–894.e13 (2018).

    Article  CAS  PubMed  Google Scholar 

  61. Monelli, E. et al. Angiocrine polyamine production regulates adiposity. Nat. Metab. 4, 327–343 (2022).

    Article  CAS  PubMed  Google Scholar 

  62. Aupetit, A. et al. Endothelial DLL4 is an adipose depot-specific fasting sensor regulating fatty acid fluxes. Arterioscler. Thromb. Vasc. Biol. 43, 684–696 (2023).

    Article  CAS  PubMed  Google Scholar 

  63. Becher, T. et al. Brown adipose tissue is associated with cardiometabolic health. Nat. Med. 27, 58–65 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Furuuchi, R. et al. Endothelial SIRT-1 has a critical role in the maintenance of capillarization in brown adipose tissue. iScience 25, 105424 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Shimizu, I. et al. Vascular rarefaction mediates whitening of brown fat in obesity. J. Clin. Invest. 124, 2099–2112 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Schlein, C. et al. Endogenous fatty acid synthesis drives brown adipose tissue involution. Cell Rep. 34, 108624 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Lee, H. J. et al. Endothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes. Nat. Commun. 14, 2754 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Sabaratnam, R. & Svenningsen, P. Adipocyte-endothelium crosstalk in obesity. Front. Endocrinol. 12, 681290 (2021).

    Article  Google Scholar 

  69. Thery, C. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 7, 1535750 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  70. Thomou, T. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542, 450–455 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Crewe, C. et al. Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metab. 33, 1853–1868.e11 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Crewe, C. et al. Deficient caveolin-1 synthesis in adipocytes stimulates systemic insulin-independent glucose uptake via extracellular vesicles. Diabetes 71, 2496–2512 (2022).

    Article  CAS  PubMed  Google Scholar 

  73. Wadey, R. M. et al. Inflammatory adipocyte-derived extracellular vesicles promote leukocyte attachment to vascular endothelial cells. Atherosclerosis 283, 19–27 (2019).

    Article  CAS  PubMed  Google Scholar 

  74. Lee, H.-J. et al. Vascular reactivity contributes to adipose tissue remodeling in obesity. J. Endocrinol. 251, 195–206 (2021).

    Article  CAS  PubMed  Google Scholar 

  75. Karpe, F. et al. Impaired postprandial adipose tissue blood flow response is related to aspects of insulin sensitivity. Diabetes 51, 2467–2473 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Frayn, K. N. & Karpe, F. Regulation of human subcutaneous adipose tissue blood flow. Int. J. Obes. 38, 1019–1026 (2014).

    Article  CAS  Google Scholar 

  77. Sotornik, R. et al. Update on adipose tissue blood flow regulation. Am. J. Physiol. Endocrinol. Metab. 302, E1157–E1170 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Goossens, G. H. et al. Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization, and inflammation. Circulation 124, 67–76 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Sakai, T. & Hosoyamada, Y. Are the precapillary sphincters and metarterioles universal components of the microcirculation? An historical review. J. Physiol. Sci. 63, 319–331 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  80. Ardilouze, J. L., Fielding, B. A., Currie, J. M., Frayn, K. N. & Karpe, F. Nitric oxide and β-adrenergic stimulation are major regulators of preprandial and postprandial subcutaneous adipose tissue blood flow in humans. Circulation 109, 47–52 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Crewe, C., An, Y. A. & Scherer, P. E. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J. Clin. Invest. 127, 74–82 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  82. Lee, Y. S. et al. Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity. Cell 157, 1339–1352 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Paavonsalo, S., Hariharan, S., Lackman, M. H. & Karaman, S. Capillary rarefaction in obesity and metabolic diseases – organ-specificity and possible mechanisms. Cells 9, 2683 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Belligoli, A. et al. Characterization of subcutaneous and omental adipose tissue in patients with obesity and with different degrees of glucose impairment. Sci. Rep. 9, 11333 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  85. Rupnick, M. A. et al. Adipose tissue mass can be regulated through the vasculature. Proc. Natl Acad. Sci. USA 99, 10730–10735 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Sun, K. et al. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc. Natl Acad. Sci. USA 109, 5874–5879 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Seki, T. et al. Ablation of endothelial VEGFR1 improves metabolic dysfunction by inducing adipose tissue browning. J. Exp. Med. 215, 611–626 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Robciuc, M. R. et al. VEGFB/VEGFR1-induced expansion of adipose vasculature counteracts obesity and related metabolic complications. Cell Metab. 23, 712–724 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Ngo, D. T. et al. Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial growth factor-A, in human obesity. Circulation 130, 1072–1080 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Guzmán, A., Hernández‐Coronado, C. G., Gutiérrez, C. G. & Rosales‐Torres, A. M. The vascular endothelial growth factor (VEGF) system as a key regulator of ovarian follicle angiogenesis and growth. Mol. Reprod. Dev. 90, 201–217 (2023).

    Article  PubMed  Google Scholar 

  91. Karki, S. et al. WNT5A regulates adipose tissue angiogenesis via antiangiogenic VEGF-A165b in obese humans. Am. J. Physiol. Heart Circ. Physiol. 313, H200–H206 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  92. AlZaim, I. et al. Adipose tissue immunomodulation: a novel therapeutic approach in cardiovascular and metabolic diseases. Front. Cardiovasc. Med. 7, 602088 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  95. Elgazar-Carmon, V., Rudich, A., Hadad, N. & Levy, R. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J. Lipid Res. 49, 1894–1903 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Talukdar, S. et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 18, 1407–1412 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Preston, K. J. et al. Postprandial activation of leukocyte-endothelium interaction by fatty acids in the visceral adipose tissue microcirculation. FASEB J. 33, 11993 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Onogi, Y. et al. Pro-inflammatory macrophages coupled with glycolysis remodel adipose vasculature by producing platelet-derived growth factor-B in obesity. Sci. Rep. 10, 670 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  99. Furukawa, S. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Invest. 114, 1752–1761 (2017).

    Article  Google Scholar 

  100. Boden, G. et al. Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men. Sci. Transl. Med. 7, 304re307 (2015).

    Article  Google Scholar 

  101. Kähler, J. et al. Oxidative stress increases endothelin-1 synthesis in human coronary artery smooth muscle cells. J. Cardiovasc. Pharmacol. 38, 49–57 (2001).

    Article  PubMed  Google Scholar 

  102. Tripathy, D. et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 52, 2882–2887 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Steinberg, H. O. et al. Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes 49, 1231–1238 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Tampakakis, E. et al. Intravenous lipid infusion induces endoplasmic reticulum stress in endothelial cells and blood mononuclear cells of healthy adults. J. Am. Heart Assoc. 5, e002574 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  105. Pellegrinelli, V., Rouault, C., Veyrie, N., Clément, K. & Lacasa, D. Endothelial cells from visceral adipose tissue disrupt adipocyte functions in a three-dimensional setting: partial rescue by angiopoietin-1. Diabetes 63, 535–549 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Hasegawa, Y. et al. Blockade of the nuclear factor-κB pathway in the endothelium prevents insulin resistance and prolongs life spans. Circulation 125, 1122–1133 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Koenen, M., Hill, M. A., Cohen, P. & Sowers, J. R. Obesity, adipose tissue and vascular dysfunction. Circ. Res. 128, 951–968 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  108. Virdis, A. et al. Tumour necrosis factor-alpha participates on the endothelin-1/nitric oxide imbalance in small arteries from obese patients: role of perivascular adipose tissue. Eur. Heart J. 36, 784–794 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Guilherme, A., Henriques, F., Bedard, A. H. & Czech, M. P. Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus. Nat. Rev. Endocrinol. 15, 207–225 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  110. Kuo, L. E. et al. Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat. Med. 13, 803–811 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Trayhurn, P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol. Rev. 93, 1–21 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. Seo, J. B. et al. Knockdown of Ant2 reduces adipocyte hypoxia and improves insulin resistance in obesity. Nat. Metab. 1, 86–97 (2019).

    Article  CAS  PubMed  Google Scholar 

  113. Ye, J., Gao, Z., Yin, J. & He, Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am. J. Physiol. Endocrinol. Metab. 293, E1118–E1128 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Halberg, N. et al. Hypoxia-inducible factor 1α induces fibrosis and insulin resistance in white adipose tissue. Mol. Cell Biol. 29, 4467–4483 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  115. Hosogai, N. et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56, 901–911 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Rudnicki, M. et al. Transcriptomic profiling reveals sex-specific molecular signatures of adipose endothelial cells under obesogenic conditions. iScience 26, 105811 (2023).

    Article  CAS  PubMed  Google Scholar 

  117. Zhang, X. et al. Adipose tissue-specific inhibition of hypoxia-inducible factor 1α induces obesity and glucose intolerance by impeding energy expenditure in mice. J. Biol. Chem. 285, 32869–32877 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  118. Sun, K., Halberg, N., Khan, M., Magalang, U. J. & Scherer, P. E. Selective inhibition of hypoxia-inducible factor 1α ameliorates adipose tissue dysfunction. Mol. Cell. Biol. 33, 904–917 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  119. Kihira, Y., Fujimura, Y., Tomita, S., Tamaki, T. & Sato, E. Hypoxia-inducible factor-1α regulates Lipin1 differently in pre-adipocytes and mature adipocytes. Mol. Med. Rep. 22, 559–565 (2020).

    CAS  PubMed  Google Scholar 

  120. Todorčević, M. et al. Markers of adipose tissue hypoxia are elevated in subcutaneous adipose tissue of severely obese patients with obesity hypoventilation syndrome but not in the moderately obese. Int. J. Obes. 45, 1618–1622 (2021).

    Article  Google Scholar 

  121. Gozal, D. et al. Visceral white adipose tissue after chronic intermittent and sustained hypoxia in mice. Am. J. Respir. Cell Mol. Biol. 56, 477–487 (2017).

    Article  CAS  PubMed  Google Scholar 

  122. Borgeson, E., Boucher, J. & Hagberg, C. E. Of mice and men: pinpointing species differences in adipose tissue biology. Front. Cell Dev. Biol. 10, 1003118 (2022).

    Article  PubMed Central  PubMed  Google Scholar 

  123. Pasarica, M. et al. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 58, 718–725 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  124. Cifarelli, V. et al. Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity. J. Clin. Invest. 130, 6688–6699 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. ElShazly, M., Salama, M. & Elessawy, K. Changes in the macular vascular density after bariatric surgery measured by optical coherence tomography angiography. Clin. Ophthalmol. 15, 3131–3137 (2021).

    Article  PubMed Central  PubMed  Google Scholar 

  126. Laiginhas, R., Guimarães, M., Nora, M., Chibante, J. & Falcão, M. Gastric bypass improves microvascular perfusion in patients with obesity. Obes. Surg. 31, 2080–2086 (2021).

    Article  PubMed  Google Scholar 

  127. Ungvari, Z. et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat. Rev. Cardiol. 15, 555–565 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  128. Jiang, Y. et al. A PPARγ transcriptional cascade directs adipose progenitor cell-niche interaction and niche expansion. Nat. Commun. 8, 15926 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  129. Donato, A. J. et al. The impact of ageing on adipose structure, function and vasculature in the B6D2F1 mouse: evidence of significant multisystem dysfunction. J. Physiol. 592, 4083–4096 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  130. Grunewald, M. et al. Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span. Science 373, eabc8479 (2021).

    Article  CAS  PubMed  Google Scholar 

  131. Sung, H.-K. et al. Adipose vascular endothelial growth factor regulates metabolic homeostasis through angiogenesis. Cell Metab. 17, 61–72 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Elias, I. et al. Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance. Diabetes 61, 1801–1813 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  133. Wang, B. et al. Retinoic acid induces white adipose tissue browning by increasing adipose vascularity and inducing beige adipogenesis of PDGFRα+ adipose progenitors. Cell Discov. 3, 17036 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  134. Bagchi, M. et al. Vascular endothelial growth factor is important for brown adipose tissue development and maintenance. FASEB J. 27, 3257 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  135. Picchi, A. et al. Tumor necrosis factor-α induces endothelial dysfunction in the prediabetic metabolic syndrome. Circ. Res. 99, 69–77 (2006).

    Article  CAS  PubMed  Google Scholar 

  136. Naessen, T., Einarsson, G., Henrohn, D. & Wikstrom, G. Peripheral vascular ageing in pulmonary arterial hypertension as assessed by common carotid artery intima thickness and intima/media thickness ratio: an investigation using non-invasive high-resolution ultrasound. Heart Lung Circ. 32, 338–347 (2022).

    Article  PubMed  Google Scholar 

  137. Dou, H. et al. Role of adipose tissue endothelial ADAM17 in age-related coronary microvascular dysfunction. Arterioscler. Thromb. Vasc. Biol. 37, 1180–1193 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  138. Cartwright, M. J., Tchkonia, T. & Kirkland, J. L. Aging in adipocytes: potential impact of inherent, depot-specific mechanisms. Exp. Gerontol. 42, 463–471 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  139. Nguyen, H. P. et al. Aging-dependent regulatory cells emerge in subcutaneous fat to inhibit adipogenesis. Dev. Cell 56, 1437–1451.e3 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  140. Tabula Muris Consortium A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020).

    Article  Google Scholar 

  141. Zhou, W. et al. High-resolution aging niche of human adipose tissues. Signal. Transduct. Target. Ther. 8, 105 (2023).

    Article  PubMed Central  PubMed  Google Scholar 

  142. Barinda, A. J. et al. Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype. Nat. Commun. 11, 481 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  143. Wang, Y. et al. Aging affects KV7 channels and perivascular adipose tissue-mediated vascular tone. Front. Physiol. 12, 749709 (2021).

    Article  PubMed Central  PubMed  Google Scholar 

  144. Trim, W. V. et al. Divergent immunometabolic changes in adipose tissue and skeletal muscle with ageing in healthy humans. J. Physiol. 600, 921–947 (2022).

    Article  CAS  PubMed  Google Scholar 

  145. Agabiti-Rosei, C. et al. Effect of long-term treatment with melatonin on vascular markers of oxidative stress/inflammation and on the anticontractile activity of perivascular fat in aging mice. Hypertens. Res. 40, 41–50 (2017).

    Article  CAS  PubMed  Google Scholar 

  146. Bailey-Downs, L. C. et al. Aging exacerbates obesity-induced oxidative stress and inflammation in perivascular adipose tissue in mice: a paracrine mechanism contributing to vascular redox dysregulation and inflammation. J. Gerontol.: Ser. A 68, 780–792 (2013).

    Article  CAS  Google Scholar 

  147. Sena, C. M., Pereira, A., Fernandes, R., Letra, L. & Seiça, R. M. Adiponectin improves endothelial function in mesenteric arteries of rats fed a high-fat diet: role of perivascular adipose tissue. Br. J. Pharmacol. 174, 3514–3526 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  148. Mahabala, C., Kamath, P., Bhaskaran, U., Pai, N. D. & Pai, A. U. Antihypertensive therapy: nocturnal dippers and nondippers. Do we treat them differently? Vasc. Health Risk Manag. 9, 125–133 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  149. Viswambharan, H. et al. Mutation of the circadian clock gene Per2 alters vascular endothelial function. Circulation 115, 2188–2195 (2007).

    Article  CAS  PubMed  Google Scholar 

  150. Nernpermpisooth, N. et al. Obesity alters the peripheral circadian clock in the aorta and microcirculation. Microcirculation 22, 257–266 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  151. Padgett, C. A. et al. Obesity induces disruption of microvascular endothelial circadian rhythm. Front. Physiol. 13, 887559 (2022).

    Article  PubMed Central  PubMed  Google Scholar 

  152. Moczulska, B., Zechowicz, M., Lesniewska, S., Osowiecka, K. & Gromadzinski, L. The impact of obesity on nighttime blood pressure dipping. Medicina 56, 700 (2020).

    Article  PubMed Central  PubMed  Google Scholar 

  153. Stenvers, D. J., Scheer, F., Schrauwen, P., la Fleur, S. E. & Kalsbeek, A. Circadian clocks and insulin resistance. Nat. Rev. Endocrinol. 15, 75–89 (2019).

    Article  PubMed  Google Scholar 

  154. Manoogian, E. N. et al. Feasibility of time-restricted eating and impacts on cardiometabolic health in 24-h shift workers: the Healthy Heroes randomized control trial. Cell Metab. 34, 1442–1456.e7 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  155. Ribas-Latre, A. et al. Cellular and physiological circadian mechanisms drive diurnal cell proliferation and expansion of white adipose tissue. Nat. Commun. 12, 3482 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  156. Turek, F. W. et al. Obesity and metabolic syndrome in circadian clock mutant mice. Science 308, 1043–1045 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  157. Paschos, G. K. et al. Obesity in mice with adipocyte-specific deletion of clock component Arntl. Nat. Med. 18, 1768–1777 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  158. Yue, K., Rensen, P. C. N. & Kooijman, S. Circadian control of white and brown adipose tissues. Curr. Opin. Genet. Dev. 80, 102056 (2023).

    Article  CAS  PubMed  Google Scholar 

  159. Poirier, P. et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 113, 898–918 (2006).

    Article  PubMed  Google Scholar 

  160. Maniyadath, B., Zhang, Q., Gupta, R. K. & Mandrup, S. Adipose tissue at single-cell resolution. Cell Metab. 35, 386–413 (2023).

    Article  CAS  PubMed  Google Scholar 

  161. Jiang, Y., Berry, D. C., Tang, W. & Graff, J. M. Independent stem cell lineages regulate adipose organogenesis and adipose homeostasis. Cell Rep. 9, 1007–1022 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  162. Cawthorn, W. P., Scheller, E. L. & MacDougald, O. A. Adipose tissue stem cells meet preadipocyte commitment: going back to the future. J. Lipid Res. 53, 227–246 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  163. Min, S. Y. et al. Human ‘brite/beige’ adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat. Med. 22, 312–318 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  165. Tran, K.-V. et al. The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells. Cell Metab. 15, 222–229 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  166. Gupta, R. K. et al. Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab. 15, 230–239 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  168. Cattaneo, P. et al. Parallel lineage-tracing studies establish fibroblasts as the prevailing in vivo adipocyte progenitor. Cell Rep. 30, 571–582.e2 (2020).

    Article  CAS  PubMed  Google Scholar 

  169. Han, X. et al. A suite of new Dre recombinase drivers markedly expands the ability to perform intersectional genetic targeting. Cell Stem Cell 28, 1160–1176.e7 (2021).

    Article  CAS  PubMed  Google Scholar 

  170. Medici, D. et al. Conversion of vascular endothelial cells into multipotent stem-like cells. Nat. Med. 16, 1400–1406 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  171. Yang Loureiro, Z. et al. Wnt signaling preserves progenitor cell multipotency during adipose tissue development. Nat. Metab. 5, 1014–1028 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  172. Palani, N. P. et al. Adipogenic and SWAT cells separate from a common progenitor in human brown and white adipose depots. Nat. Metab. 5, 996–1013 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  173. Park, K. et al. Endothelial cells induced progenitors into brown fat to reduce atherosclerosis. Circ. Res. 131, 168–183 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  174. Seki, T. et al. Endothelial PDGF-CC regulates angiogenesis-dependent thermogenesis in beige fat. Nat. Commun. 7, 12152 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  175. Luger, K., Mader, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389, 251–260 (1997).

    Article  CAS  PubMed  Google Scholar 

  176. Wang, Z. et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat. Genet. 40, 897–903 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  177. Zhao, Y. & Garcia, B. A. Comprehensive catalog of currently documented histone modifications. Cold Spring Harb. Perspect. Biol. 7, a025064 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  178. Sheikh, B. N. & Akhtar, A. The many lives of KATs – detectors, integrators and modulators of the cellular environment. Nat. Rev. Genet. 20, 7–23 (2019).

    Article  CAS  PubMed  Google Scholar 

  179. Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J. M., Madeo, F. & Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805–821 (2015).

    Article  CAS  PubMed  Google Scholar 

  180. Simithy, J. et al. Characterization of histone acylations links chromatin modifications with metabolism. Nat. Commun. 8, 1141 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  181. Marino, G. et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol. Cell 53, 710–725 (2014).

    Article  CAS  PubMed  Google Scholar 

  182. Zheng, Y., Thomas, P. M. & Kelleher, N. L. Measurement of acetylation turnover at distinct lysines in human histones identifies long-lived acetylation sites. Nat. Commun. 4, 2203 (2013).

    Article  PubMed  Google Scholar 

  183. Allfrey, V. G., Faulkner, R. & Mirsky, A. E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc. Natl Acad. Sci. USA 51, 786–794 (1964).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  184. Li, X., Egervari, G., Wang, Y., Berger, S. L. & Lu, Z. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat. Rev. Mol. Cell Biol. 19, 563–578 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  185. Chakraborty, A. A. et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 363, 1217–1222 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  186. Batie, M. et al. Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science 363, 1222–1226 (2019).

    Article  CAS  PubMed  Google Scholar 

  187. Chen, Y. et al. Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol. Cell Proteom. 6, 812–819 (2007).

    Article  CAS  Google Scholar 

  188. Xie, Z. et al. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation. Mol. Cell 62, 194–206 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  189. Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  190. Zou, C. et al. Acyl-CoA:lysophosphatidylcholine acyltransferase I (Lpcat1) catalyzes histone protein O-palmitoylation to regulate mRNA synthesis. J. Biol. Chem. 286, 28019–28025 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  191. Xie, Z. et al. Lysine succinylation and lysine malonylation in histones. Mol. Cell Proteom. 11, 100–107 (2012).

    Article  CAS  Google Scholar 

  192. Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  193. Andrade, J. et al. Control of endothelial quiescence by FOXO-regulated metabolites. Nat. Cell Biol. 23, 413–423 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  194. Rudnicki, M. et al. Endothelial-specific FoxO1 depletion prevents obesity-related disorders by increasing vascular metabolism and growth. Elife 7, e39780 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  195. Gan, F. et al. Effects of adipose-derived stromal cells and endothelial progenitor cells on adipose transplant survival and angiogenesis. PLoS ONE 17, e0261498 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  196. Miranville, A. et al. Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation 110, 349–355 (2004).

    Article  CAS  PubMed  Google Scholar 

  197. Nakagami, H. et al. Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells. Arterioscler. Thromb. Vasc. Biol. 25, 2542–2547 (2005).

    Article  CAS  PubMed  Google Scholar 

  198. Planat-Benard, V. et al. Plasticity of human adipose lineage cells toward endothelial cells. Circulation 109, 656–663 (2004).

    Article  PubMed  Google Scholar 

  199. Arderiu, G. et al. MicroRNA-145 regulates the differentiation of adipose stem cells toward microvascular endothelial cells and promotes angiogenesis. Circ. Res. 125, 74–89 (2019).

    Article  CAS  PubMed  Google Scholar 

  200. Shang, T. et al. Hypoxia promotes differentiation of adipose-derived stem cells into endothelial cells through demethylation of ephrinB2. Stem Cell Res. Ther. 10, 133 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  201. Cheng, F. et al. Conversion of human adipose-derived stem cells into functional and expandable endothelial-like cells for cell-based therapies. Stem Cell Res. Ther. 9, 350 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  202. Jumabay, M. et al. Endothelial differentiation in multipotent cells derived from mouse and human white mature adipocytes. J. Mol. Cell Cardiol. 53, 790–800 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  203. Poloni, A. et al. Plasticity of human dedifferentiated adipocytes toward endothelial cells. Exp. Hematol. 43, 137–146 (2015).

    Article  CAS  PubMed  Google Scholar 

  204. Watanabe, H. et al. The neovascularization effect of dedifferentiated fat cells. Sci. Rep. 10, 9211 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

The work of B.N.S. is funded by the DFG (grants 45720345, 511049882), the German Diabetes Foundation, the free-state of Saxony, and the Helmholtz Centre Munich. E.B. receives support from the European Research Council (ERC-StG no. 804418), Aarhus University Research Foundation (AUFF-E-2022-7-8), Novo Nordisk Foundation (NNF22OC0079363), the Swedish state’s ALF-agreement (ALFGBG-978978), and Regionala FoU-medel, Västra Götalandsregionen (OLG-2023-02-22). The work of J.K. is funded by Lundbeckfonden (R307-2018-3667), Carlsberg Fonden (CF19-0687), Kræftens Bekæmpelse (R302-A17296), Novo Nordisk Fonden (0073440), Riisfort Fonden. J.K and I.A. are supported by Steno Diabetes Center Aarhus (SDCA).

Author information

Authors and Affiliations

  1. Department of Biomedicine, Aarhus University, Aarhus C, Denmark

    Ibrahim AlZaim, Emma Börgeson & Joanna Kalucka

  2. Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark

    Ibrahim AlZaim, Emma Börgeson & Joanna Kalucka

  3. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Laura P.M.H de Rooij

  4. Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich, Leipzig, Germany

    Bilal N. Sheikh

  5. Medical Faculty, University of Leipzig, Leipzig, Germany

    Bilal N. Sheikh

  6. Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden

    Emma Börgeson

Authors
  1. Ibrahim AlZaim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura P.M.H de Rooij
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bilal N. Sheikh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emma Börgeson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joanna Kalucka
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Joanna Kalucka.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Endocrinology thanks Jian Xu and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

AlZaim, I., de Rooij, L.P., Sheikh, B.N. et al. The evolving functions of the vasculature in regulating adipose tissue biology in health and obesity. Nat Rev Endocrinol 19, 691–707 (2023). https://doi.org/10.1038/s41574-023-00893-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-023-00893-6

This article is cited by

Search

Advanced search

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