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Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity


Multiple organs cooperate to regulate appetite, metabolism, and glucose and fatty acid homeostasis. Here, we identified and characterized lymphatic vasculature dysfunction as a cause of adult-onset obesity. We found that functional inactivation of a single allele of the homeobox gene Prox1 led to adult-onset obesity due to abnormal lymph leakage from mispatterned and ruptured lymphatic vessels. Prox1 heterozygous mice are a new model for adult-onset obesity and lymphatic vascular disease.

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Figure 1: Adult Prox1+/− mice are obese.
Figure 2: Obese Prox1+/− mice have elevated levels of circulating insulin and leptin.
Figure 3: Obese Prox1+/− mice have abnormal hepatic lipid deposition.
Figure 4: Prox1+/− mice have dysfunctional lymphatic vessels.
Figure 5: Lymphatic vascular mispatterning in Prox1+/− mice is most marked in the intestine and mesentery.
Figure 6: Lymphatic flow abnormalities and lymphatic vascular leakage are characteristic of the visceral lymphatic vessels of Prox1+/− mice.
Figure 7: Lymph promotes adipocyte differentiation in vitro.
Figure 8: Prox1Δ/+ mice recapitulate the lymphatic defects evident in standard Prox1+/− mice.

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  1. Wigle, J.T., Chowdhury, K., Gruss, P. & Oliver, G. Prox1 function is crucial for mouse lens-fibre elongation. Nat. Genet. 21, 318–322 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Wigle, J.T. & Oliver, G. Prox1 function is required for the development of the murine lymphatic system. Cell 98, 769–778 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Sosa-Pineda, B., Wigle, J.T. & Oliver, G. Hepatocyte migration during liver development requires Prox1. Nat. Genet. 25, 254–255 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Burke, Z. & Oliver, G. Prox1 is an early specific marker for the developing liver and pancreas in the mammalian foregut endoderm. Mech. Dev. 118, 147–155 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Dyer, M.A., Livesey, F.J., Cepko, C.L. & Oliver, G. Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina. Nat. Genet. 34, 53–58 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Wigle, J.T. et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 21, 1505–1513 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Flier, J.S. Obesity wars: molecular progress confronts an expanding epidemic. Cell 116, 337–350 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Schwartz, M.W. & Porte, D. Jr. Diabetes, obesity, and the brain. Science 307, 375–379 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Browning, J.D. & Horton, J.D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest. 114, 147–152 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Angulo, P. Nonalcoholic fatty liver disease. N. Engl. J. Med. 346, 1221–1231 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Ho, M.K. & Springer, T.A. Mac-2, a novel 32,000 Mr mouse macrophage subpopulation-specific antigen defined by monoclonal antibodies. J. Immunol. 128, 1221–1228 (1982).

    CAS  PubMed  Google Scholar 

  13. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Esther, C.R. Jr. & Barker, P.M. Pulmonary lymphangiectasia: diagnosis and clinical course. Pediatr. Pulmonol. 38, 308–313 (2004).

    Article  PubMed  Google Scholar 

  16. Brorson, H. Liposuction in arm lymphedema treatment. Scand. J. Surg. 92, 287–295 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Karkkainen, M.J. et al. A model for gene therapy of human hereditary lymphedema. Proc. Natl. Acad. Sci. USA 98, 12677–12682 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Banerji, S. et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J. Cell Biol. 144, 789–801 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rosen, E.D. The molecular control of adipogenesis, with special reference to lymphatic pathology. Ann. NY Acad. Sci. 979, 143–158 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Nougues, J., Reyne, Y. & Dulor, J.P. Differentiation of rabbit adipocyte precursors in primary culture. Int. J. Obes. 12, 321–333 (1988).

    CAS  PubMed  Google Scholar 

  21. MacDougald, O.A. & Lane, M.D. Transcriptional regulation of gene expression during adipocyte differentiation. Annu. Rev. Biochem. 64, 345–373 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Kisanuki, Y.Y. et al. Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo . Dev. Biol. 230, 230–242 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Schnurch, H. & Risau, W. Expression of tie-2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage. Development 119, 957–968 (1993).

    CAS  PubMed  Google Scholar 

  24. Sato, T.N., Qin, Y., Kozak, C.A. & Audus, K.L. Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc. Natl. Acad. Sci. USA 90, 9355–9358 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pond, C.M. & Mattacks, C.A. Interactions between adipose tissue around lymph nodes and lymphoid cells in vitro . J. Lipid Res. 36, 2219–2231 (1995).

    CAS  PubMed  Google Scholar 

  26. Pond, C.M. & Mattacks, C.A. The source of fatty acids incorporated into proliferating lymphoid cells in immune-stimulated lymph nodes. Br. J. Nutr. 89, 375–383 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Pond, C.M. Paracrine relationships between adipose and lymphoid tissues: implications for the mechanism of HIV-associated adipose redistribution syndrome. Trends Immunol. 24, 13–18 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Mattacks, C.A., Sadler, D. & Pond, C.M. The cellular structure and lipid/protein composition of adipose tissue surrounding chronically stimulated lymph nodes in rats. J. Anat. 202, 551–561 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schacht, V. et al. T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J. 22, 3546–3556 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yuan, L. et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129, 4797–4806 (2002).

    CAS  PubMed  Google Scholar 

  31. Gale, N.W. et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev. Cell 3, 411–423 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Di Girolamo, M., Mendlinger, S. & Fertig, J.W. A simple method to determine fat cell size and number in four mammalian species. Am. J. Physiol. 221, 850–858 (1971).

    Article  CAS  PubMed  Google Scholar 

  33. Jandacek, R.J., Heubi, J.E. & Tso, P. A novel, non-invasive method for the measurement of intestinal fat absorption. Gastroenterology 127, 139–144 (2004).

    Article  CAS  PubMed  Google Scholar 

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We thank N. Gale for the LYVE-1 antibody and for discussions; M. Kahn for advice regarding the BODIPY FL C16 assay; M. Yanagisawa for the Tie2-Cre mice; R. Jandacek and P. Tso for the fatty acid absorption assay; M. Self for technical assistance; Y. Lee, A. Lavado and T. Nastasi for help with tissue dissections; M. Straign for the blood chemistry analysis; L. Mann and G. Murti for electron microscopy; G. Neale for help with microarray analysis; A. McArthur for editing the manuscript; B. Sosa-Pineda for discussions and critical reading of the manuscript; and D. Wasserman and G. Grosveld for discussions. This work was supported in part by a grant from the US National Institutes of Health to G.O., a Cancer Center Support Grant and the American Lebanese Syrian Associated Charities.

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Correspondence to Guillermo Oliver.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Expression of POMC, NPY, and CART is unaltered in the hypothalamus of adult Prox1+/− mice. (PDF 617 kb)

Supplementary Fig. 2

Metabolic features of Prox1-heterozygous mice and their wild-type counterparts. (PDF 241 kb)

Supplementary Fig. 3

Microarray analysis of muscle and adipose tissue from adult Prox1+/− and wild-type mice. (PDF 145 kb)

Supplementary Fig. 4

Prox1+/− mice exhibit alterations in directional lymph flow. (PDF 1692 kb)

Supplementary Fig. 5

Scheme of the Prox1 conditional knock-out construct. (PDF 129 kb)

Supplementary Table 1

Primer sequences used for RT-PCR amplification of the genes indicated from 3T3-L1 cells. (PDF 94 kb)

Supplementary Note (PDF 24 kb)

Supplementary Methods (PDF 28 kb)

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Harvey, N., Srinivasan, R., Dillard, M. et al. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nat Genet 37, 1072–1081 (2005).

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