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

Nature Genetics volume 37, pages 1072–1081 (2005)Cite this article

Abstract

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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Acknowledgements

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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Author notes

  1. R Sathish Srinivasan, Miriam E Dillard and Nicole C Johnson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, 38105-2794, Tennessee, USA

    Natasha L Harvey, R Sathish Srinivasan, Miriam E Dillard, Nicole C Johnson & Guillermo Oliver

  2. Animal Resources Center, St. Jude Children's Research Hospital, Memphis, 38105-2794, Tennessee, USA

    Kelli Boyd

  3. Department of Surgery, University of Arizona College of Medicine, Tucson, 85724-5063, Arizona, USA

    Marlys H Witte

  4. Regeneron Pharmaceuticals, Inc., Tarrytown, 10591-6707, New York, USA

    Mark W Sleeman

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Corresponding author

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). https://doi.org/10.1038/ng1642

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