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

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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Correspondence to Guillermo Oliver.

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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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