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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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.
The authors declare no competing financial interests.
Expression of POMC, NPY, and CART is unaltered in the hypothalamus of adult Prox1+/− mice. (PDF 617 kb)
Metabolic features of Prox1-heterozygous mice and their wild-type counterparts. (PDF 241 kb)
Microarray analysis of muscle and adipose tissue from adult Prox1+/− and wild-type mice. (PDF 145 kb)
Prox1+/− mice exhibit alterations in directional lymph flow. (PDF 1692 kb)
Scheme of the Prox1 conditional knock-out construct. (PDF 129 kb)
Primer sequences used for RT-PCR amplification of the genes indicated from 3T3-L1 cells. (PDF 94 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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