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.

[1]  H. Brorson.  Liposuction in arm lymphedema treatment. , 2003, Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society.

[2]  R. Hammer,et al.  Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. , 2001, Developmental biology.

[3]  G. Oliver,et al.  Prox1 Function Is Required for the Development of the Murine Lymphatic System , 1999, Cell.

[4]  J. Horton,et al.  Molecular mediators of hepatic steatosis and liver injury. , 2004, The Journal of clinical investigation.

[5]  M. Detmar,et al.  An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype , 2002, The EMBO journal.

[6]  J. Flier.  Obesity Wars Molecular Progress Confronts an Expanding Epidemic , 2004, Cell.

[7]  H. Dvorak,et al.  T1α/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema , 2003, The EMBO journal.

[8]  P. Campochiaro,et al.  Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. , 2002, Developmental cell.

[9]  F. J. Livesey,et al.  Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina , 2003, Nature Genetics.

[10]  M. Desai,et al.  Obesity is associated with macrophage accumulation in adipose tissue. , 2003, The Journal of clinical investigation.

[11]  M. Karkkainen,et al.  Abnormal lymphatic vessel development in neuropilin 2 mutant mice. , 2002, Development.

[12]  F. Schaffner,et al.  Nonalcoholic fatty liver disease. , 1986, Progress in liver diseases.

[13]  C. Pond,et al.  Interactions between adipose tissue around lymph nodes and lymphoid cells in vitro. , 1995, Journal of lipid research.

[14]  Guillermo Oliver,et al.  Hepatocyte migration during liver development requires Prox1 , 2000, Nature Genetics.

[15]  P. Tso,et al.  A novel, noninvasive method for the measurement of intestinal fat absorption. , 2004, Gastroenterology.

[16]  J W Fertig,et al.  A simple method to determine fat cell size and number in four mammalian species. , 1971, The American journal of physiology.

[17]  P. Gruss,et al.  Prox1 function is crucial for mouse lens-fibre elongation , 1999, Nature Genetics.

[18]  D. Jackson,et al.  LYVE-1, a New Homologue of the CD44 Glycoprotein, Is a Lymph-specific Receptor for Hyaluronan , 1999, The Journal of cell biology.

[19]  E. Rosen.  The Molecular Control of Adipogenesis, with Special Reference to Lymphatic Pathology , 2002, Annals of the New York Academy of Sciences.

[20]  T. Springer,et al.  Mac-2, a novel 32,000 Mr mouse macrophage subpopulation-specific antigen defined by monoclonal antibodies. , 1982, Journal of immunology.

[21]  T. Sato,et al.  Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[22]  C. Pond,et al.  The source of fatty acids incorporated into proliferating lymphoid cells in immune-stimulated lymph nodes , 2003, British Journal of Nutrition.

[23]  J. Dulor,et al.  Differentiation of rabbit adipocyte precursors in primary culture. , 1988, International journal of obesity.

[24]  C. Pond.  Paracrine relationships between adipose and lymphoid tissues: implications for the mechanism of HIV-associated adipose redistribution syndrome. , 2003, Trends in immunology.

[25]  O. MacDougald,et al.  Transcriptional regulation of gene expression during adipocyte differentiation. , 1995, Annual review of biochemistry.

[26]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1994, Nature.

[27]  L. Tartaglia,et al.  Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. , 2003, The Journal of clinical investigation.

[28]  D. Porte,et al.  Diabetes, Obesity, and the Brain , 2005, Science.

[29]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1995, Nature.

[30]  H. Schnürch,et al.  Expression of tie-2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage. , 1993, Development.

[31]  R. Kauppinen,et al.  A model for gene therapy of human hereditary lymphedema , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[32]  C. Pond,et al.  The cellular structure and lipid/protein composition of adipose tissue surrounding chronically stimulated lymph nodes in rats , 2003, Journal of anatomy.

[33]  C. Esther,et al.  Pulmonary lymphangiectasia: Diagnosis and clinical course , 2004, Pediatric pulmonology.