Defective Lymphatic Vessels Identified As A Novel Cause Of Adult Onset Obesity

The St. Jude investigators showed that removal of one of the two copiesof the gene Prox1 disrupts normal development of the lymphaticvasculature, leading to leakage of lymph from ruptured lymphaticvessels, and subsequent obesity. Specifically, the researchers foundthat adipocytes (fat cells) near leaking lymphatic vessels under theskin and in the abdomen were significantly larger than normal, andtherefore able to store more lipids (e.g., fatty acids andtriglycerides, used as an energy source).

"This is the first such evidence in an in vivo model showing thatdefects in the integrity of the lymphatic vasculature could lead toadult obesity," said Guillermo Oliver, Ph.D., an associate member ofthe Genetics and Tumor Cell Biology Department at St. Jude. "Andtherefore, this is the first model available for studying obesitylinked to faulty lymphatic vessels. It will be an important tool forstudying this novel form of adult-onset obesity, as well as diseases oflymphatic vessels, and eventually, extending those findings to humans."Oliver is senior author of a report on this work that appears in theSeptember 18 online issue of Nature Genetics.

The laboratory model (Prox1+/- ) lacked one of two copies of the Prox1gene, which is required for proper development of the lymphatic system.Previously, Oliver's laboratory reported that Prox1 activity isnecessary for the normal development of cells making up the lymphaticvasculature; and that it is the subsequent budding and sprouting ofthose cells that give rise to the lymphatic system (Cell [98]:769-778;1999).

Most Prox1+/- heterozygous (i.e., having only one copy of the gene)models die quickly in the postnatal period as a consequence ofextensive lymphatic leakage that accumulates in the abdomen and thorax(chest). "However, those with a milder disruption of their lymphaticvasculature were able to survive and become obese with age," Oliversaid.

"Interestingly, those that survived did not develop diabetes, ascommonly seen in different types of obesity," he added. "This told usthat the type of obesity we were seeing in this laboratory model wasdifferent from forms of obesity that are commonly associated withdiabetes." The researchers also demonstrated that lymph removed fromthe abdominal cavity of the Prox1+/- models and added to cultured cellscan promote adipocyte differentiation, most likely due to certainfactors present in the collected lymph.

"Our findings might encourage physicians to consider that at least someof their obese patients might be suffering from a problem that can't besolved by eating less and exercising more," Oliver said. Just as manyvascular disorders arise because of blood vessel defects, other defectsof the closely related lymphatic vessels in addition to edema couldalso occur in humans, he added.

Other authors of the report include Natasha L. Harvey, R. SathishSrinivasan, Mirian E. Dillard, Nicole C. Johnson, and Kelli Boyd (St.Jude); Marlys H. Witte (University of Arizona College of Medicine;Tucson); and Mark W. Sleeman (Regeneron Pharmaceuticals, Inc.;Tarrytown, NY).

This work was supported in part by the National Institutes of Health, a Cancer Center Support Grant and ALSAC.

St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized forits pioneering work in finding cures and saving children with cancerand other catastrophic diseases. Founded by late entertainer DannyThomas and based in Memphis, Tenn., St. Jude freely shares itsdiscoveries with scientific and medical communities around the world.No family ever pays for treatments not covered by insurance, andfamilies without insurance are never asked to pay. St. Jude isfinancially supported by ALSAC, its fund-raising organization. For moreinformation, please visit www.stjude.org.<