title: Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice.
abstract: Prox1heterozygous mice have a defective lymphatic vasculature and develop late-onset obesity. Chyle abnormally leaks from those vessels, accumulates in the surrounding tissues, and causes an increase in adipose tissue. We characterized the lymphatics ofProx1+/-mice to determine whether the extent of obesity correlated with the severity of lymphatic defects. The lymphatic vasculature inProx1+/-mice exhibited reduced tracer clearance from the ear skin, dysfunctional perfusion of the lower legs, and reduced tracer uptake into the deep lymphatic collectors during mechanostimulation prior to the onset of obesity. Ear lymphatic vessels and leg collectors inProx1+/-mice were disorganized and irregular, further confirming that defective lymphatic vessels are associated with obesity inProx1+/-mice. We now provide conclusive in vivo evidence that demonstrates that leaky lymphatics mediate obesity inProx1+/-mice, as restoration of lymphatic vasculature function was sufficient to rescue the obesity features inProx1+/-mice. Finally, depth-lipomic profiling of lymph contents showed that free fatty acids induce adipogenesis in vitro.
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Noelia
authors.initials: N
authors.lastname: Escobedo
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Proulx
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Sinem
authors.initials: S
authors.lastname: Karaman
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Miriam E
authors.initials: ME
authors.lastname: Dillard
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Johnson
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Oliver