Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice

Abstract

<i>Prox1</i> heterozygous 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 of <i>Prox1</i>^+/- mice to determine whether the extent of obesity correlated with the severity of lymphatic defects. The lymphatic vasculature in <i>Prox1</i>^+/- 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 in <i>Prox1^+/</i>^- mice were disorganized and irregular, further confirming that defective lymphatic vessels are associated with obesity in <i>Prox1^+/</i>^- mice. We now provide conclusive in vivo evidence that demonstrates that leaky lymphatics mediate obesity in <i>Prox1^+/</i>^- mice, as restoration of lymphatic vasculature function was sufficient to rescue the obesity features in <i>Prox1</i>^+/- mice. Finally, depth-lipomic profiling of lymph contents showed that free fatty acids induce adipogenesis in vitro.