Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice
Noelia Escobedo, … , Michael Detmar, Guillermo Oliver
Noelia Escobedo, … , Michael Detmar, Guillermo Oliver
Published February 25, 2016
Citation Information: JCI Insight. 2016;1(2):e85096. https://doi.org/10.1172/jci.insight.85096.
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Research Article Development Metabolism

Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice

Abstract

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

Authors

Noelia Escobedo, Steven T. Proulx, Sinem Karaman, Miriam E. Dillard, Nicole Johnson, Michael Detmar, Guillermo Oliver

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Figure 4

Conditional Prox1 mice frequently die prematurely and display defects in lymph flow.

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Conditional Prox1 mice frequently die prematurely and display defects in...
(A) E14.5 Lyve1+/GFPCre;Prox1+/Flox embryos consistently exhibited edema and blood-filled lymphatics. (B and C) Most Lyve1+/GFPCre;Prox1+/Flox mice died soon after birth, and accumulation of chylous ascites was seen in pups at around P1 to P8. (D) Percentage of deaths of Lyve1+/GFPCre;Prox1+/Flox mice versus age. Of the few surviving during the first week, approximately 50% die before weaning (3 weeks of age). (E–K) Among those few surviving pups (10–33 weeks of age), Evans blue visual lymphangiography and subsequent quantification was performed to follow lymph drainage patterns. Evans blue injection into the dermis of the ear of a WT mouse (injection site is marked by a white dot) resulted in unidirectional drainage and convergence of the dye into lymphatic collecting vessels (E). Retrograde lymph flow (marked by an asterisk) and increased lateral spread occurred when Evans blue dye was injected into the ear of a Lyve1+/GFPCre;Prox1+/Flox mouse (H), and increased retention was seen after 24 hours (I). (K) Extravasation of Evans blue dye after 24 hours was measured in the ear skin. Total dye remaining in Lyve1+/GFPCre;Prox1+/Flox mice was significantly higher than their WT (WT, Lyve1+/GFPCre, or Prox1+/Flox) siblings. Plot shows mean ± SEM. *P ≤ 0.05, 2-tailed Student’s t test, (n = 5).