Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice
Noelia Escobedo, Steven T. Proulx, Sinem Karaman, Miriam E. Dillard, Nicole Johnson, Michael Detmar, Guillermo Oliver
Noelia Escobedo, Steven T. Proulx, Sinem Karaman, Miriam E. Dillard, Nicole Johnson, Michael Detmar, Guillermo Oliver
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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 2

Collecting lymphatic vessel function in the lower limbs.

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Collecting lymphatic vessel function in the lower limbs. (A–D) Near-infr...
(A–D) Near-infrared fluorescence imaging of the normal lower limb lymphatic network in WT mice (A) and three representative images of the phenotype seen in Prox1+/– mice (B–D). Three phenotypes are consistently observed in all Prox1 heterozygous mice: dermal backflow (brackets), collateral rerouting (white arrow), and interstitial leakage (arrowheads). All the pictures are oriented in the same direction, where P is proximal and D is distal to the popliteal lymph node. Red arrows indicate the direction of the flow. (E and F) Collecting vessel contractility in young (E) and old (F) WT and Prox1+/– mice. No difference was seen between young WT and Prox1+/– mice, but contractility was significantly reduced in old Prox1+/– mice. (G and H) Response to mechanostimulation in young (G) and old (H) WT and Prox1+/– mice. Young and old Prox1+/– mice had less efficient uptake into deep collectors after mechanostimulation. MFI, mean fluorescence intensity. **P ≤ 0.01; ***P ≤ 0.0001, 2-tailed Student’s t test. Scale bar: 2,000 μm.