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 6

Lipids are the adipogenic stimulus in chyle.

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Lipids are the adipogenic stimulus in chyle. (A and B) 3T3-L1 preadipocy...
(A and B) 3T3-L1 preadipocytes in control culture media plus vehicle (A) and culture media containing dexamethasone (Dex), 3-isobuty-1-methylxanthine (IBMX), and insulin (Ins) (B). The adipocyte indicator Oil Red O (red) was used to show differentiated adipocytes. (C–K) In vitro adipogenic studies of 3T3-L1 preadipocytes showed Oil Red O accumulation after treatment with 10 μM of various fatty acids for 2 days in the absence of dexamethasone, IBMX, and insulin during the induction phase, followed by 6 days in progression media (DMEM plus 5% fetal bovine serum plus 1.5 μg/ml insulin). (L) RT-PCR showing expression of Pparγ and adiponectin (indicative of adipocyte differentiation) induced in response to the different lipids tested. β-Actin was used as a loading control. Scale bar: 100 μm.