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Enhanced Lymphangiogenesis and Lymphatic Function Protects Diet‐induced Obesity and Insulin Resistance

Obesity is the primary cause for multiple metabolic impairments including insulin resistance and chronic inflammation. Obesity is associated with impaired lymphatic function, decreased lymphatic vessel density, and reduced VEGFR3 expression and signaling. Whether repairing defective lymphangiogenesis prevents obesity and its associated metabolic syndrome is poorly studied. We hypothesize that enhanced lymphangiogenesis and improved lymphatic function can prevent the onset and development of the metabolic disease, including obesity. To this end, we investigate the role of the crucial lymphatic endothelial transcription factor, Foxc2. In this study, we determined the physiological and pathological roles of Foxc2 in adult lymphatics and whether enhanced lymphangiogenesis and lymphatic functions by Foxc2 deficiency can prevent diet‐induced obesity and the consequent insulin resistance. The inducible lymphatic endothelium‐specific Foxc2 loss of function mice (LEC‐iFoxc2 KO) were generated. Foxc2 was depleted in lymphatic endothelium in 3–6 month old adult mice. We confirmed the effective depletion of Foxc2 in various regions of lymphatics including mesentery, myocardium, intestine, and skeletal muscle tissues while we did not see any differences in blood and lymphatic vascular architecture or patterning or in lymphatic valves in the initial collecting lymphatic vessels between littermate controls (WT) and LEC‐iFoxc2KO mice. However, when we tested lymphatic function in the wound‐induced tail lymphedema assay, LEC‐iFoxc2KO mice showed improved tail lymphedema resolution with less swelling compared to WT. To further examine the lymphatic function in LEC‐iFoxc2 KO mice, we used a high sensitive near‐infrared (NIR) imaging method for non‐invasive in vivo lymph flow assessment. We found that LEC‐iFoxc2 KO mice exhibited higher NIR signal intensity and pulse rate, suggesting enhanced lymphatic function. To explore whether enhanced lymphatic function protects against diet‐induced obesity, we fed WT and LEC‐iFoxc2 KO mice with a high‐fat diet for at least 16 weeks. WT HFD mice showed elevated body weight and fat mass coupled with impaired lymphangiogenesis and lymphatic function. However, LEC‐iFoxc2 KO mice showed less weight gain and improved insulin sensitivity compared to WT mice. We again examined lymphatic function using the wound‐induced tail lymphedema assay and NIR imaging. HFD‐fed Foxc2‐deficient mice showed enhanced lymphatic function, improved wound‐induced tail edema resolution, and increased lymph transport compared to HFD‐fed WT mice. Finally, LEC‐iFoxc2 KO mice exhibited augmented lymphangiogenesis in adipose tissues. These results reveal an essential inhibiting role of LEC Foxc2 in lymphangiogenesis and lymphatic function in adult mice that regulates diet‐induced obesity and insulin resistance.