In conclusion, our study showed that HFD-induced obesity plays a protective role in VILI by suppressing the pulmonary endothelial barrier hyperpermeability and inflammatory response via adipose-derived exosomes, at least partially, through inhibiting the TRPV4/Ca2+ signaling pathway, further providing novel insights into the “obesity paradox” in VILI and suggesting potential exosome-based therapeutics for patients with VILI in clinical practice. The gene discussed is TRPV4; the disease is Obesity.