Obesity impacts hypoxia adaptation of the lung.

Obesity is mostly associated with adverse health consequences, but may also elicit favorable effects under chronic conditions. This "obesity paradox" is under debate for pulmonary diseases. Since confounding factors complicate conclusions from human studies, this study utilized a controlled animal model combining diet-induced obesity and chronic hypoxia as model for pulmonary hypertension and COPD. Male C57BL/6 mice were fed control or high fat diet for 30 weeks, half of the animals were exposed to chronic hypoxia (13% O) for 3 weeks. Hypoxia induced right ventricular hypertrophy, thickening of pulmonary arterial and capillary walls, higher lung volumes, and increased hemoglobin concentrations irrespective of the body weight. In contrast, lung proteomes differed substantially between lean and obese-hypoxic mice. Many of the observed changes were linked to vascular and extracellular matrix (ECM) proteins. In lean-hypoxic animals, circulating platelets were reduced and abundances of various clotting-related proteins were altered, indicating a hypercoagulable phenotype. Moreover, the septal ECM composition was changed, and airspaces were significantly distended pointing to lung hyperinflation. These differences were mostly absent in the obese‑hypoxic group. However, the obesity-hypoxia-combination induced the lowest blood CO concentrations, indicating hyperventilation for sufficient oxygen supply. Moreover, endothelial surface areas were increased in obese-hypoxic mice. Thus, obesity exerts differential effects on lung adaptation to hypoxia, which paradoxically include adverse, but also rather protective changes. These differences have a molecular basis in the lung proteome, and may influence pathogenesis of lung diseases. This should be taken into account for future individualized prevention and therapy.