Spermidine supplementation and voluntary activity differentially affect obesity-related structural changes in the mouse lung

Obesity is associated with lung function impairment and respiratory diseases; however, the underlying pathophysiological mechanisms are still elusive and therapeutic options are limited. This study examined the effects of prolonged excess fat intake on lung mechanics and microstructure and tested spermidine supplementation and physical activity as intervention strategies. C57BL/6N mice fed control diet (CD, 10% fat) or high fat diet (HFD, 60% fat) were left untreated, were supplemented with 3 mM spermidine, had access to running wheels for voluntary activity or a combination of both. After 30 weeks, lung mechanics was assessed and left lungs were analyzed by design-based stereology. HFD exerted minor effects on lung mechanics, and resulted in higher body weight and elevated lung, air and septal volumes. The number of alveoli was higher in HFD-fed animals. This was accompanied by an increase in epithelial, but not endothelial surface area. Moreover, air-blood-barrier and endothelium were significantly thicker. Neither treatment affected HFD-related body weights. Spermidine lowered lung volumes as well as endothelial and air-blood barrier thicknesses towards control levels and substantially increased the endothelial surface area under HFD. Activity resulted in decreased volumes of lung, septa and septal compartments, but did not affect vascular changes in HFD-fed mice. The combination treatment showed no additive effect. In conclusion, excess fat consumption induced alveolar capillary remodeling indicative of impaired perfusion and gas diffusion. Spermidine alleviated obesity-related endothelial alterations indicating a beneficial effect, whereas physical activity reduced lung volumes apparently by other, possibly systemic effects.

Keywords: diet-induced obesity; lung ultrastructure; physical activity; polyamine spermidine.