Testosterone protects from metabolic syndrome-associated lung dysfunction in a high-fat diet rabbit model

Metabolic syndrome (MetS), including obesity, dyslipidemia, hypertension, insulin resistance, and often testosterone (T) deficiency, is increasingly linked to impaired lung function, worsened by systemic inflammation. COVID-19 highlighted the vulnerability of metabolically impaired patients to respiratory complications. Preclinical mechanistic studies remain limited. This study examined MetS effects on lung function and morphology, and the impact of T therapy in a high-fat diet (HFD)-induced MetS rabbit model. Male New Zealand White rabbits were assigned to: regular diet (RD12W), HFD 6 weeks (HFD6W), HFD 12 weeks (HFD12W), HFD + T 12 weeks (HFD + T12W), and HFD + T last 6 weeks (HFD12W + T6W). Lung function was measured via airway opening pressure (PAO), and tissues analyzed for macrophages (RAM11), collagen (Picrosirius Red), and inflammatory/fibrotic gene expression. HFD induced MetS features, hypogonadism, increased PAO, reduced compliance, elevated fatty acids, and early macrophage remodeling. At 12 weeks, inflammation and fibrosis were prominent, with upregulation of IL1β, LOX1, RORγt, TLR2, COL1A1, COL3A1, and TGFβ1. T therapy increased plasma T, improved metabolic parameters, reduced PAO, and reversed inflammatory/fibrotic gene expression. Histology confirmed decreased macrophage clustering and fibrosis. PAO inversely correlated with T, with levels <3.76 nM predicting abnormal PAO with >80% sensitivity and specificity. MetS causes progressive lung injury via macrophage dysregulation, inflammation, and peribronchiolar fibrosis. T deficiency is central, as hormone administration improved lung function and histology. Immune-driven mechanisms, including Th2/Th17 cytokines and EMT markers, likely contribute. T's anti-inflammatory and anti-fibrotic effects may involve cAMP-signaling. Clinically, assessing T and metabolic status is crucial, and T therapy may help mitigate lung consequences of MetS.