# Sucrose- and fat-related metabolic states influence the adaptation of the pulmonary lipid metabolism to hypoxia

## TL;DR

This study shows how diets high in fat or sucrose change how lungs handle lipids under low oxygen conditions, affecting surfactant production and lung function.

## Contribution

The study reveals that diet-induced metabolic states alter pulmonary lipid metabolism adaptation to hypoxia in a diet-specific manner.

## Key findings

- Hypoxia caused smaller lamellar bodies and increased surfactant precursor formation in control diet mice.
- High-sucrose and high-fat diets led to lipid accumulation in liver and AE2 cells.
- Hypoxia-induced lung mechanics changes were less severe in mice on high-sucrose or high-fat diets.

## Abstract

Pulmonary surfactant is essential for lung function and consists mainly of lipids, almost half of which in adult mammals originate from de novo synthesis in alveolar epithelial type-2 (AE2) cells. Obesogenic nutrition and hypoxia coexist in obese patients with chronic lung diseases. This study tested the hypothesis that diet-induced obesity and chronic hypoxia alter lipid metabolism and thereby deteriorate surfactant homeostasis. Male C57BL/6N mice were fed control diet (4% fat, 6% sucrose; CD), high-sucrose diet (4% fat, 46% sucrose; HSD) or high-fat diet (35% fat, 7% sucrose; HFD). After 27 weeks, half of each diet group was exposed to hypoxia (13% O2, Hyp) for 3 weeks. After 30 weeks, lung mechanics were assessed, and the blood, livers, and lungs were analyzed. In CD-fed mice, hypoxia induced lung mechanical changes indicative of reduced elastic recoil properties, as well as smaller lamellar bodies (LBs) and higher composite body volumes, suggesting an increased surfactant precursor formation. HSD and HFD induced lipid accumulation in liver and AE2 cells. In HSD-Hyp and HFD-Hyp, LB volumes per alveolar surface area were elevated, indicating compensatory increases in intracellular surfactant pools which were absent in CD-Hyp. Additionally, hypoxia-related lung mechanics alterations were less pronounced in HSD-Hyp and HFD-Hyp. Lung proteome analysis revealed that only a few lipid metabolism-associated proteins were similarly regulated within diet groups under hypoxia, with the most prominent changes in sucrose-fed hypoxic animals. Thus, individual diet-related metabolic states specifically affect the adaptation of the pulmonary lipid metabolism and intracellular surfactant assembly to chronic hypoxia.

The online version contains supplementary material available at 10.1007/s00441-025-03968-0.