Lipidomics on a High Fat Diet mouse model indicate alterations in lipid metabolism upon aerobic exercise and calories restriction

Importance of the Topic

Lipid metabolism in the liver and adipose tissue plays a central role in energy homeostasis and is profoundly altered in conditions such as obesity, type 2 diabetes and nonalcoholic fatty liver disease. Detailed lipidomic profiling under dietary and exercise interventions offers insights into the molecular mechanisms driving dyslipidemia and supports the development of targeted therapeutic strategies.

Objectives and Study Overview

This study compared high-fat diet (HFD) mice with groups undergoing weight loss by caloric restriction (WL), aerobic exercise (EX) or both (WLEX). The goal was to delineate tissue-specific lipidomic changes in liver and adipose tissue associated with diet and exercise interventions.

Methodology and Instrumentation

Seven male C57BL/6 mice per group were maintained on HFD or calorie-restricted diets for 20 weeks; the final 8 weeks included EX, WL or combined treatments. Liver samples were extracted using a methyl tert-butyl ether/methanol protocol, and adipose tissue using chloroform/methanol. Lipids were separated on a Waters Acquity UPLC CSH C18 column (2.1×100 mm, 1.7 μm) at 55 °C with an H2O-ACN-IPA gradient (ammonium formate and formic acid additives) at 0.4 mL/min. A Bruker timsTOF mass spectrometer acquired data in data-dependent mode over 50–1200 m/z in both polarities for liver and positive mode for adipose tissue. Data processing was conducted with MetaboScape software.

Used Instrumentation

• Bead mill homogenizer for tissue disruption
• Waters Acquity UPLC CSH C18 column (2.1×100 mm, 1.7 μm)
• Bruker timsTOF mass spectrometer
• MetaboScape data analysis software

Results and Discussion

• A strong positive correlation between phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species of matching chain lengths indicated dysregulated PE/PC biosynthesis in HFD livers.
• Phosphatidylserine (PS) levels were reduced, likely due to limited PE and PC substrates for PS synthases.
• Total fatty acid content decreased in HFD mice, notably 18:2 n-6 and 18:3 n-3, with a marked increase in the n-6/n-3 ratio driven by reduced n-3 PUFAs (18:4, 20:5, 22:5).
• In WLEX mice, diglycerides (DGs) enriched in polyunsaturated fatty acids were up-regulated, concurrent with lowered saturated fatty acids, suggesting mobilization of stored lipids through exercise.
• PLS models and volcano plots distinctly separated HFD and WLEX groups in both tissues, underscoring specific lipidomic signatures of each intervention.

Benefits and Practical Applications of the Method

This comprehensive lipidomic approach enables identification of biomarkers for dietary and exercise responses, supports mechanistic understanding of metabolic disorders and informs the design of nutritional and pharmacological interventions in obesity and fatty liver disease.

Future Trends and Potential Applications

Future work will integrate targeted metabolomics of hydrophilic metabolites to map correlated pathways. Emerging techniques such as single-cell lipidomics, multi-omic integration and computational modeling promise deeper insights and translation to clinical studies in humans.

Conclusion

Distinct liver and adipose tissue lipidomic profiles characterize HFD and weight loss/exercise interventions. Dysregulation of PE, PC and PS synthesis and alterations in fatty acid composition highlight key metabolic adaptations. Upcoming targeted analyses will further elucidate the underlying biochemical pathways.

References

• 1. Eisinger K et al. Experimental and Molecular Pathology. 2014 May 14. doi:10.1016/j.yexmp.2014.05.002. PMID:24830603.