The brain is the second-most lipid-rich organ, with lipids playing essential roles in membrane formation, signalling, inflammation regulation, neurogenesis, energy storage, and protection against oxidative stress. Dysregulation of lipid metabolism is a key factor in obesity-related diseases and neurodegenerative disorders, highlighting the importance of lipid homeostasis for brain function. Despite recent advances in lipidomics technology, how brain lipid metabolism is affected by diet and the energy status of an organism remains poorly understood.
The hypothalamus regulates energy homeostasis by integrating nutrient and hormonal signals to control energy expenditure and feeding behaviour. While high-fat diets are known to disrupt hypothalamic function, whether and how they disrupt lipid metabolism in the hypothalamus remains unclear. This study leveraged lipidomics (quantifying 750+ individual lipid species) and bulk RNA sequencing to examine the impact of short- (3 days) and long-term (8 weeks) high-fat diet on hypothalamic lipid metabolism.
Obesity has recently been shown to reduce the "metabolic elasticity" of peripheral organs, i.e. their ability to respond to energy balance disturbances and return to baseline homeostasis. We applied this concept to the hypothalamus to assess its adaptability to metabolic challenges, such as cycles of fasting and refeeding, under different diet conditions. Originally developed for transcriptome data, we extended this concept to analyse lipidome elasticity. Our findings revealed that just three days of a high-fat diet significantly altered hypothalamic elasticity, identifying pathway perturbations not evident when comparing single metabolic state snapshots in high-fat diet versus chow-fed mice.
Understanding the interplay between obesity, lipid metabolism and brain function is essential for developing new therapeutic strategies. This study shows that metabolic elasticity scoring offers a promising approach to identify novel pathways involved in the neurological aspects of obesity-related metabolic disorders.