A metabolome atlas of mouse brain on the global metabolic signature dynamics following short-term fasting

Abstract

Calorie restriction (CR) or a fasting regimen is considered one of the most potent non-pharmacological interventions to prevent chronic metabolic disorders, ameliorate autoimmune diseases, and attenuate aging. Despite efforts, the mechanisms by which CR improves health, particularly brain health, are still not fully understood. Metabolic homeostasis is vital for brain function, and a detailed metabolome atlas of the brain is essential for understanding the networks connecting different brain regions. Herein, we applied gas chromatography-mass spectrometry-based metabolomics and lipidomics, covering 797 structurally annotated metabolites, to investigate the metabolome of seven brain regions in fasted (3, 6, 12, and 24 h) and ad libitum fed mice. Using multivariate and univariate statistical techniques, we generated a metabolome atlas of mouse brain on the global metabolic signature dynamics across multiple brain regions following short-term fasting (STF). Significant metabolic differences across brain regions along with STF-triggered region-dependent metabolic remodeling were identified. We found that STF elicited triacylglycerol degradation and lipolysis to compensate for energy demand under fasting conditions. Besides, changes in amino acid profiles were observed, which may play crucial roles in the regulation of energy metabolism, neurotransmitter signaling, and anti-inflammatory and antioxidant in response to STF. Additionally, this study reported, for the first time, that STF triggers a significant elevation of N-acylethanolamines, a class of neuroprotective lipids, in the brain and liver. These findings provide novel insights into the molecular basis and mechanisms of CR and offer a comprehensive resource for further investigation.

Fasting mimicking diet extends lifespan and improves intestinal and cognitive health

“…Branched-chain amino acids, a crucial raw material for the synthesis of Glu and GABA, also gained an increase after fasting. 23…”

Elucidating brain metabolic changes during short-term fasting: a comprehensive atlas

“…The recent study, published in Signal Transduction and Targeted Therapy by Le's team (Shao et al, 2023 ), provides a comprehensive and detailed metabolome atlas of the mouse brain based on the global metabolic signature dynamics across multiple brain regions in response to short-term fasting (STF) (Shao et al, 2023 ). This research revealed significant region-specific metabolic remodeling involving lipids, saccharides, and amino acid neurotransmitters under food deprivation ( Figure 1 ) (Shao et al, 2023 ). These discoveries furnish a crucial molecular foundation and novel insights into the mechanisms through which STF improves brain health.…”

“… Metabolomic analysis of seven brain regions in C57BL/6 mice under fasting conditions (3 h, 6 h, 12 h, and 24 h) and ad libitum feeding. A heat map was presented to illustrate the differential expression of metabolites in these seven brain regions (Shao et al, 2023 ). The analysis revealed that short-term fasting induced a global lipid and amino acid metabolism remodeling, mainly targeting FAs, BCAAs, Glu, GABA, and the citrulline–NO cycle.…”

“…In this study, Le's group conducted comprehensive metabolomics and lipidomics analyses on seven brain regions of mice subjected to different periods of fasting (3 h, 6 h, 12 h, and 24 h). They employed gas chromatography–mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) techniques, encompassing the profiling of 797 structurally identified metabolites ( Figure 1 ) (Shao et al, 2023 ). The results unveiled distinctive metabolic signatures within different functional brain regions, highlighting the emergence of a unique repertoire of metabolites in response to STF.…”

“…Notably, significant variations in metabolites and lipids were discerned in the hippocampus (HIP), olfactory bulb (OB), and spinal cord (SC) regions. The principal metabolic adjustments triggered by STF primarily encompass increased triacylglycerol degradation and heightened fatty acid (FA) production across most brain regions (Shao et al, 2023 ). FAs assume a pivotal role in upholding cell membrane integrity and function.…”