The metabolic footprint during adipocyte commitment highlights ceramide modulation as an adequate approach for obesity treatment

BACKGROUND: Metabolic modulation is capable of maintaining cell potency, regulating niche homeostasis, or determining cell fate. However, little is known regarding the metabolic landscape during early adipogenesis or whether metabolic modulation could be a potential approach for obesity treatment. METHODS: The metabolic footprint during adipocyte commitment was evaluated by metabolomics analysis in mouse embryonic fibroblasts (MEFs). The role of apoptosis induced by ceramide and how ceramide is regulated were evaluated by omics analysis in vitro, human database and the adipocyte-specific Sirt1 knockout mouse. FINDINGS: The metabolic footprint showed that a complicated diversity of metabolism was enriched as early as 3 h and tended to fluctuate throughout differentiation. Subsequently, the scale of these perturbed metabolic patterns was reduced to reach a balanced state. Of high relevance is the presence of apoptosis induced by ceramide accumulation, which is associated with metabolic dynamics. Interestingly, apoptotic cells were not merely a byproduct of adipogenesis but rather promoted the release of lipid components to facilitate adipogenesis. Mechanistically, ceramide accumulation stemming from hydrolysis and the de novo pathway during early adipogenesis is regulated by Sirt1 upon epigenetic alterations of constitutive Histone H3K4 methylation and H3K9 acetylation. INTERPRETATION: The metabolic footprint during adipocyte commitment highlights that apoptosis induced by ceramide is essential for adipogenesis, which is reversed by suppression of Sirt1. Therefore, Sirt1 may constitute a target to treat obesity or other ceramide-associated metabolic syndromes. FUNDING: This project was supported by grants from the University of Macau (SRG2015-00008-FHS, MYRG2016-00054-FHS and MYRG2017-00096-FHS to RHW; CPG2019-00019-FHS to CXD) and from the National Natural Science Foundation of China (81672603 and 81401978) to QC.