The Hydrophilic Metabolite UMP Alleviates Obesity Traits through a HIF2α-ACER2-Ceramide Signaling Axis.
Huiying LiuPengcheng WangFeng XuQixing NieSen YanZhipeng ZhangYi ZhangChangtao JiangXiaomei QinYanli PangPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2024)
Metabolic abnormalities contribute to the pathogenesis of obesity and its complications. Yet, the understanding of the interactions between critical metabolic pathways that underlie obesity remains to be improved, in part owing to the lack of comprehensive metabolomics studies that reconcile data from both hydrophilic and lipophilic metabolome analyses that can lead to the identification and characterization of key signaling networks. Here, the study conducts a comprehensive metabolomics analysis, surveying lipids and hydrophilic metabolites of the plasma and omental adipose tissue of obese individuals and the plasma and epididymal adipose tissue of mice. Through these approaches, it is found that a significant accumulation of ceramide due to inhibited sphingolipid catabolism, while a significant reduction in the levels of uridine monophosphate (UMP), is critical to pyrimidine biosynthesis. Further, it is found that UMP administration restores sphingolipid homeostasis and can reduce obesity in mice by reversing obesity-induced inhibition of adipocyte hypoxia inducible factor 2a (Hif2α) and its target gene alkaline ceramidase 2 (Acer2), so as to promote ceramide catabolism and alleviate its accumulation within cells. Using adipose tissue Hif2α-specific knockout mice, the study further demonstrates that the presence of UMP can alleviate obesity through a HIF2α-ACER2-ceramide pathway, which can be a new signaling axis for obesity improvement.
Keyphrases
- insulin resistance
- high fat diet induced
- adipose tissue
- metabolic syndrome
- weight loss
- type diabetes
- weight gain
- high fat diet
- skeletal muscle
- endothelial cells
- genome wide
- oxidative stress
- ms ms
- mass spectrometry
- risk factors
- high resolution
- machine learning
- copy number
- artificial intelligence
- physical activity
- big data
- obese patients
- high glucose
- cell cycle arrest