DataVXAdvanced SciencePaper
journal article·2024-06Open access

The Hydrophilic Metabolite UMP Alleviates Obesity Traits through a HIF2α‐ACER2‐Ceramide Signaling Axis

Huiying Liu, Pengcheng Wang, Feng Xu, Qixing Nie, Sen Yan, Zhipeng Zhang, Yi Zhang, Changtao Jiang, Xiaomei Qin, Yanli Pang

Advanced Science· Volume 11· Issue 21
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Source abstract

Abstract

Abstract 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.
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Research context

OpenAlex topics: Sphingolipid Metabolism and Signaling · Autophagy in Disease and Therapy · Calcium signaling and nucleotide metabolism

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Peking University Beijing 100191 China

Center for Obesity and Metabolic Disease Research School of Basic Medical Sciences Peking University Beijing 100191 China

Center of Basic Medical Research Institute of Medical Innovation and Research Third Hospital Peking University Beijing 100191 China

Clinical Pharmacology and Pharmacometrics Janssen China Research & Development Beijing 100191 China

State Key Laboratory of Food Science and Resources China‐Canada Joint Lab of Food Science and Technology Key Laboratory of Bioactive Polysaccharides of Jiangxi Province Nanchang University Nanchang 330013 China

Center for Reproductive Medicine Department of Obstetrics and Gynecology State Key Laboratory of Female Fertility Preservation and Promotion Peking University Third Hospital Beijing 100191 China

General Surgery Department Third Hospital Peking University Beijing 100191 China

Department of Immunology School of Basic Medical Sciences NHC Key Laboratory of Medical Immunology Peking University Beijing 100191 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China

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