期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 219, 期 7, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20211894
关键词
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资金
- European Regional Development Fund of the European Union
- Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation [T2E.K-00843]
- Hellenic Foundation for Research and Innovation (H.F.R.I.) [HFRI-FM17-886]
- Hellenic State Scholarship Foundation IKY-Siemens Research Projects of Excellence [11/3056]
- Hellenic Foundation for Research and Innovation
- Deutsche Forschungsgemeinschaft [CRC1366/1 B1, 39404578, EXC 2026, 390649896]
- Swiss National Research Foundation (SNSF) [31003A_179434]
- Swiss National Science Foundation (SNF) [31003A_179434] Funding Source: Swiss National Science Foundation (SNF)
This study found that levels of MPST are downregulated in white adipose tissue in obesity. Deletion of the MPST gene leads to fat accumulation in mice fed a high-fat diet. MPST deficiency also affects mitochondrial protein import as well as metabolic reactions such as the TCA cycle, oxidative phosphorylation, and fatty acid oxidation.
Given the clinical, economic, and societal impact of obesity, unraveling the mechanisms of adipose tissue expansion remains of fundamental significance. We previously showed that white adipose tissue (WAT) levels of 3-mercaptopyruvate sulfurtransferase (MPST), a mitochondrial cysteine-catabolizing enzyme that yields pyruvate and sulfide species, are downregulated in obesity. Here, we report that Mpst deletion results in fat accumulation in mice fed a high-fat diet (HFD) through transcriptional and metabolic maladaptation. Mpst-deficient mice on HFD exhibit increased body weight and inguinal WAT mass, reduced metabolic rate, and impaired glucose/insulin tolerance. At the molecular level, Mpst ablation activates HIF1 alpha, downregulates subunits of the translocase of outer/inner membrane (TIM/TOM) complex, and impairs mitochondrial protein import. MPST deficiency suppresses the TCA cycle, oxidative phosphorylation, and fatty acid oxidation, enhancing lipid accumulation. Sulfide donor administration to obese mice reverses the HFD-induced changes. These findings reveal the significance of MPST for white adipose tissue biology and metabolic health and identify a potential new therapeutic target for obesity.
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