Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.
J Exp Med. 2022 Jul 4;219(7). doi: 10.1084/jem.20211894. Epub 2022 May 26.
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 HIF1α, 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.
鉴于肥胖对临床、经济和社会的影响，阐明脂肪组织扩张的机制仍然具有重要意义。我们之前曾表明，作为一种线粒体半胱氨酸分解代谢酶，生成丙酮酸和硫化物的 3-巯基丙酮酸硫转移酶（MPST）在肥胖症患者的白色脂肪组织（WAT）中的水平降低。在这里，我们报告说，Mpst 缺失会导致高脂肪饮食（HFD）喂养的小鼠脂肪堆积，这是由于转录和代谢适应不良所致。在高脂肪饮食下，Mpst 缺陷型小鼠的体重和腹股沟白色脂肪组织质量增加，代谢率降低，葡萄糖/胰岛素耐量受损。在分子水平上，Mpst 缺失激活 HIF1α，下调外/内膜转位酶（TIM/TOM）复合物的亚基，并损害线粒体蛋白的输入。MPST 缺乏抑制三羧酸循环、氧化磷酸化和脂肪酸氧化，从而促进脂质积累。向肥胖小鼠给予硫供体可逆转 HFD 诱导的变化。这些发现揭示了 MPST 对白色脂肪组织生物学和代谢健康的重要性，并确定了肥胖症的一个潜在新治疗靶点。
