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Dietary pyruvate targets cytosolic phospholipase A2 to mitigate inflammation and obesity in mice

PrOTEIN & CELL 2024年第9期15卷 661-685页

作者： Hasan, Sadaf Ghani, Nabil Zhao, Xiangli Good, Julia Huang, Amanda Wrona, Hailey Lynn Liu, Jody Liu, Chuan-ju NYU Grossman Sch Med Dept Orthoped Surg New York NY 10016 USA Yale Univ Sch Med Dept Orthoped & Rehabil New Haven CT 06510 USA Cornell Univ Ithaca NY USA Univ North Carolina Chapel Hill Dept Biomed Engn Chapel Hill NC USA NYU New York NY 14853 USA NYU Grossman Sch Med Dept Cell Biol New York NY 10016 USA rutgers State Univ St Peters Univ Hosp Dept Med Div Internal Med New Brunswick NJ 08901 USA

Obesity has a multifactorial etiology and is known to be a state of chronic low-grade inflammation, known as meta-inflammation. This state is associated with the development of metabolic disorders such as glucose intolerance and nonalcoholic fatty liver disease. Pyruvate is a glycolytic metabolite and a crucial node in various metabolic pathways. However, its role and molecular mechanism in obesity and associated complications are obscure. In this study, we reported that pyruvate substantially inhibited adipogenic differentiation in vitro and its administration significantly prevented HFD-induced weight gain, white adipose tissue inflammation, and metabolic dysregulation. To identify the target proteins of pyruvate, drug affinity responsive target stability was employed with proteomics, cellular thermal shift assay, and isothermal drug response to detect the interactions between pyruvate and its molecular targets. Consequently, we identified cytosolic phospholipase A2 (cPLA2) as a novel molecular target of pyruvate and demonstrated that pyruvate restrained diet-induced obesity, white adipose tissue inflammation, and hepatic steatosis in a cPLA2-dependent manner. Studies with global ablation of cPLA2 in mice showed that the protective effects of pyruvate were largely abrogated, confirming the importance of pyruvate/cPLA2 interaction in pyruvate attenuation of inflammation and obesity. Overall, our study not only establishes pyruvate as an antagonist of cPLA2 signaling and a potential therapeutic option for obesity but it also sheds light on the mechanism of its action. Pyruvate's prior clinical use indicates that it can be considered a safe and viable alternative for obesity, whether consumed as a dietary supplement or as part of a regular diet.

关键词： metabolic disease pyruvate cytosolic phospholipase obesity ADIPOSE-TISSUE INFLAMMATION ADIPOCYTE DIFFErENTIATION MACrOPHAGE POLArIZATION METABOLIC SYNDrOME KAPPA-B SUPPLEMENTATION INFILTrATION EXPrESSION GLUCOSE MOUSE

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