Methionine restriction alleviates diabetes-associated cognitive impairment via activation of FGF21
Yuyu Zhang,
Yajie Wang,
Yiju Li,
Jingxi Pang,
Annika Höhn,
Weixuan Dong,
Rui Gao,
Yan Liu,
Da Wang,
Yongbo She,
Rui Guo,
Zhigang Liu
Affiliations
Yuyu Zhang
Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
Yajie Wang
Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
Yiju Li
Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
Jingxi Pang
Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
Annika Höhn
German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Department of Molecular Toxicology, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, Muenchen, Neuherberg, Germany
Weixuan Dong
The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
Rui Gao
The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
Yan Liu
The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
Da Wang
Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
Yongbo She
Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
Rui Guo
Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
Zhigang Liu
Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China; Northwest A&F University Shenzhen Research Institute, Shenzhen, Guangdong, 518000, China; Corresponding author. Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China.
Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17 % methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism.
