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
Abstract
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. • Methionine restriction (MR) improves peripheral insulin sensitivity in T2DM mice. • MR activates ATF4/PPARα and enhances hepatic FGF21 generation in T2DM mice. • MR alleviates cognitive impairment and boosts brain glucose uptake in T2DM mice. • MR balances redox homeostasis and neuroinflammation in the brain of T2DM mice. • FGFR1 is essential for regulating brain glucose uptake in response to MR.