Topical Area: Energy and Macronutrient Metabolism, Obesity
Objectives : Methionine restriction (MR) has emerged as a promising dietary restriction on metabolic syndrome as its beneficial effects on increasing metabolic flexibility and up-regulating mitochondrial function. The circadian clock directs many aspects of metabolism and macronutrients can function as zeitgebers for the clock in a tissue-specific way. It has been demonstrated that high-fat diet could alter daily oscillations via gut-brain axis. We hypothesis that MR is a new strategy could reverse the high-fat diet induced circadian rhythm disorders and cognitive impairments.
Methods : 3 month-old male C57BL/6J mice were assigned to four groups based on diet: low-fat diet (0.86% methionine), low-fat diet with MR(0.17% methionine), high-fat diet, and high-fat diet with MR. After 8 weeks treatment, we employed behavioral test, transmission electron microscope, and 16S rDNA sequencing to evaluate cognitive function, rhythmic variation and the interconnection between gut microbiota and central nervous system.
MR diminished HFD-induced body weight gain and restored the glucose tolerance at ZT0 (light phase) and ZT12 (dark phase). The neuroprotective effects of MR were connected with the ERK/CREB/BDNF signaling pathway and synaptic plasticity. MR changed energy metabolism via activated mTOR/ULK/AMPK signaling in brain. MR ameliorated rhythmic oscillations of clock control gene Bmal1/Per2 in gut-brain axis. Moreover, MR attenuated HFD-induced intestinal inflammatory and protected gut barrier integrity via enhancing the expression of intestinal tight junction protein. The gut microbiome was re-shaped by MR treatment, accompanied by the alteration of short chain fatty acids, the microbial products mediating systemic metabolism and has benefits on brain function. MR increased microbiota-derived butyric and isovaleric which possible synchronizers of peripheral circadian clocks.
The present study provided comprehensive evidence that MR attenuated obesity-induced cognitive impairment via balancing the circadian rhythm in gut-brain axis and that is a potential new therapeutic avenue for treating metabolic syndrome-related neurodegenerative diseases.
Funding Sources : This work was financially supported by the National Key Research and Development Program of China, National Natural Science Foundation of China.