Leucine-Restricted Diet Ameliorates Obesity-Linked Cognitive Deficits: Involvement of the Microbiota–Gut–Brain Axis

Leucine restriction (LR) improves insulin resistance and promotes white adipose tissue browning. However, the effect of LR on obesity-associated cognitive impairment remains unclear. The present study found that an 8-week LR dramatically improved high-fat diet (HFD)-induced cognitive decline by preventing synaptic dysfunction, increasing the expressions of neurotrophic factors, and inhibiting neuroinflammation in memory-related brain regions. Moreover, LR notably reshaped the structure of gut microbiota, which was manifested by downregulating the Firmicutes/Bacteroidetes ratio, reducing the relative abundance of inflammation-related bacteria including Acetatifactor, Helicobacter, Mucispirillum, and Oscillibacter but increasing short-chain fatty acid (SCFA)-producing bacterial genera including Alistipes, Allobaculum, Odoribacter, and Olsenella. Notably, HFD-caused SCFA reduction, gut barrier damage, and LPS leakage were recovered by LR. Our findings suggested that LR could serve as an effective approach to attenuate obesity-induced cognitive deficits, which may be achieved by balancing gut microbiota homeostasis and enhancing SCFA production.