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

Leucine restriction (LR) improves insulin resistanceand promoteswhite adipose tissue browning. However, the effect of LR on obesity-associatedcognitive impairment remains unclear. The present study found thatan 8-week LR dramatically improved high-fat diet (HFD)-induced cognitivedecline by preventing synaptic dysfunction, increasing the expressionsof neurotrophic factors, and inhibiting neuroinflammation in memory-relatedbrain regions. Moreover, LR notably reshaped the structure of gutmicrobiota, which was manifested by downregulating the Firmicutes/Bacteroidetesratio, reducing the relative abundance of inflammation-related bacteriaincluding Acetatifactor, Helicobacter, Mucispirillum, and Oscillibacter but increasing short-chain fatty acid (SCFA)-producing bacterialgenera including Alistipes, Allobaculum, Odoribacter, and Olsenella. Notably,HFD-caused SCFA reduction, gut barrier damage, and LPS leakage wererecovered by LR. Our findings suggested that LR could serve as aneffective approach to attenuate obesity-induced cognitive deficits,which may be achieved by balancing gut microbiota homeostasis andenhancing SCFA production.

Automated summary

The research shows that Leucine restriction (LR) has a positive impact on insulin resistance and white adipose tissue browning. However, the effect of LR on obesity-associated cognitive impairment has not been well studied. This study found that LR for 8 weeks significantly improved cognitive decline caused by a high-fat diet (HFD), preventing synaptic dysfunction, increasing neurotrophic factors, and inhibiting neuroinflammation in memory-related brain regions. Additionally, LR reshaped the gut microbiota structure by reducing inflammation-related bacteria and increasing short-chain fatty acid (SCFA)-producing bacteria. LR also restored HFD-induced SCFA reduction, gut barrier damage, and LPS leakage. These findings suggest that LR could be a beneficial approach to mitigate obesity-induced cognitive deficits by balancing gut microbiota homeostasis and enhancing SCFA production.