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

Abstract

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 <i>Acetatifactor</i>, <i>Helicobacter</i>, <i>Mucispirillum</i>, and <i>Oscillibacter</i> but increasing short-chain fatty acid (SCFA)-producing bacterial genera including <i>Alistipes</i>, <i>Allobaculum</i>, <i>Odoribacter</i>, and <i>Olsenella</i>. 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.