Sex-Specific Effects of Ketogenic Diet on Anxiety-like Behavior and Neuroimmune Response in C57Bl/6J Mice.

The ketogenic diet (KD) has been shown to reduce anxiety and enhance cognitive functions. However, the sex-specific effects of KD on anxiety-like behavior and the underlying molecular mechanisms contributing to these effects, including neuroinflammation, are unelucidated. This study investigated the sex-specific effects of KD on anxiety-like behavior and the neuroimmune response in the prefrontal cortex (PFC) and hippocampus of male and female C57BL/6J mice. Animals were fed either a control diet (CD- 17% fat, 65% carb, 18% protein) or a KD (80% fat, 5% carb, 15% protein) for four weeks. KD increased the levels of circulating β-hydroxybutyrate (BHB) both in males and females however, PFC BHB levels were found to be elevated only in KD males. However, KD did not affect the behavior of females but improved motor abilities and reduced anxiety levels in males. KD suppressed the mRNA expression of the putative microglial markers (Cd68, P2ry12, Nox2) and induced morphological changes in the male PFC microglia. A sex-specific decrease in IL1β and an increase in IL-10 levels was found in the PFC of KD males. A similar trend was observed in the hippocampus of males where KD reduced the mRNA expression of P2ry12, Il1β and cFos. Additionally, BHB increased the production of IL-10 whereas it decreased the production of IL1β by human microglia in in-vitro conditions. In summary, these results demonstrate that the anxiolytic and motor function enhancement abilities of KD are male-specific. Reduced pro-inflammatory and improved anti-inflammatory factors in the male PFC and hippocampus may underlie these effects.