The ketone body metabolite β‐hydroxybutyrate induces an antidepression‐associated ramification of microglia via HDACs inhibition‐triggered Akt‐small RhoGTPase activation

Abstact Direct induction of macrophage ramification has been shown to promote an alternative (M2) polarization, suggesting that the ramified morphology may determine the function of immune cells. The ketone body metabolite β‐hydroxybutyrate (BHB) elevated in conditions including fasting and low‐carbohydrate ketogenic diet (KD) can reduce neuroinflammation. However, how exactly BHB impacts microglia remains unclear. We report that BHB as well as its producing stimuli fasting and KD induced obvious ramifications of murine microglia in basal and inflammatory conditions in a reversible manner, and these ramifications were accompanied with microglial profile toward M2 polarization and phagocytosis. The protein kinase B (Akt)‐small RhoGTPase axis was found to mediate the effect of BHB on microglial shape change, as (i) BHB activated the microglial small RhoGTPase (Rac1, Cdc42) and Akt; (ii) Akt and Rac1‐Cdc42 inhibition abolished the pro‐ramification effect of BHB; (iii) Akt inhibition prevented the activation of Rac1‐Cdc42 induced by BHB treatment. Incubation of microglia with other classical histone deacetylases (HDACs) inhibitors, but not G protein‐coupled receptor 109a (GPR109a) activators, also induced microglial ramification and Akt activation, suggesting that the BHB‐induced ramification of microglia may be triggered by HDACs inhibition. Functionally, Akt inhibition was found to abrogate the effects of BHB on microglial polarization and phagocytosis. In neuroinflammatory models induced by lipopolysaccharide (LPS) or chronic unpredictable stress (CUS), BHB prevented the microglial process retraction and depressive‐like behaviors, and these effects were abolished by Akt inhibition. Our findings for the first time showed that BHB exerts anti‐inflammatory actions via promotion of microglial ramification.