Unveiling the role of CB2 receptor in beta-hydroxybutyrate mediated modulation of

The cannabinoid receptor type 2 (CB2R), primarily expressed in microglia, the brain's resident immune cells, acts as a central regulator of neuroinflammatory responses. When CB2R is activated, it triggers anti-inflammatory signaling, making it a promising target for modulating microglial function in neuroinflammatory diseases. The ketone body, β-hydroxybutyrate (BHB), is gaining attention as a therapeutic agent for neurodegenerative disorders due to its ability to modulate neuroinflammation and preserve blood-brain barrier integrity. One mechanism by which BHB exerts anti-inflammatory effects is through regulation of microglial function; however, the precise mechanisms remain unclear. Since the role of BHB in this context is unexplored, we used two neuroinflammation models to test the hypothesis that CB2R-associated signaling contributes to the effects of BHB. In a mouse model of diet-induced obesity (DIO), characterized by chronic low-grade neuroinflammation, BHB treatment promoted ramified microglial morphology and enhanced debris clearance while sparing synaptic elements. These changes were accompanied by alterations in CB2R-related signaling markers and a slight increase in hydroxycarboxylic acid receptor 2 (HCA2), a known BHB target. When primary microglial cultures were challenged with lipopolysaccharide (LPS), BHB helped restore their function. However, that benefit disappeared when CB2R was pharmacologically blocked. Importantly, BHB increased the expression of arginase 1 (Arg1), a hallmark of anti-inflammatory responses, a change reversed by CB2R blockade. Moreover, BHB reduced NF-κB signaling, and CB2R inhibition attenuated this effect, suggesting that CB2R-associated signaling contributes to BHB's anti-inflammatory actions. Collectively, our findings demonstrate that BHB's anti-inflammatory effects are mediated, at least in part, through CB2R signaling, providing new insight into its therapeutic potential for neuroinflammation.