Anti-inflammatory action of β-hydroxybutyrate via modulation of PGC-1α and FoxO1, mimicking calorie restriction

β-Hydroxybutyrate (HB) is a ketone body used as an energy source that has shown anti-inflammatory effects similar to calorie restriction (CR); Here, PGC-1α, an abundantly expressed co-factor in the kidney, was reported to interact with both FoxO1 and NF-κB although the definitive interactive mechanism has not yet been reported. In this study, we investigated whether renal aging-related inflammation is modulated by HB. We compared aged rats administered with HB to calorie restricted rats and examined the modulation of FoxO1 and the NF-κB pathway through interactions with PGC-1α. We found that in aged rats treated with HB, pro-inflammatory signaling changes were reversed and showed effects comparable to CR. As FoxO1 and its target genes catalase/MnSOD were upregulated by HB treatment and PGC-1α selectively interacted with FoxO1, not with NF-κB, and ameliorated the renal inflammatory response. These findings were further confirmed using FoxO1 overexpression and siRNA transfection in vitro. Our findings suggest that HB suppressed aging-related inflammation as a CR mimetic by enabling the co-activation and selective interaction between FoxO1 and PGC-1α. This study demonstrates the potential therapeutic role of HB as a CR mimetic, which ameliorates inflammation by a novel mechanism where FoxO1 outcompetes NF-κB by interacting with PGC-1α in aging kidneys.