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

Abstract

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.

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

“…It is expected that a better understanding of senoinflam mechanisms will provide a basis for the discovery of molecular targets that modulate age-related chronic inflammatory conditions and enable the develop effective interventions to delay aging and prevent the occurrence of aging-assoc FOXO3, both of which exert antioxidant effects [209]. It is thought that HB exer signaling mechanisms comparable to that of CR by inducing co-activation through deactivation of the PI3K/Akt pathway [218]. HB is an effector that transduces signals via G-protein coupled receptors.…”

“…K neuroprotective and lifespan extension effects similar to CR in C. elegans [21 transcription of antioxidant genes, including manganese superoxide dismu FOXO3, both of which exert antioxidant effects [209]. It is thought that HB exer signaling mechanisms comparable to that of CR by inducing co-activation through deactivation of the PI3K/Akt pathway [218]. HB is an effector that transduces signals via G-protein coupled receptors.…”

“…HB upregulates transcription of antioxidant genes, including manganese superoxide dismutase (MnSOD) and FOXO3, both of which exert antioxidant effects [209]. It is thought that HB exerts its effect through signaling mechanisms comparable to that of CR by inducing co-activation of FOXO1/PGC-1α through deactivation of the PI3K/Akt pathway [218].…”

Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction

“…The interactions between FOXOs and co-activators, for example, PGC-1α, also play important roles in DR response [23]. PGC-1α has been shown to interact directly with both FoxO1 and FoxO3 and activate FOXO-dependent gene transcription [132,133].…”

“…It was also reported that FoxO1-mediated antioxidant activity and autophagy are essential for the protective effect of DR against liver injury [4]. Moreover, a recent study reveals that FoxO1 also regulate the anti-inflammatory action of DR by interacting with PGC-1α (peroxisome proliferator-activated receptor gamma (PPAR-γ) coactivator 1-alpha) [23]. Interestingly, it was recently reported that in C. elegans, daf-16 could modulate immunity and promote longevity by inhibiting feeding behavior, which appears to mimic a DR-like situation [24].…”