Intermittent fasting (IF) improves metabolic health, yet whether hepatic ketogenesis is required for mediating its effects remains unclear. Here, we investigated how ketogenesis contributes to the systemic and liver-specific metabolic effects of IF in male and female mice. Fasting increased circulating ketone bodies in both sexes, with females showing a greater increase, indicating intrinsic sex differences in ketone metabolism. IF reduced body weight gain and adiposity in both sexes, and these benefits persisted when Hmgcs2 expression was knocked down in adult mice, using an antisense oligonucleotide approach to inhibit ketogenesis. In contrast, hepatic benefits were sex- and ketogenesis-dependent. IF markedly reduced steatosis and fibrosis in male mice, but these improvements were attenuated when Hmgcs2 expression was suppressed. In contrast, female mice showed minimal hepatic benefit from IF and had heightened susceptibility to steatosis, fibrosis, and inflammatory activation upon Hmgcs2 knockdown. Single-cell transcriptomic analyses identified neutrophils and myofibroblasts as key responders to hepatocyte-derived ketone bodies. IF suppressed neutrophil-driven inflammatory signaling in an Hmgcs2-dependent manner, and ketone bodies attenuated low-grade inflammation in cultured neutrophil-like cells. This ketogenesis-inflammation-fibrosis axis was further supported by human Genotype-Tissue Expression liver coexpression analyses. Together, these findings demonstrate that although body weight and antiobesity actions of IF are largely ketogenesis-independent in both sexes of mice, its hepatic antisteatotic and antifibrotic effects are sexually dimorphic and ketogenesis-dependent in male mice.
- We investigated whether ketogenesis is required for the metabolic benefits of intermittent fasting (IF) and whether these effects differ between sexes.
- We specifically asked whether ketogenesis drives IF-mediated protection against obesity and fatty liver disease in male and female mice.
- We found that IF reduced adiposity independently of ketogenesis in both sexes, but its antisteatotic and antifibrotic effects were ketogenesis-dependent in male mice and minimal in female mice.
- These findings reveal a sex-dependent ketogenesis-inflammation-fibrosis axis and highlight the need to consider sex and ketone metabolism when designing dietary or therapeutic interventions.
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