Intermittent fasting reduces adiposity independent of hepatic ketogenesis but requires ketogenesis for liver protection in male mice
In a mouse model, intermittent fasting (IF) lowered body weight gain and fat mass in both sexes without needing hepatic ketogenesis. However, the anti‑steatotic and antifibrotic effects of IF were observed only in males and disappeared when hepatic Hmgcs2, the key ketogenesis enzyme, was silenced. Female mice showed little liver benefit and worsened pathology when ketogenesis was inhibited.
Study and findings
The investigators used adult C57BL/6J mice of both sexes and applied a time‑restricted intermittent fasting regimen. Circulating ketone bodies rose in fasting mice, with a larger increase in females, indicating sex‑specific ketone metabolism. Body weight gain and adiposity were reduced by IF in both males and females, and this effect persisted after hepatic Hmgcs2 knock‑down achieved by antisense oligonucleotides, demonstrating that weight‑loss benefits are largely ketogenesis‑independent. Liver histology revealed that IF markedly decreased steatosis and fibrosis in male mice; these hepatic improvements were attenuated when Hmgcs2 expression was suppressed. In contrast, female mice derived minimal hepatic benefit from IF, and Hmgcs2 knock‑down exacerbated steatosis, fibrosis, and inflammatory markers. Single‑cell RNA‑seq identified neutrophils and myofibroblasts as cellular targets of hepatocyte‑derived ketone bodies. IF suppressed neutrophil‑driven inflammatory signaling in an Hmgcs2‑dependent manner, and ketone bodies reduced low‑grade inflammation in cultured neutrophil‑like cells. Human liver co‑expression data from GTEx supported a similar ketogenesis‑inflammation‑fibrosis axis.
Clinical interpretation
The data suggest that the anti‑obesity actions of intermittent fasting operate through mechanisms that do not require hepatic ketone production, which may be relevant for designing weight‑loss protocols that are effective in both sexes. By contrast, the liver‑protective effects of IF appear to depend on ketone body signaling, but this dependency is sex‑specific: male mice benefit from ketogenesis‑mediated suppression of neutrophil inflammation and subsequent fibrosis, whereas females do not. If comparable pathways exist in humans, therapeutic strategies that augment hepatic ketogenesis could enhance IF‑induced liver protection in men, but the same approach might be ineffective or even harmful in women.
Limitations and open questions
The study was performed in a single inbred mouse strain, limiting extrapolation to the genetic diversity of human populations. Only short‑term fasting cycles were examined; long‑term outcomes remain unknown. The antisense approach reduced Hmgcs2 globally in the liver but did not assess potential off‑target effects or compensatory metabolic pathways. Human relevance is inferred from transcriptomic co‑expression, not from interventional data. Future work should test whether pharmacologic or dietary induction of hepatic ketogenesis reproduces the male‑specific liver benefits in other animal models and, ultimately, in clinical trials that stratify participants by sex and baseline ketone metabolism.
Source
Source: PMID 42690152.