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Life sciences · Journal article
Diabetes · September 3, 2026
Raises a question worth testing. It does not answer one.
This preclinical study in male and female mice demonstrates that intermittent fasting reduces body weight and adiposity independently of hepatic ketogenesis in both sexes, but its antisteatotic and antifibrotic effects on the liver are ketogenesis-dependent in males and largely absent in females. The work identifies a sex-dependent ketogenesis-inflammation-fibrosis axis via single-cell and human genomic analysis, but remains mechanistic and does not establish clinical efficacy or human relevance.
Preclinical mechanistic study in male and female mice. Male and female mice; in vitro cultured neutrophil-like cells; human liver tissue from GTEx database. Intervention: Intermittent fasting; Hmgcs2 expression knockdown using antisense oligonucleotide. Compared with: Control mice without IF and/or without Hmgcs2 knockdown.
Fasting increased circulating ketone bodies in both sexes, with females showing greater increase IF reduced body weight gain and adiposity in both sexes independently of Hmgcs2 knockdown IF markedly reduced steatosis and fibrosis in male mice; benefits attenuated upon Hmgcs2 suppression
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These findings are preclinical and do not directly inform clinical practice. They suggest that sex and ketone metabolism may need to be considered in designing dietary or therapeutic interventions for metabolic disease, but human evidence is required before translation.
Mechanistic animal study identifying sex-dependent pathways in intermittent fasting; raises questions about human applicability and sex-specific therapeutic design rather than establishing clinical evidence.
As stated by the source record.
These findings are preclinical and do not directly inform clinical practice. They suggest that sex and ketone metabolism may need to be considered in designing dietary or therapeutic interventions for metabolic disease, but human evidence is required before translation.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
What is missing. This record has no reported figures. That is a gap in the analysis, not a judgement about the study.
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. ARTICLE HIGHLIGHTS 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.
Taken from the source record, never inferred. Follow any of these and new work involving them reaches your briefing.