Sexual dimorphism shapes renal metabolic adaptation to a ketogenic diet

While kidneys are essential for maintaining systemic metabolic homeostasis and exhibit sexual dimorphism, the effects of sex and environmental factors, such as diet, on renal metabolism remain unclear. Using kidney-specific arteriovenous (AV) metabolomics, in vivo isotope tracing, and transcriptomics, we discover profound sex differences in kidney metabolic reprogramming under ketogenic diet (KD) in C57BL/6J mice. Tissue metabolomics shows the accumulation of aldosterone and acylcarnitines exclusively in female kidneys under a normal chow (NC) diet, suggesting basal sex differences in sodium and fatty acid metabolism. Under KD, AV metabolomics reveals that only female kidneys activate ketogenesis and gluconeogenesis, supported by transcriptional sex differences in related rate-limiting enzymes and transporters. Given the widespread public and clinical interest in KD for treating epilepsy, metabolic disorders, and cancers, our findings underscore the importance of considering sex differences in kidney metabolism as a fundamental variable when interpreting KD's diverse effects on pathophysiology and therapeutics.