Sex-dependent effects of a gestational ketogenic diet on offspring birth and lifespan

Low-carbohydrate, high-fat ketogenic diets (KDs) are used to treat drug-resistant epilepsy, and other potential benefits for treating neurological disorders, metabolic syndrome, and cancer are being explored. In addition to these and other medical applications, KDs have also become popular for rapid weight-loss and enhancing athletic performance. However, the effects of exposing developing offspring to KDs during pregnancy (gestational KD) are poorly understood, and especially their long-term health consequences. In this study, we investigated the effects of a partial gestational KD during the second half of pregnancy in mice and assessed the consequences on the offspring over their entire lifespan compared to offspring exposed to a control diet. We found that a gestational KD significantly reduced dams’ litter size and litter mass and altered the sex ratio at birth, reducing the proportion of female offspring, which also had lower body mass early in their life. In contrast, male offspring exposed to a gestational KD suffered a significantly reduced lifespan and a late-onset increase in body mass. We found no evidence that our KD diet influenced adult offspring behavior (locomotion, anxiety, depression, circadian rhythms, food and water consumption) or reproduction. These findings highlight the potential of even a partial maternal exposure to a KD to have surprisingly detrimental effects on offspring health and longevity, and thus raising concerns about its use during pregnancy.