Exposure of male mice to nicotine leads to metabolic dysfunction in their male and female offspring.

Paternal exposure to nicotine has been linked to altered metabolic phenotypes in offspring, yet the underlying mechanisms and sex-specific outcomes remain elusive. In this study, we investigated the effects of paternal nicotine exposure on glucose metabolism, and adipose tissue, and liver transcriptomic profiles in male and female offspring. Despite no differences in body weight during early postnatal life, female offspring displayed lower fasting glucose and reduced glucose levels during glucose tolerance tests, without alterations in insulin sensitivity. These effects were accompanied by decreased circulating insulin and upregulation of genes involved in the insulin signaling pathway in gonadal white adipose tissue (gWAT), consistent with enhanced glucose uptake capacity. In contrast, male offspring showed no overt changes in glucose tolerance or insulin sensitivity, despite reduced plasma insulin and glucagon levels. In male offspring, liver transcriptomic analyses revealed downregulation of glucagon signaling, insulin resistance, and PPARα pathways, suggesting impaired fasting adaptation and reduced hepatic catabolic capacity. Collectively, these findings demonstrate that paternal nicotine exposure induces sex-dependent metabolic reprogramming, with pronounced effects on glucose homeostasis in females and transcriptional signatures of reduced fasting resilience in males. These results identify the liver and adipose tissue as targets of paternal nicotine exposure in the offspring and underscore the need for longitudinal studies to determine whether these alterations predispose offspring to metabolic disease across the lifespan.