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

ABSTRACT: 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 key 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

ORGANISM(S): Mus musculus

PROVIDER: GSE313674 | GEO | 2026/03/18

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE313674_DESeq2_normcounts_fem_fat.txt.gz	Txt
	GSE313674_DESeq2_normcounts_fem_liver.txt.gz	Txt
	GSE313674_DESeq2_normcounts_male_fat.txt.gz	Txt
	GSE313674_DESeq2_normcounts_male_liver.txt.gz	Txt

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Project description:The global prevalence of type 2 diabetes (T2D) is increasing, and it is contributing to the susceptibility to diabetes and its related epidemic in offspring. Although the impacts of paternal T2D on metabolism of offspring have been well established, the exact molecular and mechanistic basis that mediates these impacts remains largely unclear. Here we show that paternal T2D increases the susceptibility to diabetes in offspring through the gametic epigenetic alterations. Paternal T2D led to glucose intolerance and insulin resistance in offspring. Relative to controls, offspring of T2D fathers exhibited altered gene expression patterns in the pancreatic islets, with downregulation of several genes involved in glucose metabolism and insulin signaling pathway. Epigenomic profiling of offspring pancreatic islets revealed numerous changes in cytosine methylation depending on paternal T2D, including reproducible changes in methylation over several insulin signaling genes. Paternal T2D altered overall methylome patterns in sperm, with a large portion of differentially methylated genes overlapped with that of pancreatic islets in offspring. Our study revealed, for the first time, that T2D can be inherited transgenerationally through the mammalian germline by an epigenetic manner. For all comparisons shown, male F0 founders were weaned from mothers at 3 weeks of age, and sibling males were put into cages with high-fat diet (33% energy as fat) or control diet until 12 weeks of age, at which point mice fed with HFD were injected intraperitoneally with a low dose of STZ and kept on the same diet for 4 weeks. Fasting blood glucose was examined each week post-STZ for 4 weeks, and only glucose level at 7~11 mM was considered as type 2 diabetes. Females were always raised on standard diet. At 16 weeks, male F0 founders were mated with females. After 1 or 2 days, males were removed, and pregnant females were left alone until their litters were 3 weeks of age. Note that we always used virgin females to avoid confounding effects brought about by the females. At 3 weeks of age a portion of the offspring were sacrificed and islets were generated, each from an independent father.Samples from six control and six paternal type 2 diabetes offspring were chosen for microarray analysis.

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

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