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The let-7 family of miRNA mediates paternal intergenerational inheritance of metabolic disorders via post-transcriptional regulation of mitochondrial dynamics.

ABSTRACT: This study aims to investigate the molecular mechanisms and nature of impaired soma-germline crosstalk in IEI by focusing on the miRNA regulations in soma and sperm of obese male mice. We found that F0 HFD deteriorated glucose metabolism in F0 and F1, whereas F0 weight loss largely corrected glucose metabolism in both generations. F0 and F1 mice from HFD and REV group exhibited eWAT hypertrophy, and increased Leptin and insulin levels. Transcriptomics and proteomics revealed metabolic dysfunction in F0 and F1 eWAT which correlated with dysregulation of mitochondrial genes. Notably, miRNA Let-7 was obesity-induced in eWAT and sperm, and mice sired from Let-7d/e-microinjected embryos showed impaired glucose metabolism, suggesting Let-7 participated in IEI of metabolic disorders. Our data demonstrated that paternal obesity-induced pre-diabetes and mitochondrial dysfunction in eWAT correlated with similar observations in offspring and the phenomena could be partially precluded by paternal weight-loss before conception.

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ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Epididymal White Adipose Tissue

SUBMITTER: Proteomics Facility

LAB HEAD: Aleksandra Trifunovic

PROVIDER: PXD042800 | Pride | 2026-01-06

REPOSITORIES: Pride

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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.

			Action	DRS
	PRIDE__2437.zip	Other
	Q1_2437_01.raw	Raw
	Q1_2437_02.raw	Raw
	Q1_2437_03.raw	Raw
	Q1_2437_04.raw	Raw

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The let-7 family of miRNA mediates paternal intergenerational inheritance of metabolic disorders via post-transcriptional regulation of mitochondrial dynamics.

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