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Posted On: 03/08/2025 11:19:51 PM
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New MANF research in diabetes and metabolic dysfunction:
Paternal Obesity-Induced H3K27me3 Elevation Leads to MANF-Mediated Transgenerational Metabolic Dysfunction in Female Offspring
Yajun Shi et al. Adv Sci (Weinh). 2025.
Abstract
Paternal lifestyle and environmental exposures can alter epigenetic changes in sperm and play a critical role in the offspring's future health, yet the underlying mechanisms remain elusive. The present study established a model of paternal obesity and found that the increased levels of H3K27me3 in sperm persist into the 8-cell embryo stage, resulting in a transgenerational decrease of Manf, which causes endoplasmic reticulum stress and activates the GRP78-PERK-EIF2α-ATF4-CHOP axis. This consequently leads to impaired glucose metabolism and apoptosis in the liver of female offspring. Based on these findings, the F0 mice are treated with 3-deazaneplanocin A, an EZH2 inhibitor, which successfully prevented metabolic dysfunction in F0 mice of the high-fat diet (HFD) group. Meanwhile, intravenous injection of recombinant human MANF in F1 female offspring can successfully rescue the metabolic dysfunction in the HFD-F1 group. These results demonstrate that paternal obesity triggers transgenerational metabolic dysfunction through sperm H3K27me3-dependent epigenetic regulation. The present study also identifies the H3K27me3-MANF pathway as a potentially preventive and therapeutic strategy for diabetes, although further studies are needed to validate its clinical applicability.
https://pubmed.ncbi.nlm.nih.gov/40041941/
Paternal Obesity-Induced H3K27me3 Elevation Leads to MANF-Mediated Transgenerational Metabolic Dysfunction in Female Offspring
Yajun Shi et al. Adv Sci (Weinh). 2025.
Abstract
Paternal lifestyle and environmental exposures can alter epigenetic changes in sperm and play a critical role in the offspring's future health, yet the underlying mechanisms remain elusive. The present study established a model of paternal obesity and found that the increased levels of H3K27me3 in sperm persist into the 8-cell embryo stage, resulting in a transgenerational decrease of Manf, which causes endoplasmic reticulum stress and activates the GRP78-PERK-EIF2α-ATF4-CHOP axis. This consequently leads to impaired glucose metabolism and apoptosis in the liver of female offspring. Based on these findings, the F0 mice are treated with 3-deazaneplanocin A, an EZH2 inhibitor, which successfully prevented metabolic dysfunction in F0 mice of the high-fat diet (HFD) group. Meanwhile, intravenous injection of recombinant human MANF in F1 female offspring can successfully rescue the metabolic dysfunction in the HFD-F1 group. These results demonstrate that paternal obesity triggers transgenerational metabolic dysfunction through sperm H3K27me3-dependent epigenetic regulation. The present study also identifies the H3K27me3-MANF pathway as a potentially preventive and therapeutic strategy for diabetes, although further studies are needed to validate its clinical applicability.
https://pubmed.ncbi.nlm.nih.gov/40041941/
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