Scholarlink

<p>The escalating global burden of obesity and diabetes underscores the need to elucidate generational effects of parental metabolic health. This study investigates the generational inheritance of paternal obesity and glucose dysregulation in offspring, along with its underlying epigenetic mechanisms. Four-week-old male C57BL/6 J mice were randomly assigned to either a control diet (CON) or high-glucose/high-fat (HGF) group. After 4&#xa0;weeks, these males were mated with healthy females to produce F1 male offspring, with the same breeding strategy applied to generate F2 males. Metabolic phenotyping revealed impaired glucose tolerance and insulin sensitivity in HGF-fed F0 males and F1/F2 male offspring, demonstrating intergenerational transmission of paternal HGF-induced metabolic dysfunction. Liver transcriptomic profiling identified elevated expression of the gluconeogenic enzyme glucose-6-phosphatase 1 (G6pc1) and reduced levels of miR-29a/c-3p in HGF males across three generations. Luciferase assay and molecular studies confirmed that G6pc1 is a direct target of miR-29a/c-3p, and miR-29a/c-3p negatively regulates G6pc1 expression. Functional analyses showed that hepatic miR-29a-3p knockdown in wild-type mice increased G6pc1 expression, inducing glucose intolerance and insulin resistance. Conversely, miR-29a-3p overexpression in HGF offspring suppressed G6pc1 and restored glucose homeostasis. Notably, sperm miR-29a/c-3p levels were consistently reduced in HGF-fed males, suggesting its role as an epigenetic carrier mediating intergenerational metabolic dysregulation. This study uncovers a paternal intergenerational inheritance mechanism whereby HGF-induced glucose dysregulation propagates intergenerationally through the miR-29a/c-3p-G6pc1 axis. These findings advance our understanding of the origins of metabolic disorders and highlight potential miRNA-targeted strategies for mitigating intergenerational metabolic risks.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Intergenerational inheritance of paternal metabolic disorder: miR-29a/c-3p/glucose-6-phosphatase 1 axis in glucose intolerance propagation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月24日

查看全文
  • Chenxuan Zhao,
  • Muxue Lu,
  • Ting Xu,
  • Lei He,
  • Fengying Deng,
  • Meihua Zhang,
  • Qinqin Gao

摘要

The escalating global burden of obesity and diabetes underscores the need to elucidate generational effects of parental metabolic health. This study investigates the generational inheritance of paternal obesity and glucose dysregulation in offspring, along with its underlying epigenetic mechanisms. Four-week-old male C57BL/6 J mice were randomly assigned to either a control diet (CON) or high-glucose/high-fat (HGF) group. After 4 weeks, these males were mated with healthy females to produce F1 male offspring, with the same breeding strategy applied to generate F2 males. Metabolic phenotyping revealed impaired glucose tolerance and insulin sensitivity in HGF-fed F0 males and F1/F2 male offspring, demonstrating intergenerational transmission of paternal HGF-induced metabolic dysfunction. Liver transcriptomic profiling identified elevated expression of the gluconeogenic enzyme glucose-6-phosphatase 1 (G6pc1) and reduced levels of miR-29a/c-3p in HGF males across three generations. Luciferase assay and molecular studies confirmed that G6pc1 is a direct target of miR-29a/c-3p, and miR-29a/c-3p negatively regulates G6pc1 expression. Functional analyses showed that hepatic miR-29a-3p knockdown in wild-type mice increased G6pc1 expression, inducing glucose intolerance and insulin resistance. Conversely, miR-29a-3p overexpression in HGF offspring suppressed G6pc1 and restored glucose homeostasis. Notably, sperm miR-29a/c-3p levels were consistently reduced in HGF-fed males, suggesting its role as an epigenetic carrier mediating intergenerational metabolic dysregulation. This study uncovers a paternal intergenerational inheritance mechanism whereby HGF-induced glucose dysregulation propagates intergenerationally through the miR-29a/c-3p-G6pc1 axis. These findings advance our understanding of the origins of metabolic disorders and highlight potential miRNA-targeted strategies for mitigating intergenerational metabolic risks.