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<p>Male obesity negative affects gametic function and offspring metabolism. We here describe that (F<sub>0</sub>) obesity and weight loss in male mice reversibly alter metabolism and impair adipose mitochondrial function. These metabolic aberrations are transmitted to male offsprings (F<sub>1</sub>), which display reduced mitochondrial gene expression. Mechanistically, we identify microRNAs <i>let-7d/e</i> as epigenetic mediators induced in obese F<sub>0</sub> sperm and in&#xa0;F<sub>0</sub>/F<sub>1</sub> adipose tissue, where they silence the miRNA processor DICER1 and impair mitochondrial activity. Microinjecting <i>let-7d/e</i> into lean zygotes phenocopies the paternal obesity phenotype, inducing glucose intolerance and mitochondrial gene suppression in sired offspring. Single-cell RNA sequencing of blastomeres reveals that <i>let-7d/e</i> impair oxidative metabolism in early embryos. Furthermore, lifestyle-induced weight loss in males with obesity downregulates human <i>HSA-LET-7D/E</i> in semen, indicating a conserved role for <i>let-7</i> in transmission of metabolic health. These findings demonstrate that microRNA <i>let-7</i> in sperm reprograms offspring metabolism by modulating mitochondrial function during early development.</p>

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Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月24日

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  • Chien Huang,
  • Joo-Hyun Park,
  • Ali Altıntaş,
  • Natasa Stanic,
  • Kristine Kyle de Leon,
  • Signe Isacson,
  • Panagiotis Kalogeropoulos,
  • Hande Topel,
  • Tobias Madsen,
  • Sebastian Zanner,
  • Phillip MM Ruppert,
  • Rocio Valdebenito,
  • Jesper Havelund,
  • Bjørk Ditlev Marcher Larsen,
  • Yen-Ting Chien,
  • Wen-Chi Huang,
  • Yovita Permata Budi,
  • Yi-Fan Jiang,
  • Andréa Livia Rocha,
  • Niedson Correia Lima-Junior,
  • Karolina Szczepanowska,
  • Jan-Wilm Lackmann,
  • Aleksandra Trifunovic,
  • Eva Kildall Hejbøl,
  • Sönke Detlefsen,
  • Ida Engberg Jepsen,
  • Stefanie Hansborg Kolstrup,
  • Ricardo Laguna-Barraza,
  • Javier Martin-Gonzalez,
  • Konstantin Khodosevich,
  • Nils J. Færgeman,
  • Marcelo A. Mori,
  • Marc R. Friedländer,
  • Anita Öst,
  • Romain Barrès,
  • Jan-Wilhelm Kornfeld

摘要

Male obesity negative affects gametic function and offspring metabolism. We here describe that (F0) obesity and weight loss in male mice reversibly alter metabolism and impair adipose mitochondrial function. These metabolic aberrations are transmitted to male offsprings (F1), which display reduced mitochondrial gene expression. Mechanistically, we identify microRNAs let-7d/e as epigenetic mediators induced in obese F0 sperm and in F0/F1 adipose tissue, where they silence the miRNA processor DICER1 and impair mitochondrial activity. Microinjecting let-7d/e into lean zygotes phenocopies the paternal obesity phenotype, inducing glucose intolerance and mitochondrial gene suppression in sired offspring. Single-cell RNA sequencing of blastomeres reveals that let-7d/e impair oxidative metabolism in early embryos. Furthermore, lifestyle-induced weight loss in males with obesity downregulates human HSA-LET-7D/E in semen, indicating a conserved role for let-7 in transmission of metabolic health. These findings demonstrate that microRNA let-7 in sperm reprograms offspring metabolism by modulating mitochondrial function during early development.