Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis
Abstract
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 micro-RNA let-7 in sperm reprograms offspring metabolism by modulating mitochondrial function during early development.
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BibTeX
@article{huang2026male,
title = {{Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis}},
author = {Chien Huang and Joo-Hyun Park and Ali Altıntaş and Natasa Stanic and Kristine Kyle de Leon and Signe Isacson and Panagiotis Kalogeropoulos and Hande Topel and Tobias Madsen and Sebastian Zanner and Phillip Mm Ruppert and Rocio Valdebenito and Jesper Havelund and Bjørk Ditlev Marcher Larsen and Yen-Ting Chien and Wen-Chi Huang and Yovita Permata Budi and Yi-Fan Jiang and Andréa Livia Rocha and Niedson Correia Lima-Junior and Karolina Szczepanowska and Jan-Wilm Lackmann and Aleksandra Trifunovic and Eva Kildall Hejbøl and Sönke Detlefsen and Ida Engberg Jepsen and Stefanie Hansborg Kolstrup and Ricardo Laguna-Barraza and Javier Martin-Gonzalez and Konstantin Khodosevich and Nils J Færgeman and Marcelo A Mori and Marc R Friedländer and Anita Öst and Romain Barrès and Jan-Wilhelm Kornfeld},
journal = {Nature Communications},
year = {2026},
month = nov,
doi = {10.1038/s41467-026-69686-5},
url = {https://hal.science/hal-05849825v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis
AU - Chien Huang
AU - Joo-Hyun Park
AU - Ali Altıntaş
AU - Natasa Stanic
AU - Kristine Kyle de Leon
AU - Signe Isacson
AU - Panagiotis Kalogeropoulos
AU - Hande Topel
AU - Tobias Madsen
AU - Sebastian Zanner
AU - Phillip Mm Ruppert
AU - Rocio Valdebenito
AU - Jesper Havelund
AU - Bjørk Ditlev Marcher Larsen
AU - Yen-Ting Chien
AU - Wen-Chi Huang
AU - Yovita Permata Budi
AU - Yi-Fan Jiang
AU - Andréa Livia Rocha
AU - Niedson Correia Lima-Junior
AU - Karolina Szczepanowska
AU - Jan-Wilm Lackmann
AU - Aleksandra Trifunovic
AU - Eva Kildall Hejbøl
AU - Sönke Detlefsen
AU - Ida Engberg Jepsen
AU - Stefanie Hansborg Kolstrup
AU - Ricardo Laguna-Barraza
AU - Javier Martin-Gonzalez
AU - Konstantin Khodosevich
AU - Nils J Færgeman
AU - Marcelo A Mori
AU - Marc R Friedländer
AU - Anita Öst
AU - Romain Barrès
AU - Jan-Wilhelm Kornfeld
PY - 2026
DA - 2026/11/03
JO - Nature Communications
DO - 10.1038/s41467-026-69686-5
UR - https://hal.science/hal-05849825v1
AB - 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 micro-RNA let-7 in sperm reprograms offspring metabolism by modulating mitochondrial function during early development.
SN - 2041-1723
SN - 2041-1723
ER -