TY - JOUR
T1 - Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis
AU - Huang, Chien
AU - Park, Joo-Hyun
AU - Altıntaş, Ali
AU - Stanic, Natasa
AU - Kyle de Leon, Kristine
AU - Isacson, Signe
AU - Kalogeropoulos, Panagiotis
AU - Topel, Hande
AU - Madsen, Tobias
AU - Zanner, Sebastian
AU - Ruppert, Phillip Mm
AU - Valdebenito, Rocio
AU - Havelund, Jesper
AU - Larsen, Bjørk Ditlev Marcher
AU - Chien, Yen-Ting
AU - Huang, Wen-Chi
AU - Budi, Yovita Permata
AU - Jiang, Yi-Fan
AU - Rocha, Andréa Livia
AU - Lima-Junior, Niedson Correia
AU - Szczepanowska, Karolina
AU - Lackmann, Jan-Wilm
AU - Trifunovic, Aleksandra
AU - Hejbøl, Eva Kildall
AU - Detlefsen, Sönke
AU - Jepsen, Ida Engberg
AU - Kolstrup, Stefanie Hansborg
AU - Laguna-Barraza, Ricardo
AU - Martin-Gonzalez, Javier
AU - Khodosevich, Konstantin
AU - Færgeman, Nils J
AU - Mori, Marcelo A
AU - Friedländer, Marc R
AU - Öst, Anita
AU - Barrès, Romain
AU - Kornfeld, Jan-Wilhelm
N1 - © 2026. The Author(s).
PY - 2026/2/24
Y1 - 2026/2/24
N2 - 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.
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 microRNA let-7 in sperm reprograms offspring metabolism by modulating mitochondrial function during early development.
KW - Adipose Tissue/metabolism
KW - Animals
KW - DEAD-box RNA Helicases/metabolism
KW - Epigenesis, Genetic
KW - Female
KW - Humans
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - MicroRNAs/metabolism
KW - Mitochondria/metabolism
KW - Obesity/genetics
KW - Ribonuclease III/metabolism
KW - Spermatozoa/metabolism
U2 - 10.1038/s41467-026-69686-5
DO - 10.1038/s41467-026-69686-5
M3 - Article
C2 - 41735303
SN - 2041-1723
VL - 17
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3125
ER -