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

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

doi:10.1038/s41467-026-69686-5

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

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^*

^*Corresponding author for this work

Gynaecology and Obstetrics

Research output: Contribution to journal › Article › Research › peer-review

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 microRNA let-7 in sperm reprograms offspring metabolism by modulating mitochondrial function during early development.

Original language	English
Article number	3125
Number of pages	19
Journal	Nature communications
Volume	17
Issue number	1
Early online date	24 Feb 2026
DOIs	https://doi.org/10.1038/s41467-026-69686-5
Publication status	Published - 24 Feb 2026

Keywords

Adipose Tissue/metabolism
Animals
DEAD-box RNA Helicases/metabolism
Epigenesis, Genetic
Female
Humans
Male
Mice
Mice, Inbred C57BL
MicroRNAs/metabolism
Mitochondria/metabolism
Obesity/genetics
Ribonuclease III/metabolism
Spermatozoa/metabolism

Access to Document

10.1038/s41467-026-69686-5Licence: CC BY-NC-ND

Cite this

Huang, C., Park, J.-H., Altıntaş, A., Stanic, N., Kyle de Leon, K., Isacson, S., Kalogeropoulos, P., Topel, H., Madsen, T., Zanner, S., Ruppert, P. M., Valdebenito, R., Havelund, J., Larsen, B. D. M., Chien, Y.-T., Huang, W.-C., Budi, Y. P., Jiang, Y.-F., Rocha, A. L., ... Kornfeld, J.-W. (2026). Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis. Nature communications, 17(1), Article 3125. https://doi.org/10.1038/s41467-026-69686-5

@article{4784218a31af40c8b77471e70ff9b840,

title = "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 microRNA let-7 in sperm reprograms offspring metabolism by modulating mitochondrial function during early development.",

keywords = "Adipose Tissue/metabolism, Animals, DEAD-box RNA Helicases/metabolism, Epigenesis, Genetic, Female, Humans, Male, Mice, Mice, Inbred C57BL, MicroRNAs/metabolism, Mitochondria/metabolism, Obesity/genetics, Ribonuclease III/metabolism, Spermatozoa/metabolism",

author = "Chien Huang and Joo-Hyun Park and Ali Altınta{\c s} and Natasa Stanic and \{Kyle de Leon\}, Kristine and Signe Isacson and Panagiotis Kalogeropoulos and Hande Topel and Tobias Madsen and Sebastian Zanner and Ruppert, \{Phillip Mm\} and Rocio Valdebenito and Jesper Havelund and Larsen, \{Bj{\o}rk Ditlev Marcher\} and Yen-Ting Chien and Wen-Chi Huang and Budi, \{Yovita Permata\} and Yi-Fan Jiang and Rocha, \{Andr{\'e}a Livia\} and Lima-Junior, \{Niedson Correia\} and Karolina Szczepanowska and Jan-Wilm Lackmann and Aleksandra Trifunovic and Hejb{\o}l, \{Eva Kildall\} and S{\"o}nke Detlefsen and Jepsen, \{Ida Engberg\} and Kolstrup, \{Stefanie Hansborg\} and Ricardo Laguna-Barraza and Javier Martin-Gonzalez and Konstantin Khodosevich and F{\ae}rgeman, \{Nils J\} and Mori, \{Marcelo A\} and Friedl{\"a}nder, \{Marc R\} and Anita {\"O}st and Romain Barr{\`e}s and Jan-Wilhelm Kornfeld",

note = "{\textcopyright} 2026. The Author(s).",

year = "2026",

month = feb,

day = "24",

doi = "10.1038/s41467-026-69686-5",

language = "English",

volume = "17",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Huang, C, Park, J-H, Altıntaş, A, Stanic, N, Kyle de Leon, K, Isacson, S, Kalogeropoulos, P, Topel, H, Madsen, T, Zanner, S, Ruppert, PM, Valdebenito, R, Havelund, J, Larsen, BDM, Chien, Y-T, Huang, W-C, Budi, YP, Jiang, Y-F, Rocha, AL, Lima-Junior, NC, Szczepanowska, K, Lackmann, J-W, Trifunovic, A, Hejbøl, EK, Detlefsen, S, Jepsen, IE, Kolstrup, SH, Laguna-Barraza, R, Martin-Gonzalez, J, Khodosevich, K, Færgeman, NJ, Mori, MA, Friedländer, MR, Öst, A, Barrès, R & Kornfeld, J-W 2026, 'Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis', Nature communications, vol. 17, no. 1, 3125. https://doi.org/10.1038/s41467-026-69686-5

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

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 -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this