Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis
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 let-7d/e as epigenetic mediators induced in obese F<sub>0</sub> sperm and in F<sub>0</sub>/F<sub>1</sub> 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.
Authors
- Eva Kildall Hejbøl (ORCID: https://orcid.org/0000-0002-3462-321X)
- Panagiotis Kalogeropoulos (ORCID: https://orcid.org/0000-0002-6717-5011)
- Romain Barrès (ORCID: https://orcid.org/0000-0002-0158-519X)
- Marc R. Friedländer (ORCID: https://orcid.org/0000-0001-6577-4363)
- Wen-Chi Huang
- Marcelo A. Mori
- A. Trifunovic
- Yi-Fan Jiang (ORCID: https://orcid.org/0000-0002-1692-4385)
- Nataša Stanić
- Sebastian Zanner (ORCID: https://orcid.org/0000-0002-1831-4695)
- Anita Öst (ORCID: https://orcid.org/0000-0003-0547-1904)
- Niedson Correia Lima-Junior
- Yovita Permata Budi (ORCID: https://orcid.org/0000-0002-9901-6752)
- Rocío Valdebenito (ORCID: https://orcid.org/0000-0001-8754-0146)
- Ali Altıntaş (ORCID: https://orcid.org/0000-0002-8932-0160)
- Ida Engberg Jepsen (ORCID: https://orcid.org/0000-0002-4632-4292)
- Konstantin V. Khodosevich (ORCID: https://orcid.org/0000-0001-7232-5558)
- Jesper Foged Havelund (ORCID: https://orcid.org/0000-0002-9797-5431)
- Chien Huang (ORCID: https://orcid.org/0000-0001-8307-3544)
- J. Lackmann
- Stefanie Hansborg Kolstrup
- J. W. Kornfeld
- N. J. Færgeman
- P. M. M. Ruppert
- Yen-Ting Chien
- Tobias Madsen
- Hande Topel
- Andréa Livia Rocha
- Javier Martin-Gonzalez
- Karolina Szczepanowska
- Signe Isacson
- Sönke Detlefsen
- Bjørk Ditlev Marcher Larsen
Institutions
- Linköping University (SE)
- University of Copenhagen (DK)
- Salk Institute for Biological Studies (US)
- National Taiwan University of Science and Technology (TW)
- National Taiwan University (TW)
- University of Southern Denmark (DK)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Novo Nordisk Foundation (DK)
- Odense University Hospital (DK)
- Zealand University Hospital (DK)
- Wenner-Gren Foundations (SE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Zealand University Hospital Køge (DK)
- Institut de Pharmacologie Moléculaire et Cellulaire (FR)
- Polish Academy of Sciences (PL)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-24
- DOI
- https://doi.org/10.1038/s41467-026-69686-5
- Primary Topic
- Sperm and Testicular Function
- Type
- article
- Field-Weighted Citation Impact
- 0.00