Male obesity causes adipose mitochondrial dysfunction in F1progeny via a let-7-DICER axis
Date Issued
2024-10-04
Author(s)
Joo Hyun Park
Ali Altıntaş
Natasa Stanic
Kristine Kyle de Leon
Signe Isacson
Panagiotis Kalogeropoulos
Hande Topel Batarlar
Rocio Valdebenito Malmros
Jesper Havelund
Bjørk Ditlev Marcher Larsen
Yen-Ting Chien
Karolina Szczepanowska
Wen-Chi Huang
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 Oest
Romain Barrès
Jan-Wilhelm Kornfeld
Abstract
Abstract We here describe that obesity and weight loss in male mice cause reversible abnormalities in glucose and lipid metabolism, serum metabolomes and lipidomes as well as expression of microRNAs, mRNAs and proteins controlling mitochondrial function in epididymal white adipose tissue. When mating obese male mice with lean females, we observed reductions in expression and translation of genes encoding mitochondrial respiratory components in (F 1 ) offspring that closely resemble those observed in the paternal (F 0 ) generation. When mapping miRNA regulation across somatic organs (i.e., liver, adipose) and sperm and F 0/1 generations, we found that obesity and weight loss reversibly affected miRNA levels, and that let-7 isoforms were induced in obese F 0 and F 1 adipose tissue and sperm of obese F 0 mice, eliciting qualitatively similar responses in two adjacent tissues. Overexpressing let-7 in adipocytes silenced DICER1, a miRNA processing enzyme crucial for adipose adaptation to obesity as evidenced by deficiencies in mitochondrial function following DICER1 loss in primary adipocytes. Also, microinjection of synthetic let-7 mimetics at physiological levels found in obese sperm into zygotes from lean mice elicited glucose intolerance and impediments in adipose mitochondrial gene expression in mice sired from let-7 microinjected zygotes, phenocopying hereditary aspects of paternal obesity. When performing single-cell RNA-Seq of miRNA-injected embryos, let-7 impaired mitochondrial gene expression, suggesting altered oxidative metabolism following zygotic let-7 delivery. When studying miRNA alterations in human semen, lifestyle-induced weight loss downregulated hsa-let-7 , suggesting similar roles for human let-7 in gametic epigenomes and embryogenesis.
Type
other