A multi-omics census reveals obesity-associated microRNA miR-let-7 as novel instigator of adipose mitochondrial dysfunction and of intergenerational metabolic decline.

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 (F1) offspring that closely resemble those observed in the paternal (F0) generation. When mapping miRNA regulation across somatic organs (i.e., liver, adipose) and sperm and F0/1 generations, we found that obesity and weight loss reversibly affected miRNA levels, and that let-7 isoforms were induced in obese F0 and F1 adipose tissue and sperm of obese F0 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.