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 causes reversible abnormalities in glucose and lipid metabolism, serum metabolomes and reduced expression of genes controlling mitochondrial energy dissipation in white adipose tissue. When mating obese male mice with lean females, we observed concordant reductions in adipose mitochondrial gene expression and translation in offspring (F 1 ) that resemble those observed in the paternal (F 0 ) generation. When mapping miRNA differential expression across somatic organs and the germline (i.e., liver, adipose tissue, sperm) and generations, we found that obesity and weight loss reversible affected miRNA levels, and that miR-let7 isoforms were induced in adipose tissues of obese F 0 and F 1 adipose tissue and sperm of obese F 0 mice. Overexpressing miR-let-7 in adipocytes silenced DICER1, a cellular rheostat required for adipose tissue adaptation in obesity as evidenced by deficiencies in mitochondrial function following DICER1 loss in adipocytes. Delivery of miR-let-7 into lean oocytes elicited glucose intolerance and impediments in adipose mitochondrial gene expression in mice sired from miRNA-injected embryos, thus phenocopying important aspects of obesity heredity. When performing single-cell RNA-Seq of miRNA-injected embryos, miR-let7 impaired mitochondrial gene expression, suggesting altered energy metabolism following alterations in zygotic miRNAs. When studying miRNA alterations in human semen, lifestyle-induced weight loss downregulated MIR-LET-7 in human subjects, suggesting similar roles for human MIR-LET-7 in gametic epigenomes and embryogenesis.