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

Abstract

We here describe that obesity and weight loss in male mice causes reversible abnormalities in glucose and lipid metabolism, serum metabolomes and white adipose tissue alongside reversible reductions in expression of genes controlling mitochondrial energy dissipation. When mating obese male mice with lean females, we observed concordant reductions in mitochondrial gene expression and translation in offspring (F1) that resemble those observed in the paternal (F0) generation. When mapping miRNA differential expression across somatic organs and the germline (liver, adiposem, 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 F0 and F1 adipose tissue and in sperm of obese F0 mice. When overexpressing miR-let-7 in adipocytes, we found it to silence DICER1, a cellular rheostat required for adipose tissue adaptation in obesity as evidenced by functional deficiency in mitochondrial function following DICER1 loss in adipocytes. Delivery of miR-let-7 into 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 was found to impair 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-7D/E in human subjects, suggesting similar roles for human MIR-LET-7D/E in gametic epigenomes and embryogenesis.