父性肥満はlet-7-DICER軸を介してF1マウス子孫のアディポネクチンミトコンドリア機能障害を引き起こす

Male obesity negative affects gametic function and offspring metabolism. We here describe that (F₀) obesity and weight loss in male mice reversibly alter metabolism and impair adipose mitochondrial function. These metabolic aberrations are transmitted to male offsprings (F₁), which display reduced mitochondrial gene expression. Mechanistically, we identify microRNAs let-7d/e as epigenetic mediators induced in obese F₀ sperm and in F₀/F₁ 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.