miR-1a-3p impairs β-cell function in male offspring via disrupted NBR1-dependent mitochondrial function but not apoptosis after maternal high-saturated-fat diet in mice.

Early-life maternal high-saturated fat (HSF) exposure increases offspring susceptibility to type 2 diabetes, but mechanisms linking it to β-cell dysfunction remain poorly defined. This study aimed to identify key miRNAs mediating this programming and evaluate their therapeutic potential. Female mice were fed control, high-lard, or high-palm oil diets during gestation and lactation. Islets from adult male offspring were isolated for miRNA sequencing to identify candidates. β-cell-specific overexpression of miR-1a-3p was achieved via AAV8-Ins1 vector. Proteomics analysis was performed to screen its downstream targets. miR-1a-3p was the only miRNA showing interactive effects between maternal and offspring diets. It was upregulated in male offspring islets, further exacerbated by late-adulthood HFD re-exposure. Functionally, miR-1a-3p overexpression increased fasting glucose, impaired glucose and insulin tolerance, reduced ATP production and mitochondrial membrane potential, without affecting apoptosis. NBR1 was confirmed as a direct target of miR-1a-3p. NBR1 silencing mimicked miR-1a-3p's detrimental effects on β-cell mitochondria and function. Inhibition of miR-1a-3p alleviated HFD-induced β-cell dysfunction. miR-1a-3p mediates β-cell dysfunction programmed by early-life maternal HSF exposure through targeting NBR1 and disrupting mitochondrial function, representing a potential therapeutic strategy for preventing type 2 diabetes transmission.