Exclusive Breastfeeding Drives AMPK‐Dependent Thermogenic Memory in BAT and Promotes Long‐Term Metabolic Benefits in Offspring

Abstract Exclusive breastfeeding reduces the risk of childhood obesity, potentially through metabolic programming of adipose tissue during lactation. However, the underlying mechanisms remain unclear. Using a mouse model, it is shown that mixed formula feeding disrupts brown adipose tissue (BAT) morphology, mitochondrial integrity, and thermogenic capacity, resulting in greater fat accumulation and glucose intolerance after weaning under a high‐fat diet. By contrast, BAT from exclusively breastfed mice preserved enhanced thermogenic function for up to 12 weeks after transplantation into recipient mice. Transcriptomic analysis revealed that AMPK activation is sustained in BAT from exclusively breastfed mice but markedly diminished in mixed‐fed counterparts. Pharmacological inhibition of AMPK abolished the long‐term metabolic benefits conferred by exclusive breastfeeding. Mechanistically, breast milk–derived extracellular vesicles enriched in miR‐125a‐5p enhanced AMPK signaling by targeting HIF1AN. AMPK‐induced α‐ketoglutarate (αKG) production proved essential for BAT development and thermogenesis, and αKG supplementation rescued impaired BAT function in mixed‐fed mice. In conclusion, exclusive breastfeeding imprints a thermogenic memory in BAT via the HIF1AN/AMPK/αKG signaling axis, thereby conferring long‐term metabolic protection to offspring.