MDPAO1 peptide from human milk enhances brown adipose tissue thermogenesis and mitigates obesity

The regulatory effect of breastfeeding on offspring metabolism has garnered significant attention as an effective strategy in combating childhood obesity. However, the underlying mechanism remains largely unknown. Through integrated analysis of multiple human milk peptide databases and functional screening, MDPAO1 (milk-derived peptide associated with obesity 1) was identified as having potential activity in promoting the expression of thermogenic genes. In lactating mice, intervention with MDPAO1 enhanced the thermogenic phenotype of brown adipose tissue (BAT) and overall metabolic activity. Moreover, MDPAO1 intervention led to reduced body weight gain, increased brown fat mass, and improved glucose tolerance and insulin sensitivity in a mouse model of high-fat diet (HFD)-induced obesity. RNA-seq analysis of BAT post-MDPAO1 intervention revealed close association with mitochondrial oxidative respiratory chain and mitophagy. Subsequent in vitro experiments conducted on primary brown adipocytes confirmed that MDPAO1 inhibited mitophagy, increased mitochondrial mass, and elevated levels of mitochondrial respiratory chain complexes. In conclusion, this study underscores the potential of MDPAO1, a peptide enriched in breast milk, in activating the thermogenic phenotype of brown adipose tissue and mitigating obesity, thus offering novel insights into the mechanisms underlying breastfeeding's role in preventing childhood obesity.