Lactoferrin Deficiency During Lactation Causes Adult Obesity‐Related Metabolic Disease Through Persistent Adipose Dysfunction Driven by Impaired Adipocyte Development

ABSTRACT Obesity is associated with metabolic disorders due to unhealthy white adipose tissue (WAT) failing to sustain energy homeostasis, highlighting the importance of adipose development. The lactation period is critical for epididymal WAT (eWAT) development and metabolic programming. However, the role of lactoferrin (LF) in the early development of adipose remains unclear. Using a mouse model of lactational LF deficiency and single‐nucleus RNA sequencing, we assessed the long‐term impact of LF deficiency on eWAT plasticity and metabolic homeostasis at weaning, adulthood, and under a high‐fat diet (HFD). LF deficiency persistently impaired eWAT development, causing restricted adipocyte hyperplasia, exacerbated hypertrophy, diminished lipid uptake, and sustained adiponectin decline with resistin elevation. These defects led to long‐term metabolic disorders, worsening HFD‐induced eWAT remodeling, glucose intolerance, dyslipidemia, and chronic inflammation. Mechanistically, LF could bind CSK and PRMT5. LF promoted CSK degradation, activating SRC to drive preadipocyte proliferation. Additionally, LF stabilized PRMT5 to enhance PPARg‐mediated differentiation and lipid uptake. Rescue experiments confirmed that CSK overexpression reversed LF‐induced proliferation, while PRMT5 knockdown blocked LF‐enhanced differentiation. This study reveals lactational LF as a key nutritional signal that programs adipose development and long‐term metabolic health via CSK‐SRC and PRMT5‐PPARg pathways, offering an early‐life intervention strategy against obesity‐related metabolic diseases.