Lactoferrin Deficiency During Lactation Causes Adult Obesity-Related Metabolic Disease Through Persistent Adipose...

Area of Science:

• Adipose tissue biology
• Metabolic disorders
• Nutritional signaling

Background:

• Obesity is linked to metabolic dysfunction driven by unhealthy white adipose tissue (WAT).
• Lactation is crucial for epididymal WAT (eWAT) development and metabolic programming.
• The role of lactoferrin (LF) in early adipose development is not well understood.

Purpose of the Study:

• To investigate the long-term effects of lactational LF deficiency on eWAT development and metabolic homeostasis.
• To elucidate the molecular mechanisms by which LF influences adipose tissue plasticity.
• To assess the potential of early-life LF intervention for preventing metabolic diseases.

Main Methods:

• Mouse model of lactational LF deficiency.
• Single-nucleus RNA sequencing (snRNA-seq) of eWAT.
• Assessment of eWAT morphology, lipid metabolism, and inflammatory markers.
• High-fat diet (HFD) challenge to evaluate metabolic outcomes.
• Rescue experiments involving CSK and PRMT5 manipulation.

Main Results:

• LF deficiency resulted in impaired eWAT development, characterized by reduced adipocyte hyperplasia and increased hypertrophy.
• Metabolic consequences included diminished lipid uptake, decreased adiponectin, elevated resistin, glucose intolerance, dyslipidemia, and chronic inflammation.
• LF deficiency exacerbated HFD-induced eWAT remodeling and metabolic dysfunction.
• Mechanistically, LF promotes preadipocyte proliferation via CSK degradation and SRC activation, and enhances differentiation and lipid uptake by stabilizing PRMT5, which activates PPARg.

Conclusions:

• Lactational LF is a critical nutritional signal programming adipose development and long-term metabolic health.
• LF regulates eWAT plasticity through the CSK-SRC and PRMT5-PPARg pathways.
• Early-life intervention with LF may offer a strategy to combat obesity and associated metabolic diseases.