113-OR: Lipocalin-2, a Mitokine That Mediates White–to–Brown Fat Cross Talk

Introduction & Aim: Metabolic dysfunction, exemplified by obesity, often results from dysregulated crosstalk among metabolically active tissues. Brown adipose tissue (BAT) undergoes whitening during obesity, yet understanding the underlying white adipose tissue (WAT) to BAT crosstalk and the factors driving BAT whitening remains a significant gap.

Methods: Using our reported amyloid precursor protein (APP) overexpression-induced mitochondrial distress model in adipocytes (APP AOE), we identified lipocalin-2 (LCN-2) through in vivo, ex vivo, and in silico screenings as a key mitokine mediating the WAT to BAT crosstalk. To further investigate the role of LCN-2, we utilized recombinant LCN-2 protein treatment in vitro and in vivo and generated the adipocyte-specific deletion of Lcn2 mouse model (Lcn2 AKO).

Results: Mitochondrial distressed adipocytes from APP AOE model induced BAT whitening, and white fat pad transplant studies confirmed that stressed WAT alone induces BAT whitening through a putative crosstalk. LCN-2, identified as a potential mitokine through a comprehensive screening (in vivo, ex vivo, and in silico), downregulates BAT browning markers following an LCN-2 recombinant protein treatment. Lcn2 AKO mice on a high-fat diet maintain similar body weights but exhibit elevated mRNA levels of Ucp1 and Pgc1a in BAT, preserving BAT characteristics.

Conclusion: Our project highlights a novel mechanism for white-to-brown fat crosstalk, whereby WAT under mitochondrial stress secretes a mitokine, LCN-2, which mediates the crosstalk from WAT to BAT, leading to BAT whitening. This study further implies LCN-2 as a promising target for preventing BAT whitening and treating obesity.