Sex-Specific Role of Adipose-Derived Lipocalin-2 in Diet-Induced Obesity and Insulin Resistance

Lipocalin-2 (LCN2) is a 25-kDa secretory adipokine that is up regulated in adipose tissues of genetically obese animals and humans. LCN2 was also proposed to regulate insulin resistance (IR) in animal studies. Besides, we have shown adipose Lcn2 expression to be negatively regulated by estradiol using a mouse reference population of over ∼100 strains, the Hybrid Mouse Diversity Panel (HMDP). Recently, LCN2 has also been implicated in recruiting neutrophils to the liver in both alcoholic and nonalcoholic steatohepatitis. To further explore the causal role of LCN2 in diet-induced obesity and its metabolic complications, we carried out systems genetics analyses on multi-omics data collected from both males and females of HMDP fed a high fat/high sucrose (HF/HS) diet: Genotypes, 200,000 high-resolution SNPs; Phenotypes, obesity (fat mass, and weight of three visceral adipose depots), IR (fasting levels of glucose, insulin and HOMA-IR) and steatosis (liver triglyceride levels); and Transcriptomics, mRNA microarrays of adipose and liver tissues. Our analyses revealed female, but not male, adipose-derived LCN2 is mechanistically linked to deregulated adiposity and enhanced insulin resistance. To functionally validate the causal role of female adipose LCN2, we conditionally overexpressed either LCN2 or GFP in adipose tissues of mice of both sexes by adeno-associated viral vectors and subjected them to HF/HS diet. We demonstrated deregulated metabolic homeostasis: increased adiposity (fat mass), glucose intolerance (GTT) and insulin resistance (ITT and HOMA-IR) only in females. Follow-up ex vivo bioenergetics studies in both adipose and liver tissues demonstrated deregulated mitochondrial respiration (lowered in adipose; enhanced in liver) mediated by LCN2 overexpression only in females, thereby revealing mitochondrial dysfunction as one of the key mechanism(s) mediated by LCN2 in diet-induced obesity and its complications.