Adipose-Derived Lipocalin-2 Causes Metabolic Dysfunction Only in Female Mice

Lipocalin-2 (LCN2) is a secreted protein involved in innate immunity and also has been associated with several cardiometabolic traits. We examined LCN2 expression in a panel of diverse inbred mouse strains and observed a striking sex difference. Adipose LCN2 was associated with obesity, insulin resistance, dyslipidemia, and hepatic steatosis in females but not males. We expressed LCN2 either in adipose or liver in a tissue specific manner on the background of a whole-body knockout mouse. Adipose LCN2 expression, acting in an autocrine/paracrine manner, promoted metabolic disturbances in females but not males, whereas liver LCN2 expression had no impact on the traits examined. The adipose expression was accompanied by adipose inflammation, fibrosis, and mitochondrial dysfunction, contributing in part to the metabolic disorders. We also show that LCN2 inversely regulates its receptor, LRP2 (or megalin), in a sex-specific manner. Our results demonstrate striking sex- and tissue- specific functions of LCN2. Eight-weeks old female Lcn2-null mice (B6.129P2- Lcn2tm1Aade/AkiJ) on C57BL/6J background were randomly injected intravenously with adeno-associated viral 8 (AAV8) vectors containing either lipocalin-2 (LCN2) or green fluorescent protein (GFP) constructs under an adiponectin promoter (10^12 titer). To increase the adipose tissue specificity of expression, this construct contains a microRNA122 target sequence at the 3’ resulting in selective degradation if expressed in the liver. The animals were then maintained on a HF/HS diet (Research Diets D12266B) until 16 weeks of age. Gonadal and subcutaneous fat samples (n = 4 per group) were taken for RNASeq expression profiling.