Regulation of Lipocalin 2 by Estrogen in Human Adipose Tissue—A Link between Erß Pathway and Insulin Resistance

Abstract

We recently showed that the adipokine lipocalin 2 (LCN2) causes insulin resistance in human adipose tissue (AT). Its expression is induced by dexamethasone (Dex) in AT from pre-menopausal women, but not from post-menopausal women or men. We also found that males had higher levels of LCN2 mRNA than females. Together, this proposes a regulation of LCN2 by glucocorticoids and sex steroids. Subcutaneous (SC) AT from post-menopausal women (n=29, 67±7 Y, BMI 28±5 kg/m2) was incubated ± 17 β-hydroxy estradiol (E2, 0.01-100 nM) and ± Dex (0.3 µM) for 24 h and LCN2 mRNA levels were measured. AT was co-treated with E2 (1 nM) and 100 nM and either estrogen receptor (ER) α or β antagonist, MPP or PHTPP, respectively, or with an ERβ agonist (DPN, 100 nM) for 24 h. E2 (1nM) increased LCN2 mRNA (p<0.01) and protein (p<0.05) levels by∼3 fold in AT, which was reversed by ERβ antagonist. Notably, E2 in presence of MPP induced LCN2 mRNA by 6 fold (p<0.05) compared to control. Likewise, ERβ agonist also induced LCN2 mRNA by 3.5 fold (p<0.05). Next, E2 induced ERβ mRNA by 1.8 fold (p<0.05), but not ERα mRNA or protein levels. Dex alone did not change LCN2 mRNA levels in AT from post-menopausal females. Dex reduced ERα mRNA and protein levels by 20% (p<0.001) and 35% (p<0.01), respectively, but increased ERβ mRNA by 220% (p<0.001). Dex-induced reduction in ERα mRNA levels was associated with BMI (r=0.569, p<0.01), waist circumference (r=0.565, p<0.01), fasting insulin (r=0.531, p<0.05) and c-peptide (r=0.560, p<0.01). In multivariate analysis BMI (std β coefficient = 0.626, p < 0.01; model: r 2 = 0.392) remained as significantly associated variable. In summary, E2 induced LCN2 expression in SCAT of postmenopausal women and this may be mediated via ERβ. Dex stimulation and inhibition of ERα and ERβ respectively implies a selective glucocorticoid mechanism to promote ERβ mediated transcriptional pathways. Overall, our data suggest that ERβ pathway may promote LCN2 expression and hence insulin resistance in AT. Disclosure P.G. Kamble: None. M.J. Pereira: None. G.J. Boersma: None. K.E. Almby: None. J.W. Eriksson: Employee; Spouse/Partner; Amgen Inc.. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Novo Nordisk A/S, Merck Sharp & Dohme Corp.. Research Support; Self; Bristol-Myers Squibb Company.