Anthropometric and glucometabolic changes in an aged mouse model of Lipocalin-2 overexpression

Background
Lipocalin-2 (LCN2) is widely expressed in the organism with pleiotropic roles. In particular, its over-expression
correlates with tissue stress conditions including inflammation, metabolic disorders, chronic diseases and cancer.
Objectives
Assess the effects of systemic LCN2 overexpression on adipose tissue and glucose metabolism.
Subjects
18-months old transgenic mice with systemic LCN2 overexpression (LCN2-Tg) and age/sex matched wild type
mice.
Methods
Metabolic cages; histology and real time PCR analysis; glucose and insulin tolerance tests; ELISA; flow cytometry;
microPET and serum analysis.
Results
LCN2-Tg mice were smaller compared to controls but they ate (P= 0.0156) and drank (P= 0.0057) more and displayed
a higher amount of visceral adipose tissue. Furthermore, LCN2-Tg mice with body weight ≥ 20g, showed
adipocytes with a higher cell area (P<0.0001), altered expression of genes involved in adipocyte differentiation and inflammation. In particular, mRNA levels of adipocyte-derived Ppar (P=<0.0001), Srbf1 (P <0.0001), Fbp4 (P= 0.056), Tnfα (P= 0.0391), Il6 (P= 0.0198) and Lep (P=0.0003) were all increased. Furthermore, LCN2- Tg mice displayed a decreased amount of basal serum insulin (P=0.0122) and a statistically significant impaired glucose tolerance and insulin sensitivity consistent with Slc2a2 mRNA (P=<0.0001) downregulated expression. On the other hand, Insr mRNA (P=<0.0001) was upregulated and correlated with microPET analysis that demonstrated a trend in reduced whole body glucose consumption and MRGlu in muscles and a significantly reduced MRGlu in brown adipose tissue (P= 0.0247). Nevertheless, an almost nine-fold acceleration of hexokinase activity was observed in LCN2-Tg mice liver compared to controls (P= 0.0027). Moreover, AST and ALT were increased (P=0.0421; P=0.0403), which indicated a liver involvement also demonstrated by histological staining. Conclusions We show that LCN2 profoundly impacts adipose tissue size and function and glucose metabolism suggesting that LCN2 should be considered as a risk factor in ageing for metabolic disorders leading to obesity.

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