Annexin A1 Regulates Adiposity in Mice
thesisposted on 2013-02-21, 00:00 authored by Rand T. Akasheh
Annexin A1 (ANXA1) is a glucocorticoid- (GC-) induced protein that mediates at least a part of the anti-inflammatory actions of these hormones. However, it is unknown whether ANXA1 also mediates some of the metabolic functions of GC. The role of this protein in adipose tissue metabolism and inflammation needs to be carefully investigated. Our aim was to study the effect of ANXA1 deficiency on markers of adiposity in mice by measuring body weight (BW), body composition, and gene expression of metabolic factors in mice fed both chow and high fat diet (HFD). We also aimed at evaluating the effect of ANXA1 deficiency on gene expression of pro- and anti-inflammatory mediators in visceral adipose tissue (VAT). Annexin A1 Knock-out (KO) mice developed significantly higher adiposity compared to while type (WT) mice. The effect of ANXA1 deficiency on adiposity was independent of food intake, as no significant difference was observed in food intake between any of the mice groups. In addition, we found a significant elevation in the gene expression levels of ANXA1 in WT-HFD mice as compared to WT-chow mice, with no changes in expression of the ANXA1 receptor, formyl peptide receptor-2 (FPR2), between the four groups of mice. In terms of glycemic control, KO-HFD mice had significantly elevated fasting blood glucose and plasma insulin as compared to KO-chow and WT-HFD mice, while no significant difference was observed comparing WT-HFD to WT-chow mice,. Furthermore, KO mice in both diet groups developed significant insulin resistance compared to both WT groups as evaluated by insulin tolerance test (ITT). Although KO-HFD mice showed a trend towards glucose intolerance in the glucose tolerance test (GTT), the difference to other groups of mice was not significant. A trend towards elevated plasma levels of corticosterone in the KO mice on both diets compared to WT mice was observed, which could help explain the increased susceptibility of ANXA1 KO mice to obesity. Additionally, gene expression of 11-beta hydroxy-steroid dehydrogenase (11βHSD1) in VAT was observed in the KO-HFD mice compared to WT-HFD mice, which might have led to increased intracellular activation of GC. However, expression of the hormone sensitive lipase (HSL), adipose triglyceride lipase (ATGL) and of peroxisome proliferator activated receptor-gamma (PPAR-γ) was comparable between the two strains. Furthermore, no significant difference in VAT inflammation was found between KO and WT mice. In conclusion, in a mouse model of DIO, we show that deletion of ANXA1 leads to metabolic alterations that switch the obesity-resistant phenotype of female BALB/c mice towards increased adiposity and insulin resistance when compared to sex-, age-, and diet-matched WT mice. Further studies are needed to replicate our findings and explain the mechanisms behind the protective roles of ANXA1 against obesity and insulin resistance.