| Objectives:Scavenger receptor A (SR-A), a pattern recognition receptors (PRRs) in macrophages, has multiple biological functions in inflammation by regulating macrophage phagocytosis, apoptosis, and cytokines secretion. Recently it has been found that SR-A is strongly associated with insulin resistance in obese humans. However, the definite role of SR-A in insulin resistance has not yet been defined. This study used both diet-induced and genetically induced obesity murine models to examine the role of SR-A in the develpoment of obesity-induced insulin resistance.Methods:We first fed SR-A-/-and wild-type contol (SR-A+/+) mice a normal diet or high fat diet (HFD) for15weeks. Body weight, blood glucose, and food uptake were measured after4,8,12weeks of the HFD and the normal diet. When the diet-induced obesity murine model was generated, we performed the glucose tolerance test (GTT) and insulin tolerance test (ITT) to investigate the impact of SR-A deficiency on insulin resistance. The infiltrated macrophages in the epididymal adipose tissue were analyzed by immunochemical staining and flow cytometry. We also examined the expression of macrophage-specific markers and inflammatory genes in the adipose tissue, Meanwhile insulin signaling was examined in the fat tissue. In order to further identify the role of SR-A in obsity-induced insulin resistance, we generated SR-A-/-mice with a leptin-deficient background (SR-A-/-Aob/ob) and investigated the phenotypes of SR-A-/-ob/ob and SR-A+/+ob/ob mice. Results:After15weeks of the HFD diet, no dramatic differences in body weight and epididymal fat weight were found between SR-A-/-mice and SR-A+/+mice. But SR-A"/" mice were shown significantly higher blood glocuse and insulin levels compared with SR-A+/+mice. To reflect the systemic insulin sensitivity, blood glocuse levels of SR-A+/+mice were significantly lower than those of SR-A-/-mice during both glucose tolerance test and insulin tolerance test demonstrated similar changes in SR-A-/-mice and SR-A+/+mice. These data indicate that lack of SR-A may aggravate HFD-induced insulin resistance.Next, we investigated mechanism of SR-A on HFD-induced insulin resistance. Expression of macrophage-specific markers was increased in the SR-A+/+epididymal fat tissue but was decreased in the SR-A-/-epididymal fat tissue when mice were fed with HFD. These data suggest that loss of SR-A affect the infiltration of macrophage in the HFD-induced obesity. We also found that there was not significant difference in the relative levels of Ml macrophages gene expression between wildtype and SR-A-/-mice. However, wildtype mice were shown higher levels of M2macrophages gene expression than SR-A-/-mice, suggesting that SR-A deficiency impair M2macrophage polarization.Furthermore, we observed that insulin-induced IR β tyrosine phosphorylation and Akt phosphorylation in adipose tissue were increased in wildtype mice compared with SR-A-/-mice fed with a HFD. These results indicated that SR-A may has a function improving insulin sensitivity.In order to confirm the role of SR-A in obsity-induced insulin resistance, we generated SR-A-/-mice with a leptin-deficient background (SR-A-/-ob/ob). Although SR-A-/-ob/ob mice gained body weight and epididymal fat weight in a similar manner compared with SR-A+/+ob/ob mice, they displayed higher blood glucose levels up to8 weeks. Similarly, SR-A+/+ob/ob mice also displayed significantly decreased glucose levels in a fasted state as well as during ITT and GTT along with enhanced insulin-stimulated Akt phosphorylation in the adipose tissue. In addition, the expression of M1macrophage markers in the eWAT of SR-A+/+ob/ob mice was similar to that of SR-A-/-ob/ob, whereas M2macrophage markers were up-regulated. These data suggested that loss of SR-A exacerbated obesity-induced insulin resistance through the reduction of M2macrophage infiltration even in a genetical obese model.Conclusions:SR-A deficiency can exacerbate obesity-induced insulin resistance by reducing the infiltration of M2macrophages into adipose tissues with the progression of obesity-induced insulin resistance. |
