Abstract
Heme oxygenase-1 (HO-1) is a stress-responsive enzyme with potent anti-oxidant and anti-inflammatory activities. Previous studies have shown that systemic induction of HO-1 by chemical inducers reduces adiposity and improves insulin sensitivity. To dissect the specific function of HO-1 in adipose tissue, we generated transgenic mice with adipose HO-1 overexpression using the adipocyte-specific aP2 promoter. The transgenic (Tg) mice exhibit similar metabolic phenotype as wild type (WT) control under chow-fed condition. High fat diet (HFD) challenge significantly increased the body weights of WT and Tg mice to a similar extent. Likewise, HFD-induced glucose intolerance and insulin resistance were not much different between WT and Tg mice. Analysis of the adipose tissue gene expression revealed that the mRNA levels of adiponectin and interleukin-10 were significantly higher in chow diet-fed Tg mice as compared to WT counterparts, whereas HFD induced downregulation of adiponectin gene expression in both Tg and WT mice to a similar level. HFD-induced proinflammatory cytokine expression in adipose tissues were comparable between WT and transgenic mice. Nevertheless, immunohistochemistry and gene expression analysis showed that the number of infiltrating macrophages with preferential expression of M2 markers was significantly higher in the adipose tissue of obese Tg mice than WT mice. Further experiment demonstrated that myeloid cells from Tg mice expressed higher level of HO-1 and exhibited greater migration response toward chemoattractant in vitro. Collectively, these data indicate that HO-1 overexpression in adipocytes does not protect against HFD-induced obesity and the development of insulin resistance in mice.
Highlights
Adipose tissue is a primary site in the body to store energy in the form of triglyceride [1] When dietary energy intake persistently exceeds energy expenditure, the adipose tissue can expand through hypertrophy of the existing adipocytes and generation of new adipocytes, leading to the development of obesity [2]
Adipocytes express a number of proinflammatory cytokines, including tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1), which are upregulated in the adipose tissues of obese subjects [6]
As assessed by Western blot analysis (Fig. 1B), the levels of Heme oxygenase-1 (HO-1) protein expression in epididymal white adipose tissue (WAT) was significantly higher in the Tg mouse lines carrying 6,8 (Tg-2) and .20 copies (Tg-3) of HO-1 gene as compared to that of wild type (WT) control
Summary
Adipose tissue is a primary site in the body to store energy in the form of triglyceride [1] When dietary energy intake persistently exceeds energy expenditure, the adipose tissue can expand through hypertrophy of the existing adipocytes and generation of new adipocytes, leading to the development of obesity [2]. Adipocytes express a number of proinflammatory cytokines, including tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1), which are upregulated in the adipose tissues of obese subjects [6]. Macrophage infiltration is increased in the adipose tissues and contributes to the adipose inflammation and the development of insulin resistance in obesity. The resident macrophages in lean adipose tissues are primarily in M2 state, which expresses immunosuppressive interleukin-10 (IL-10) but downregulates inducible nitric oxide synthase (iNOS) [7,8,9]. Obesity promotes adipose macrophage accumulation with a phenotypic switch to M1 phenotype expressing CD11c and proinflammatory cytokines [7,8,9]
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