Role of hypoxia-inducible factor 2α in the regulation of adipose tissue inflammation in obesity

Abstract

Excess caloric intake leads to expansion of adipose tissue, which induces adipose tissue hypoxia because of the relative insufficiency of the vascular network in charge of oxygen supply. In obesity, adipose tissue hypoxia has been implicated be one of important mediator of pro-inflammatory responses, which is associated with obesity-related metabolic complications. Recently, hypoxia-inducible factor (HIF) family, which is a major transcription factor induced by hypoxia, is suggested to play essential roles to mediate hypoxic responses in adipose tissue. For instance, activation of HIF-1α has been implicated in chronic inflammation, fibrosis, and insulin resistance as well as hypoxia-mediated angiogenesis in obese adipose tissue. However, the pathophysiological role of HIF-2α in adipose tissue has not been thoroughly elucidated in obesity. Evidence has suggested that HIF-2α would have its own physiological roles or opposing roles compared to HIF-1α despite of their extensive homology. Therefore, HIF-2α is also proposed to have distinctive roles in the regulation of adipose tissue angiogenesis and inflammation in obesity. In this study, I demonstrate that activation of HIF-2α in adipocytes could increase the expression level of pro-angiogenic factors as well as recruit macrophage. In the adipose tissue of short-term high-fat diet (HFD)-fed mice, adipocyte HIF-2α mRNA and protein were rapidly induced. In addition, the overexpression of HIF-2α in adipocytes significantly increased the expression level of pro-angiogenic factors such as VEGFα, and ANGPTL4 regardless of hypoxic condition. On the other hand, HIF-2α-overexpressing adipocytes promoted the recruitment and migration of macrophages, which were directly and indirectly mediated by nitric oxide signaling. Interestingly, macrophages co-cultured with adipocytes exhibited increased expression level of pro-angiogenic factors such as IGF and PDGFβ. Furthermore, macrophages sensitively and drastically stimulated the expression of VEGFα and AMD mRNA more than adipocytes in chronic hypoxic condition. These results suggest that macrophage recruited by adipocyte HIF-2α might participate in adipose tissue angiogenesis. In addition, I demonstrate that elevation of macrophage HIF-2α would attenuate adipose tissue inflammation and improve insulin resistance in obesity. In macrophages, overexpression of HIF-2α decreased nitric oxide production and suppressed expression of pro-inflammatory cytokines through induction of arginase 1 (ARG1). HIF-2α-overexpressing macrophages alleviated pro-inflammatory responses and improved insulin resistance in adipocytes. In contrast, knock-down of macrophage HIF-2α promoted palmitate-induced pro-inflammation responses in adipocytes. Furthermore, compared to wild-type mice, HIF-2α heterozygous-null mice aggravated insulin resistance and adipose tissue inflammation with more M1-like ATMs upon HFD. Moreover, glucose intolerance in HFD-fed HIF-2α heterozygote mice was relieved by macrophage deletion with clodronate treatment. Thus, unlike HIF-1α, HIF-2α in ATMs is newly suggested to contribute to the resolution of adipose tissue inflammation and insulin resistance in obesity. Taken together, these data suggest that in early stage of obesity having minimal inflammation, HIF-2α might regulate adipose tissue remodeling to adapt to the metabolic environment changes through regulation of angiogenic genes and suppression of excessive pro-inflammatory responses. Therefore, appropriate activation of HIF-2α would be crucial to maintain homeostasis of adipose tissue function and vasculature, leading to metabolically healthy adipose tissue expansion.