Red Blood Cell Endothelial Nitric Oxide Attenuates Insulin Resistance

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Nitric oxide and endothelial nitric oxide synthase (eNOS or Nos3) are well-established contributors to vascular homeostasis. Nevertheless, loss of Nos3 appears to result in metabolic derangements that contribute to insulin resistance. More specifically, a reduction in Nos3-derived NO during obesity precedes the development of insulin resistance4 and genetic deletion of Nos3 (Nos3–/– mouse) is associated with both systemic and hepatic insulin resistance. Moreover, pharmacologic strategies that restore NO bioavailability during obesity (e.g. PDE5 inhibition) and genetic strategies that increase NO production (e.g. Nos3 overexpression) restore insulin sensitivity in mice. Our laboratory and others have long attributed the salutary metabolic effects of Nos3 to endothelium-mediated improvement of blood flow that increases delivery of nutrients to insulin-sensitive tissues such as liver, muscle, and adipose tissue, thereby facilitating nutrient utilization or storage and maintaining metabolic homeostasis. However, recent work from our laboratory suggests that, during obesity, bone marrow derived cell Nos3—not endothelial Nos3—preserves metabolic homeostasis. Here we propose a novel model in which NO produced by red blood cell (RBC) Nos3 acts as a physiological brake on inflammatory activation. During obesity, we propose that a reduction in RBC- derived NO releases this brake, increasing hepatic macrophage activation and promoting insulin resistance. Crosstalk between RBC and macrophage are crucial for RBC clearance, since residential macrophages scrutinize passing RBC and remove damaged RBC in the liver and spleen and work also suggests that RBC participate in macrophage-mediated immune responses to pathogens. These observations establish an important yet under-investigated interaction between RBC and immune cells. We propose the novel hypothesis that RBC Nos3/NO is required to maintain hepatic insulin sensitivity through its effects to limit activation of Kupffer cells, and that the loss of these effects of NO leads to obesity-associated hepatic insulin resistance. If this hypothesis is correct, the translational significance will be considerable because therapeutic options that increase NO bioavailability are already available. These therapies might prevent obesity-mediated insulin resistance. Furthermore, studies proposed here may uncover a novel RBC dependent pathway for attenuating macrophage activation in states of low-grade chronic inflammation such as obesity or atherosclerosis. We propose the following aims: Aim 1. To test the hypothesis that RBC Nos3 is sufficient to maintain hepatic insulin sensitivity by attenuating Kupffer cell activation during obesity. Aim 2. To determine whether T2D is associated with reduced RBC NO content and increased arginase 1 activity.