Immunometabolic Role of 2,3-Bisphosphoglycerate: Connecting Obesity, Hypoxia, and Inflammation

Abstract: Metabolic disruption associated with obesity leads to a persistent, subclinical inflammatory state called metabolic inflammation, which in turn further exacerbates dysmetabolism. Notably, during obesity, there is also a remarkable hypoxia. The prevailing understanding is that hypoxia in obesity is primarily caused by decreased cardiac output and blood flow, as well as an increase in adipocyte diameter. Consequently, hypoxia contributes to metabolic inflammation by regulating metabolic and inflammatory pathways. However, in this perspective, we propose another mode of obesity- induced hypoxia. Aberrant systemic metabolism affects erythrocyte metabolism, impairing the production of 2,3-bisphosphoglycerate (2,3 BPG), the primary negative allosteric regulator of hemoglobin. This would lead to tissue hypoxia due to decreased oxygen release. It has been found that during obesity, elevated glucose is diverted towards sorbitol production and the synthesis of advanced glycation end products (AGEs). This diversion surpasses the increased glucose utilization by the pentose phosphate pathway, leading to the formation of reactive oxygen species. In turn, the oxidized Band 3 protein limits the rate of glycolysis, thereby reducing the synthesis of 2,3-BPG. Concurrently, reduced ATP levels impair de novo glutathione synthesis, despite an increased availability of amino acids, thereby exacerbating oxidative stress. ROS can also activate arginase, which in turn promotes further ROS generation by uncoupling nitric oxide synthase. Ultimately, increased systemic lipid accumulation leads to increased ceramide content, thereby inhibiting the adenosine monophosphate- dependent kinase, which regulates the activity of BPG mutase. Altogether, these mechanisms would hinder oxygen release by erythrocytes, leading to hypoxia.