The reprogramming of gluconeogenesis and gpr120 expression in sepsis metabolism

Abstract

Sepsis is defined as an overactive response to infection, and can progress to septic shock, multiple organ failure and death. Characteristic of sepsis is a systemic reprogramming of glucose and lipid metabolism. Preliminary data generated by the Wang, Perry, and Cintra labs demonstrates that this metabolic reprogramming is a conserved feature of type I inflammation and is crucial to survive sepsis. Wang and collaborators showed in 2016, that glucose utilization was necessary for mice survival when the inflammation was trigged by virus, but it was not needed when it was bacterial inflammation. In this work, they suggested that the viral inflammation, in the brain, needs the glucose to mitigate the ER stress response, while the bacterial inflammation in response to glucose stimuli can suppress the ketogenesis, which can cause damage in the brain. Each type of type I inflammation (bacterial and viral) can respond differently both to and through metabolic alterations. Also, several studies have identified that both hypoglycemia and hyperglycemia are associated with higher mortality in sepsis. Most septic patients exhibit hypermetabolism, highlighting the importance of a balanced diet prescription. A high protein diet before and during sepsis is generally considered an important pillar in the treatment of sepsis patients, because it can avoid the loss of body weight and muscle. In addition, omega 3 fatty acids are a potential target to optimize metabolic reprogramming in sepsis. Likely related, anti-inflammatory properties of omega-3 fatty acids have been described. For that reason, omega-3 fatty acids have been target of studies in several diseases. These agents have been used in hospitalized patients as supplementation, enteral and parenteral diets. Hirasawa and collaborators showed that GPR120, a transmembrane g-protein coupled receptor, could recognize polyunsaturated fatty acids including omega 3. Then, in 2010, Oh and collaborators showed the signaling pathway downstream of the receptor and the presence of GPR120 in the macrophage cell lineage. Once activated by omega 3 molecules, GPR120 can attenuate the inflammatory pathway dissociating the complex TAB1/TAK1, and consequently decreasing the activation of NFkB. Previous work showed that canonical and non-canonical NFkB signaling pathways are activated in sepsis, and that gene expression of TLR2, TLR4, TRAF6, NIK, RelA and RelB can be a biomarker of activation of the innate immune response in patients with sepsis. In addition, when the DNA methylation of NFkB is inhibited, progression of sepsis is also inhibited. In summary, sepsis has been studied for decades, however the mechanism and phenotype of the reprogramming of glucose metabolism in these acute inflammatory settings is poorly understood. Further, to our knowledge the primary omega 3 fatty acid receptor, GPR120, has never been studied in sepsis. Both GPR120 activation and glucose metabolism can be related to macrophages activation. In this project, our aim is to better understand why sepsis can be characterized by hypoglycemia and hyperglycemia, how the reprogramming of glucose and lipid metabolism in sepsis intersects with the prognosis, and if the GPR120 activation can be beneficial in treatment of these diseases. (AU)