MPLA‐induced endotoxin tolerance does not protect against LPS insulin resistance

Abstract

Healthcare‐associated infections are acquired by over 4% of hospital admissions and result in approximately $28 to $45 billion US dollars of direct hospital costs. In addition, the increased incidence of antibiotic resistance highlights the necessity to develop more effective methods of prevention and/or treatment of bacterial infection. Previous work has shown that exposure of mice to lipopolysaccharide (LPS), which mimics a bacterial infection, results in an elevation in plasma pro‐inflammatory cytokines and activation of the toll‐like receptor 4 (TLR4). Recently, it has also been demonstrated that prior exposure to a TLR4 agonist attenuated plasma pro‐inflammatory cytokine response to LPS and improved survival (i.e. endotoxin tolerance). One such TLR4 agonist is monophosphoryl lipid A (MPLA), an adjuvant designed based on the structure of LPS. When MPLA is given prior to or at the time of infection, there is not only a reduced mortality as the result of the infection but there is also a reduction in the plasma pro‐inflammatory cytokine levels compared to a vehicle prime. These investigations also revealed that prior treatment of MPLA altered the metabolic phenotype of bone‐marrow‐derived macrophages. These macrophages have elevated glycolysis, oxidative capacity, and ATP production. Infection is also associated with hyperglycemia and systemic insulin resistance and proinflammatory cytokines are thought to contribute to the insulin resistance. Thus, we hypothesized that systemic administration of MPLA would also result in improved systemic metabolism and insulin sensitivity. To test this hypothesis, we performed hyperinsulinemic (2 mU·kg−1·min−1), euglycemic clamps on chronically catheterized (carotid artery and jugular vein) wild‐type mice. Three days after catheterization, mice are injected intraperitoneally with MPLA (20 mg) or saline vehicle for 2 days. On day 5 all animals received LPS (2μg/g) and clamps were performed. 3‐3Hglucose and 14C‐2deoxyglucose were infused to assess whole body glucose flux and tissue specific glucose uptake, respectively. Administration of LPS resulted in impaired (~35%) insulin sensitivity in saline group relative to historical controls; as reflected in the decrease in glucose infusion rate (Figure 1). Surprisingly, we demonstrated that mice given MPLA injections had a further impairment in insulin sensitivity compared to saline treated mice in the presence of equivalent increases in insulin levels (Figure 2). This was reflected as decreases in glucose uptake (Rg) in multiple tissues (Figure 3), while insulin suppression of endogenous glucose production was similar. Overall, these data suggest that despite beneficial metabolic changes that occur in bone‐marrow derived macrophages upon exposure to MPLA, prior treatment with MPLA does not protect against LPS‐induced insulin resistance. In fact, MPLA amplifies the insulin resistance in LPS‐treated mice. In summary, the immunological protection conferred by the MPLA shown in previous studies did not protect the mice from the systemic insulin resistance. Therefore, therapies developed to combat bacterial infection may provide immunological protection for the patient without protecting from the comorbidity of hyperglycemia.The impact of pretreatment with MPLA or saline on glucose infusion rates (Figure 1); plasma insulin levels (Figure 2); and tissue glucose uptake (Figure 3) in mice after a LPS challenge.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.