RF04 | PSUN313 A Natural Antibody Against Oxidized Phospholipids Improves Glucose Metabolism in Aging Mice

Abstract

Abstract Oxidative stress-induced lipid peroxidation generates oxidized phospholipids (OxPL), such as oxidized phosphatidylcholine, that are pro-inflammatory moieties present on oxidized low density lipoproteins and apoptotic cells. OxPL have been implicated in the pathogenesis of cardiovascular, neurological, autoimmune, liver, and lung diseases. It has been shown earlier that OxPL decrease bone formation. Natural antibodies (NAb) produced by B-1 lymphocytes, bind OxPL and prevent their inflammatory activity. The NAb E06 blocks oxidized phosphatidylcholine, and transgenic expression of a single chain (scFv) form of the antigen-binding domain of E06 IgM (E06-scFv) prevents many age-associated diseases, such as atherosclerosis, non-alcoholic steatohepatitis and age-related bone loss. OxPL are also implicated in the pathogenesis of the metabolic syndrome and diabetes by either causing insulin resistance, increasing macrophage infiltration and inflammation in white adipose tissue, decreasing insulin gene expression, and/or causing death of pancreatic beta cells through induction of oxidative stress and amyloid protein misfolding. Consistent with this evidence, NAb produced by B-1b lymphocytes are protective against obesity associated inflammation, glucose intolerance, and insulin resistance. In the work reported here, we have investigated the impact of oxidized phosphatidylcholine on glucose metabolism and age–related glucose intolerance. To this end, we aged chow-fed female and male C57BL/6 E06-scFv transgenic mice (and their WT littermates) up to 22 and 24 months. Both male and female E06-scFv transgenic mice accumulated less fat mass than WT littermates during aging, as determined by sequential body composition measurements by DXA. Intraperitoneal glucose tolerance test, performed at 10 and at 15 months of age, showed that glucose tolerance was greater in both male and female E06-ScFv transgenic mice than WT littermates and did not differ from the glucose tolerance of young mice. Insulin sensitivity, measured by insulin tolerance test, was increased in 4- and 10-month-old old transgenic females and in 15-month-old transgenic males. There was no difference in food consumption calculated over 5 days or the production of glucose after pyruvate infusion, indicating similar liver gluconeogenesis in both strains. Physical activity or energy expenditure, measured by indirect calorimetry in 11-month-old females, was indistinguishable between transgenic and WT mice. However, E06-scFv transgenic mice exhibited a significant increase in the respiratory exchange ratio, indicating that utilization of glucose was the main metabolic source under basal conditions. Collectively, these results show that blocking oxidized phosphatidylcholine improves age–related glucose intolerance in mice fed a normal diet; hence, OxPL are major culprits of the aging-associated glucose intolerance. Therefore, targeting OxPL with a neutralizing antibody represents a novel therapeutic intervention that may simultaneously ameliorate several age-associated diseases, including the metabolic syndrome and diabetes. Presentation: Saturday, June 11, 2022 1:42 p.m. - 1:47 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.