Abstract 1726: L-4f Restores Insulin Sensitivity And Attenuates Adiposity In Diabetic Obese Mice By Increasing Adiponectin, pAMPK And pAKT Levels And Decreasing Nuclear SREBP-1 Expression
Background: We recently reported that the apoA-I mimetic, L-4F, reduced adiposity and improved insulin sensitivity in diabetic obese mice. This was associated with an increase in adiponectin levels. Increased adiponectin levels are known to be associated with increased glucose utilization over fatty acid utilization and increased insulin sensitivity. We sought to further determine the mechanism(s) for L-4F action in these mice.
Methods: Mice that are genetically susceptible to develop diabetes, ob and lean, were fed a normal diet until 9 weeks of age, when all ob mice had established diabetes (229 ± 21 and 154 ± 9 mg/dL, respectively). They were then divided into four groups consisting of lean mice, L-4F-treated (2 mg/kg/day by intraperitoneal injection)-lean mice, ob mice, and L-4F-treated-ob mice. Food intake, blood insulin and glucose levels were determined. Renal and aorta HO-1, pAMPK, AKT, pAKT and SREBP-1 protein were measured after 6 weeks. Glucose tolerance and insulin sensitivity were monitored throughout all experiments. Plasma IL-1β and IL-6 levels were also measured. Visceral as well as superficial and deep subcutaneous abdominal adipose tissues were quantified by magnetic resonance imaging.
Results: L-4F administration limited weight gain without altering food intake, decreased visceral (p < 0.04) and subcutaneous fat content (p < 0.05), decreased plasma IL-1β and IL-6 levels, and increased insulin sensitivity resulting in decreased glucose levels (p < 0.036). L-4F treatment increased serum adiponectin levels (p < 0.037) and decreased adipogenesis in ob bone marrow (p < .039). L-4F increased HO-1 expression and decreased renal and aorta nuclear expression of SREBP-1 (p < .002). The increase in adiponectin and decrease in SREBP-1 was associated with increases in pAMPK and pAKT.
Conclusions: L-4F increased adiponectin levels, insulin sensitivity, HO-1 expression, pAKT, and pAMPK and decreased plasma IL-1β, and IL-6 levels and nuclear expression of SREBP-1, as well as subcutaneous and visceral fat content and bone marrow adipogenesis. Based on the known actions of adiponectin, pAMPK, pAKT, and SREBP-1, the mechanism of action of L-4F can likely be accounted for by its influence on these parameters.