Abstract 5525: Leptin Receptor Signaling Pathways are protective Against Atherosclerosis in a Mouse Model of Obesity and Hyperlipidemia
Leptin is an adipocyte-derived hormone that has been shown to exert both beneficial metabolic effects and potentially adverse vascular effects in preclinical studies. To determine the effects of leptin receptor signaling pathways on atherosclerosis in the setting of obesity and hyperlipidemia, mice were generated with deficiency of apolipoprotein E (ApoE−/−) and either wild-type leptin receptor expression (Lepr+/+,ApoE−/−), mutant leptin receptor expression defective in all leptin receptor signaling pathways (Leprdb/db ,ApoE−/−), or mutant leptin receptor with selective deficiency of leptin receptor-STAT3 signaling (Leprs/s,ApoE−/−). At 27 weeks of age, which included 7 weeks on western chow, Leprdb/db,ApoE−/− developed increased weight (61.9 ±3.5 vs 28±2.5, p<0.001), increased leptin (127.8±34 vs 24±12.5, p<0.003), increased NEFAC (2.4±0.75 vs 0.65±0.11, p<0.05) and more atherosclerosis (13.9±1.7 vs 4.3±0.9, p=0.001) than Lepr+/+,ApoE−/− mice. In contrast, despite similar obesity and hyperlipidemia to Leprdb/db,ApoE−/− mice, the atherosclerosis in Leprs/s,ApoE−/− was less than Leprdb/db,ApoE−/− mice (7.3±1 vs 13.9±1.7, p=0.003) and not significantly greater than Lepr+/+,ApoE−/− mice (7.3±1 vs 4.3±0.9, p=0.06 ). Hepatic steatosis and adipose inflammation were also reduced in Leprs/s,ApoE−/− mice compared to Leprdb/db,ApoE−/− mice. In a mouse model of obesity and hyperlipidemia, leptin receptor signaling confers protection against hepatic steatosis, fat inflammation, and atherosclerosis. These effects are independent of leptin effects on energy balance.
This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).