Abstract 244: Identification of Caveolin-1 as an Inhibitor of Leptin Signaling: Implications for Leptin Resistance in a Human Weight Gain Model
Background: Obesity is associated with leptin resistance. The molecular mechanisms underlying leptin resistance are not well understood. We used a human model of weight gain to determine leptin resistance mechanisms in adipose tissue
Methods and Results: We studied 15 healthy non-obese subjects (11 men, 4 women; mean age, 30 ± 5 years). Blood sample and abdominal adipose tissue biopsy were obtained on 2 different occasions: at baseline and after 8 weeks of overfeeding during which the subjects gained approximately 5% body weight. During weight gain the systemic parameters that significantly changed were body fat mass (p=0.0001), leptin (p=0.0001), and insulin (0.03) whereas increases in LDL, triglycerides and cholesterol were not significant. Quantitative proteome profiling of adipose tissue using isotope-coded affinity tag along with tandem mass spectrometry showed increases in several proteins including caveolin-1. Western blot analysis showed that increases in caveolin-1 during weight gain significantly correlated with increases in leptin (p=0.004) and insulin (0.0002). The increased caveolin-1 corresponded with increased caveolae number (approx 3 fold) as demonstrated by EM studies. We show, using in-vitro human adipocytes and vascular endothelial cells, that leptin up-regulates the expression of caveolin-1. A two fold increase in caveolin-1 expression was observed when treated with 100 ng/ml leptin. We also show by immuno-precipitation and confocal analysis of the adipose tissue that leptin receptor colocalizes with caveolin-1. The colocalization of leptin receptor and caveolin-1 increased significantly from baseline to weight gain (16.9% Vs 22.9% respectively). We also demonstrate that in-vitro overexpression of caveolin-1 using adenovirus in vascular endothelial cells reduced leptin induced activation of MAPK and eNOS by greater than 50 %
Conclusion: Weight gain is associated with increases in caveolin-1 expression in adipose tissue. Leptin upregulates the expression of caveolin-1 and caveolin-1 overexpression impairs leptin signaling. Hence we identify a novel leptin feedback mechanism which may have implications for understanding the development of leptin resistance.
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).