Metformin Decreases Caveolin‐1 Expression in Differentiated Human White Preadipocytes But Not in Adipose Tissue From Obese Individuals

Abstract

BackgroundCaveolin‐1 is a structural protein of caveolae which forms a signaling platform for several cell surface receptors including leptin and insulin receptor. Caveolin‐1 expression is increased with obesity which is implicated in impaired adipose tissue leptin signaling. Considering the overlap between insulin and leptin cellular signaling pathways, we investigated known insulin‐sensitizing drugs which may reduce caveolin‐1 expression in adipose tissue and consequently improve leptin signaling.MethodsWe used an in‐vitro approach to identify insulin‐sensitizing drugs which may reduce caveolin‐1 expression. Differentiated human white preadipocytes (dHWP) were treated with pioglitazone (5–30 μM), troglitazone (10–30 μM), metformin (1–5 mM), or glimepiride (20–100 μM) for 24 hours. Caveolin‐1 expression was determined by Western blot. We further tested the responses in human adipose tissue from obese individuals (n=12, age: 45.4 ± 9.2 years, BMI: 48.9 ± 7.3 kg/m2) undergoing surgery. Tissue was incubated with drugs for 24 h and caveolin‐1 expression was determined. Furthermore, the effect of drugs on leptin‐dependent activation of ERK and STAT3 was examined by western blot.ResultsAmong the drugs investigated, only treatment with increasing concentrations of metformin resulted in a dose‐dependent decease in caveolin‐1 protein (p=0.01) expression in dHWP. Treatment with increasing concentrations of troglitazone upregulated caveolin‐1 (p=0.01), while pioglitazone (p=0.50) and glimepiride (p=0.09) had no effect of caveolin‐1 protein expression. Given these findings, only metformin was tested in human adipose tissue. Overall, metformin did not alter caveolin‐1 expression in adipose tissue from obese individuals (n=12, control: 0.040 ± 0.056, metformin: 0.024 ± 0.030, p=0.57), although a metformin dependent decrease in caveolin‐1 was evident in adipose tissue from 7 of the 12 obese subjects (control: 0.062 ± 0.066, metformin: 0.014 ± 0.013, p=0.02). Notably, changes in caveolin‐1 expression induced by metformin treatment were positively correlated with BMI (p=0.05, r2=0.33, n=12). Also, leptin dependent activation of ERK (control: 0.26 ± .098, leptin: 0.28 ± .08) and STAT3 (control: 0.028 ± 0.027, leptin: 0.032 ± 0.023) was impaired in obese adipose tissue and did not change with metformin treatment even in the 7 individuals with metformin associated decreases in caveolin‐1.ConclusionsMetformin reduces caveolin‐1 expression in differentiated HWP. However, metformin decreases caveolin‐1 expression in adipose tissue of some but not all obese subjects, and does not have any effects on leptin signaling. The heterogeneous effects of metformin on caveolin‐1 expression in adipose tissue from obese individuals may be related to BMI and needs further investigation.Support or Funding InformationMAP and KRS were supported by the American Physiological Society Stride Summer Undergraduate Research Fellowship NHLBI 1 R25 HL115473‐01. PS was supported by AHA scientist development grant 11SDG7260046.