Abstract
Proinflammatory cytokines play a causal role in the development of hyperinsulinemia and T2MD. FOXO1, a transcription factor which is known to enhance proinflammation, was recently shown to be involved in obesity-induced β cell dysfunction. However, molecular mechanisms for the association remained elusive. In this study, we first found that both leptin (10 nM) and TNF-α (20 ng/ml) significantly inhibited glucose-stimulated insulin secretion (GSIS) of INS-1E cells. When in combination, the GSIS function of INS-1E cells was significantly increased compared with that of the leptin alone treatment, indicating that TNF-α attenuated the inhibiting effect of leptin on GSIS of INS-1E cells. Similarly, we found that TNF-α has the same inhibitory effect on leptin in regulating insulin synthesis and secretion, and the survival and apoptosis of insulin cells. Further studies showed that TNF-α blocks leptin pathway by reducing the expression of leptin receptor (LepRb, also called OBRb) and inhibiting the activation of STAT3, a key molecule involved in the leptin signaling pathway in INS-1E cells. Besides, the downregulated expression of phosphorylated FOXO1 was found to be involved in the possible mechanism of TNF-α. Overexpression of constitutively active FOXO1 markedly aggravated the LepRb reduction by TNF-α treatment of INS-1E cells, and the endogenous FOXO1 knockdown abolished the effect of TNF-α on INS-1E cells. Furthermore, we have proved that FOXO1 could directly bind to the promoter of LepRb as a negative transcription regulator. Taken together, the results of this study reveal that TNF-α-induced LepRb downregulated in pancreatic β cells and demonstrate that transcriptional reduction of FOXO1 might be the primary mechanism underlying TNF-α promoting INS-1E leptin resistance and β cell dysfunction. Conclusions. Our current studies based on INS-1E cells in vitro indicate that the inflammatory factor TNF-α plays an important role in the development of INS-1E leptin resistance and glucose metabolism disorders, probably through FOXO1-induced transcription reduction of LepRb promoter in pancreatic β cells, and FOXO1 may be a novel target for treating β cell dysfunction in obesity-induced hyperinsulinemia and T2DM.
Highlights
Obesity is defined as a body mass index ðBMIÞ ≧ 30 kg/m2 [1]
To identify the molecular linking between tumor necrosis factor-α (TNF-α) and leptin under the state of obesity, we firstly investigated the effects of leptin and TNF-α on the glucose-stimulated insulin secretion (GSIS) function in INS-1E cells
When INS-1E cells were treated with leptin (10 nM) and TNF-α (20 ng/ml) in combination, the GSIS function of INS-1E cells was significantly increased compared with the leptin alone treatment group (Figure 2(c))
Summary
Obesity is defined as a body mass index ðBMIÞ ≧ 30 kg/m2 [1]. With this standard, the prevalence of obesity is increasing rapidly around the world and nearly a global epidemic [2, 3]. Accumulating findings indicate that obesity is one of the most important risk factors for health with cardiometabolic complications, including insulin resistance, metabolic syndrome components, type 2 diabetes (T2MD), and cardiovascular disease [4]. It is reported that β cell dysfunction is a common result of hyperinsulinemia and insulin resistance during progression of metabolic syndrome to T2MD [6]. The role of β cell dysfunction in the pathogenesis of type 2 diabetes has gradually been revealed in recent years. Increasing findings report that obesity is strongly associated with the development of leptin resistance [7], which in turn plays a key role in the pathogenesis of T2MD, but the mechanism needs to be more elucidated
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