TNF-α Antagonizes the Effect of Leptin on Insulin Secretion through FOXO1-Dependent Transcriptional Suppression of LepRb in INS-1 Cells. (14th February 2022)

• Record Type: Journal Article
• Authors: Zhang, Yang; Jin, Weidong; Zhang, Dongyun; Lin, Changhai; He, Haiyan; Xie, Fengxin; Gan, Lixia; Fu, Weiling; Wu, Lixiang; Wu, Yongzhong
• Other Names: Lloret Ana Academic Editor.
• Is Part Of: Oxidative medicine and cellular longevity. Volume 2022(2022)
• Publication Date: 2022-02-14
• Subjects: Oxidative stress -- Periodicals; Cells -- Aging -- Periodicals; Cells -- Aging; Oxidative stress; Oxidative Stress -- Periodicals; Cell Aging -- Periodicals; Periodicals; 611.0181
• DOI: 10.1155/2022/9142798
• Languages: English
• ISSNs: 1942-0900

Abstract

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.