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Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
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Department of Medicine, University of Toronto, Toronto, Ontario, Canada
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
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evidenced by an elevation in markers of unfolded protein response activation in the liver ( 6 ). Chemical chaperones that reduced ER stress, such as 4-phenylbutyric acid (PBA) and taurine-conjugated ursodeoxycholic acid (TUDCA), have been used in rodent
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Graphical abstract
Abstract
Subclinical hypothyroidism (SCH) is closely related to insulin resistance, and thyroid-stimulating hormone (TSH) level is an independent factor for insulin resistance associated with subclinical hypothyroidism. This study aims to explore the effects of TSH levels on insulin signal transduction in adipocytes and to establish the role of endoplasmic reticulum (ER) stress in this process. In this study, the SCH mouse model was established, and 3T3-L1 adipocytes were treated with TSH or tunicamycin (TM), with or without 4-phenylbutyric acid (4-PBA), an inhibitor of ER stress. Subclinical hypothyroidism mice exhibited impaired glucose tolerance, inactivation of the IRS-1/AKT pathway, and activation of the IRE1/JNK pathway in adipose tissue, which can all be alleviated by 4-PBA. Supplementation with levothyroxine restored the TSH to normal, alongside alleviated ER stress and insulin resistance in SCH mice, which is characterized by improved glucose tolerance, decreased mRNA expression of IRE1, and decreased phosphorylation of JNK in adipose tissue. In 3T3-L1 adipocytes, TSH induces insulin resistance, leading to a decrease in glucose uptake. This effect is mediated by the downregulation of IRS-1 tyrosine phosphorylation, reduced AKT phosphorylation, and inhibited GLUT4 protein expression. Notably, all these effects can be effectively reversed by 4-PBA. Moreover, TSH induced TNF-α and IL-6 production and upregulated the expression of ER stress markers. Similarly, these changes can be recovered by 4-PBA. These findings indicate that TSH has the capability to induce insulin resistance in adipocytes. The mechanism through which TSH disrupts insulin signal transduction appears to involve the ER stress–JNK pathway.
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protein folding, and modulate the UPR signaling pathway. These processes may provide targets for future drug candidates such as chemical chaperone molecules 4-phenylbutyric acid and taurine-deoxycholic acid to promote correct protein folding and cellular
