The role of salt inducible kinases in the regulation of the mammalian target of rapamycin pathway in adipocytes

University essay from Lunds universitet/Examensarbeten i molekylärbiologi

Abstract: Salt inducible kinase 2 (SIK2) is found abundantly in adipose tissue and may have a role in the development of diabetes. SIK2 is downregulated in insulin-resistant and obese individuals, thereby providing a new potential target for therapeutic solutions. Dysfunctional adipose tissue is observed in obesity and this is correlated with impaired insulin signalling, which might contribute to imbalanced adipokine secretion and ectopic fat deposition. Degradation and recycling of cellular components are important for the maintenance of the cell, and SIK2 has recently been discovered to participate in the regulation of adipocyte autophagy via the transcription factor TFEB. Phosphorylation of TFEB by mTOR (mammalian target of rapamycin complex 1) results in its inactivity and subsequent downregulation of autophagy-related genes. We investigate here whether SIK2’s role in the regulation of TFEB is via mTOR signalling pathway, and do so by analyzing the effect of SIK inhibition on mTOR activity. We found that MRT199665, which is an AMPK and AMPK-related kinase inhibitor, results in inhibition of mTOR activity – seen as reduced phosphorylation of mTOR substrates ULK1 (Unc-51 autophagy activating kinase 1) and P70s6K (P70s6K-ribosomal protein s6 kinase). However, when SIKs were inhibited using SIK inhibitor HG-9-91-01, it resulted in reduced expression levels of these proteins, rather than altered phosphorylation. In human adipocytes, there was no significant mean difference between the negative control and treatment with HG-9-91-01. Overall, we can say that AMPK-related kinases, however not SIKs, appear to have a role to play in controlling mTOR activity.

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