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PKCα Isoform Inhibits Insulin Signaling and Aggravates Neuronal Insulin Resistance

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Abstract

Overexpression of PKCα has been linked to inhibit insulin signaling disrupting IRS-1 and Akt phosphorylations in skeletal muscle. PKCα inhibits IRS-1 and Akt phosphorylations, but not required for insulin-stimulated glucose transport in skeletal muscles. Inhibition of PKCα increased whereas in some studies decreased GLUT-4 levels at the plasma membrane in skeletal muscles and adipocytes. Controversial studies have reported opposite expression pattern of PKCα expression in insulin-resistant skeletal muscles. These findings indicate that the role of PKCα on insulin signaling is controversial and could be tissue specific. Evidently, studies are required to decipher the role of PKCα in regulating insulin signaling and preferably in other cellular systems. Utilizing neuronal cells, like Neuro-2a, SHSY-5Y and insulin-resistant diabetic mice brain tissues; we have demonstrated that PKCα inhibits insulin signaling, through IRS-Akt pathway in PP2A-dependent mechanism by an AS160-independent route involving 14-3-3ζ. Inhibition and silencing of PKCα improves insulin sensitivity by increasing GLUT-4 translocation to the plasma membrane and glucose uptake. PKCα regulates GSK3 isoforms in an opposite manner in insulin-sensitive and in insulin-resistant condition. Higher activity of PKCα aggravates insulin-resistant neuronal diabetic condition through GSK3β but not GSK3α. Our results mechanistically explored the contribution of PKCα in regulating neuronal insulin resistance and diabetes, which opens up new avenues in dealing with metabolic disorders and neurodegenerative disorders.

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Acknowledgements

We are grateful to Indian Institute of Technology-Delhi for its support. We would like to thank Dr.Prosenjit Mondal, Indian Institute of Technology-Mandi, Himachal Pradesh, India, for providing us with normal diet (ND) and high fat fed diet (HFD) mouse brain samples. We are grateful to Central Instrumentation Facility (CIF), University of Delhi, South Campus, New Delhi, India, for Confocal Microscopy. We would like to thank Dr. Chinmoy Mukhopadhyay, Jawaharalal Nehru University, New Delhi, for providing us with Caveolin-1 antibody.

Funding

D.M. was a recipient of Senior Research Fellowship from CSIR, Government of India. I.R. is a recipient of Senior Research Fellowship from DBT, Government of India. C.S.D is supported by a grant from Indian Council of Medical Research, Government of India, New Delhi, 5/4/5-17/Diab./20-NCD-III.

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  1. Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, New Delhi, Hauz Khas, -110016, India

    Devanshi Mishra, Ishitha Reddy & Chinmoy Sankar Dey

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C.S.D. conceived the idea, D.M. did all the experiments; I.R. aided in interpreting the results. C.S.D., D.M. and I.R. wrote the manuscript and approved the final version of the manuscript.

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Correspondence to Chinmoy Sankar Dey.

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Mishra, D., Reddy, I. & Dey, C.S. PKCα Isoform Inhibits Insulin Signaling and Aggravates Neuronal Insulin Resistance. Mol Neurobiol 60, 6642–6659 (2023). https://doi.org/10.1007/s12035-023-03486-6

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