Abstract
Elevated levels of glucocorticoid, a steroid hormone released in response to stress, have been implicated in the pathophysiology of diabetes, which is now known to extend its effect on brain functions. Hence, we aimed to investigate the status of brain insulin signaling in response to dexamethasone (a synthetic glucocorticoid) treatment in female Charles Foster rat. This model exhibited pronounced hyperinsulinemia and glucose intolerance with loss in appetite and body weight. Immunoblotting of insulin receptor (INSR)-PI3kinase-AKT demonstrated reduced insulin signaling in hypothalamus but no change in hippocampus, cortex, and cerebellum in dexamethasone-treated rats as compared to vehicle-treated rats, signifying the diversity of distribution and function of insulin in different brain regions. These results also correlated with appetite change, a key function governed by hypothalamus. Hence, we further explored the hypothalamic feeding circuit and found altered levels of neuropeptide genes (Agrp, Npy, Pomc) and candidate nutrient sensors (GLUT1, SirT1, and PPARγ). There was also a considerable reduction in glycogen content and appetite-regulating neurotransmitters (GABA, glutamate, dopamine) in dexamethasone-treated rats. Thus, concluding that dexamethasone not only induces peripheral insulin resistance but also impairs hypothalamic function of appetite regulation via the interwoven cascade of insulin signaling, neurotransmitters, and neuropeptides.
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Acknowledgments
We extend our special thanks to Dr. Anil Pillai, Department of Psychiatry and Health Behaviour, Georgia Regents University, Augusta, GA, USA, for his critical comments and help in the preparation of the manuscript. We acknowledge Department of Biotechnology (DBT)-MSUB-ILSPARE for providing Central Instrumentation Facility, Animal House Facility of Biochemistry Department, and Department of Science and Technology for the fellowship and contingency received under DST INSPIRE FELLOWSHIP (No. 120479) to Ragitha Chruvattil.
Author’s Contribution
SG, RC, and GK conceived and designed the study; SB and SN assisted RC in the animal experiments; JM perfomed the neurotransmitter estimation under the supervision of MRY; and RC and SG analyzed the data and wrote the manuscript.
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The authors declare that they have no conflict of interest.
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Financial assistance was provided by DST-INSPIRE FELLOWSHIP SCHEME and Department of Biotechnology (DBT) under the project (BT/PR5033/MED/30/792/2012).
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Highlights
• Hypothalamus is the prime region for onset of dexamethasone-induced brain insulin resistance.
• Dexamethasone modulates the hypothalamic appetite-regulating circuitry.
• Decision of appetite depends on cross talk of insulin signaling, glucocorticoid levels, nutrient sensors, neurotransmitters, and neuropeptides in hypothalamus.
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Chruvattil, R., Banerjee, S., Nath, S. et al. Dexamethasone Alters the Appetite Regulation via Induction of Hypothalamic Insulin Resistance in Rat Brain. Mol Neurobiol 54, 7483–7496 (2017). https://doi.org/10.1007/s12035-016-0251-2
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DOI: https://doi.org/10.1007/s12035-016-0251-2