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Dexamethasone Alters the Appetite Regulation via Induction of Hypothalamic Insulin Resistance in Rat Brain

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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.

Reduced insulin signaling as well as elevated glucocorticoid levels in hypothalamus modulates the key appetite regulating neuropeptides, neurotransmitters, and nutrient sensors resulting into reduced appetite and bodyweight

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References

  1. Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A (2013) Insulin in the brain: sources, localization and functions. Mol Neurobiol 47:145–171

    Article  CAS  PubMed  Google Scholar 

  2. Kleinridders A, Ferris HA, Cai W, Kahn CR (2014) Insulin action in brain regulates systemic metabolism and brain function. Diabetes 63:2232–2243

    Article  PubMed  PubMed Central  Google Scholar 

  3. Grillo CA, Piroli GG, Lawrence RC, Wrighten SA, Green AJ, Wilson SP, Sakai RR, Kelly SJ, et al. (2015) Hippocampal insulin resistance impairs spatial learning and synaptic plasticity. Diabetes.

  4. Kleinridders A, Cai W, Cappellucci L, Ghazarian A, Collins WR, Vienberg SG, Pothos EN, Kahn CR (2015) Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proc Natl Acad Sci U S A 112:3463–3468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kullmann S, Heni M, Veit R, Scheffler K, Machann J, Haring HU, Fritsche A, Preissl H (2015) Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults. Diabetes Care 38:1044–1050

    Article  CAS  PubMed  Google Scholar 

  6. Rafacho A, Ortsater H, Nadal A, Quesada I (2014) Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes. J Endocrinol 223:R49–R62

    Article  CAS  PubMed  Google Scholar 

  7. Park S, Jang JS, Jun DW, Hong SM (2005) Exercise enhances insulin and leptin signaling in the cerebral cortex and hypothalamus during dexamethasone-induced stress in diabetic rats. Neuroendocrinology 82:282–293

    Article  CAS  PubMed  Google Scholar 

  8. Juruena MF, Cleare AJ, Pariante CM (2004) The hypothalamic pituitary adrenal axis, glucocorticoid receptor function and relevance to depression. Rev Bras Psiquiatr 26:189–201

    Article  PubMed  Google Scholar 

  9. Garcia-Caceres C, Quarta C, Varela L, Gao Y, Gruber T, Legutko B, Jastroch M, Johansson P et al (2016) Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell 166:867–880

    Article  CAS  PubMed  Google Scholar 

  10. Schwartz MW, Sipols AJ, Marks JL, Sanacora G, White JD, Scheurink A, Kahn SE, Baskin DG et al (1992) Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology 130:3608–3616

    Article  CAS  PubMed  Google Scholar 

  11. Sato I, Arima H, Ozaki N, Watanabe M, Goto M, Hayashi M, Banno R, Nagasaki H et al (2005) Insulin inhibits neuropeptide Y gene expression in the arcuate nucleus through GABAergic systems. J Neurosci 25:8657–8664

    Article  CAS  PubMed  Google Scholar 

  12. Zhang J (2007) The direct involvement of SirT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphorylation. J Biol Chem 282:34356–34364

    Article  CAS  PubMed  Google Scholar 

  13. Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers MG Jr, Seeley RJ, Schwartz MW (2003) Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52:227–231

    Article  CAS  PubMed  Google Scholar 

  14. Mayer CM, Belsham DD (2009) Insulin directly regulates NPY and AgRP gene expression via the MAPK MEK/ERK signal transduction pathway in mHypoE-46 hypothalamic neurons. Mol Cell Endocrinol 307:99–108

    Article  CAS  PubMed  Google Scholar 

  15. Morley JE (1987) Neuropeptide regulation of appetite and weight. Endocr Rev 8:256–287

    Article  CAS  PubMed  Google Scholar 

  16. He J, Xu C, Kuang J, Liu Q, Jiang H, Mo L, Geng B, Xu G (2015) Thiazolidinediones attenuate lipolysis and ameliorate dexamethasone-induced insulin resistance. Metabolism 64:826–836

    Article  CAS  PubMed  Google Scholar 

  17. Kuo LE, Czarnecka M, Kitlinska JB, Tilan JU, Kvetnansky R, Zukowska Z (2008) Chronic stress, combined with a high-fat/high-sugar diet, shifts sympathetic signaling toward neuropeptide Y and leads to obesity and the metabolic syndrome. Ann N Y Acad Sci 1148:232–237

    Article  PubMed  PubMed Central  Google Scholar 

  18. Calogero AE, Liapi C, Chrousos GP (1991) Hypothalamic and suprahypothalamic effects of prolonged treatment with dexamethasone in the rat. J Endocrinol Investig 14:277–286

    Article  CAS  Google Scholar 

  19. Shimizu H, Arima H, Ozawa Y, Watanabe M, Banno R, Sugimura Y, Ozaki N, Nagasaki H et al (2010) Glucocorticoids increase NPY gene expression in the arcuate nucleus by inhibiting mTOR signaling in rat hypothalamic organotypic cultures. Peptides 31:145–149

    Article  CAS  PubMed  Google Scholar 

  20. Popoli M, Yan Z, McEwen BS, Sanacora G (2013) The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 13:22–37

    Google Scholar 

  21. Rhoads DE, DiRocco RJ, Osburn LD, Peterson NA, Raghupathy E (1984) Stimulation of synaptosomal uptake of neurotransmitter amino acids by insulin: possible role of insulin as a neuromodulator. Biochem Biophys Res Commun 119:1198–1204

    Article  CAS  PubMed  Google Scholar 

  22. Delgado TC (2013) Glutamate and GABA in appetite regulation. Front Endocrinol (Lausanne) 4:103

    Google Scholar 

  23. Meguid MM, Fetissov SO, Varma M, Sato T, Zhang L, Laviano A, Rossi-Fanelli F (2000) Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition 16:843–857

    Article  CAS  PubMed  Google Scholar 

  24. Kinote A, Faria JA, Roman EA, Solon C, Razolli DS, Ignacio-Souza LM, Sollon CS, Nascimento LF et al (2012) Fructose-induced hypothalamic AMPK activation stimulates hepatic PEPCK and gluconeogenesis due to increased corticosterone levels. Endocrinology 153:3633–3645

    Article  CAS  PubMed  Google Scholar 

  25. De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146:4192–4199

    Article  CAS  PubMed  Google Scholar 

  26. El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS (2000) Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 105:1827–1832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Melnyk RB (1987) Decreased binding to hypothalamic insulin receptors in young genetically obese rats. Physiol Behav 40:237–241

    Article  CAS  PubMed  Google Scholar 

  28. Belani M, Purohit N, Pillai P, Gupta S, Gupta S (2014) Modulation of steroidogenic pathway in rat granulosa cells with subclinical Cd exposure and insulin resistance: an impact on female fertility. Biomed Res Int 2014:460251

    Article  PubMed  PubMed Central  Google Scholar 

  29. Duncan M, Singh B, Wise P, Carter G, Zadeh J (1995) A simple measure of insulin resistance. Lancet 346:120–121

    Article  CAS  PubMed  Google Scholar 

  30. Katyare SS, Pandya JD (2005) A simplified fluorimetric method for corticosterone estimation in rat serum, tissues and mitochondria. Indian J Biochem Biophys 42:48–53

    CAS  PubMed  Google Scholar 

  31. Silber RH, Busch RD, Oslapas R (1958) Practical procedure for estimation of corticosterone or hydrocortisone. Clin Chem 4:278–285

    CAS  PubMed  Google Scholar 

  32. Wingerd BD, and Stein G (1988) Rat dissection manual (Johns Hopkins University Press).

  33. Chiu K, Lau W, Lau H, So K-F, Chang R-C (2007) Micro-dissection of rat brain for RNA or protein extraction from specific brain region journal of visualized experiments: JoVE 7.

  34. Bhattacharyya S, Khanna S, Chakrabarty K, Mahadevan A, Christopher R, Shankar SK (2009) Anti-brain autoantibodies and altered excitatory neurotransmitters in obsessive-compulsive disorder. Neuropsychopharmacology 34:2489–2496

    Article  CAS  PubMed  Google Scholar 

  35. Reinhoud NJ, Brouwer HJ, van Heerwaarden LM, Korte-Bouws GA (2013) Analysis of glutamate, GABA, noradrenaline, dopamine, serotonin, and metabolites using microbore UHPLC with electrochemical detection. ACS Chem Neurosci 4:888–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kilcoyne M, Gerlach JQ, Farrell MP, Bhavanandan VP, Joshi L (2011) Periodic acid-Schiff’s reagent assay for carbohydrates in a microtiter plate format. Anal Biochem 416:18–26

    Article  CAS  PubMed  Google Scholar 

  37. Ward CW, Menting JG, Lawrence MC (2013) The insulin receptor changes conformation in unforeseen ways on ligand binding: sharpening the picture of insulin receptor activation. BioEssays 35:945–954. doi:10.1002/bies 201370111

    Article  CAS  PubMed  Google Scholar 

  38. Derakhshan F, Toth C (2013) Insulin and the brain. Curr Diabetes Rev 9:102–116

    PubMed  Google Scholar 

  39. Sakoda H, Ogihara T, Anai M, Funaki M, Inukai K, Katagiri H, Fukushima Y, Onishi Y, et al (2000) Dexamethasone-induced insulin resistance in 3 T3-L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction. Diabetes 49:1700–1708

  40. Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P (1995) Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin a. J Clin Invest 96:1698–1705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Miller AH, Spencer RL, Pulera M, Kang S, McEwen BS, Stein M (1992) Adrenal steroid receptor activation in rat brain and pituitary following dexamethasone: implications for the dexamethasone suppression test. Biol Psychiatry 32:850–869

    Article  CAS  PubMed  Google Scholar 

  42. Yin W, Gore AC (2010) The hypothalamic median eminence and its role in reproductive aging. Ann N Y Acad Sci 1204:113–122

    Article  PubMed  PubMed Central  Google Scholar 

  43. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR et al (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimers Dis 7:63–80

    Article  CAS  PubMed  Google Scholar 

  44. Mastaitis JW, Wurmbach E, Cheng H, Sealfon SC, Mobbs CV (2005) Acute induction of gene expression in brain and liver by insulin-induced hypoglycemia. Diabetes 54:952–958

    Article  CAS  PubMed  Google Scholar 

  45. Cotero VE, Routh VH (2009) Insulin blunts the response of glucose-excited neurons in the ventrolateral-ventromedial hypothalamic nucleus to decreased glucose. Am J Physiol Endocrinol Metab 296:E1101–E1109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shimizu H, Arima H, Watanabe M, Goto M, Banno R, Sato I, Ozaki N, Nagasaki H et al (2008) Glucocorticoids increase neuropeptide Y and agouti-related peptide gene expression via adenosine monophosphate-activated protein kinase signaling in the arcuate nucleus of rats. Endocrinology 149:4544–4553

    Article  CAS  PubMed  Google Scholar 

  47. Klockener T, Hess S, Belgardt BF, Paeger L, Verhagen LA, Husch A, Sohn JW, Hampel B et al (2011) High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat Neurosci 14:911–918

    Article  PubMed  PubMed Central  Google Scholar 

  48. Barthel A, Okino ST, Liao J, Nakatani K, Li J, Whitlock JP Jr, Roth RA (1999) Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem 274:20281–20286

    Article  CAS  PubMed  Google Scholar 

  49. Chari M, Yang CS, Lam CK, Lee K, Mighiu P, Kokorovic A, Cheung GW, Lai TY et al (2011) Glucose transporter-1 in the hypothalamic glial cells mediates glucose sensing to regulate glucose production in vivo. Diabetes 60:1901–1906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Qi W-w, Zhong L-y, Li X-r, Li G, Liu Z-x, Hu J-f, Chen N-h (2012) Hyperglycemia induces the variations of 11-hydroxysteroid dehydrogenase type 1 and peroxisome proliferator-activated receptor—G expression in hippocampus and hypothalamus of diabetic rats. Exp Diabetes Res 2012:107130

    Article  PubMed  PubMed Central  Google Scholar 

  51. Sarruf DA, Yu F, Nguyen HT, Williams DL, Printz RL, Niswender KD, Schwartz MW (2009) Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis. Endocrinology 150:707–712

    Article  CAS  PubMed  Google Scholar 

  52. Lu M, Sarruf DA, Talukdar S, Sharma S, Li P, Bandyopadhyay G, Nalbandian S, Fan W et al (2011) Brain PPAR-gamma promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat Med 17:618–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Obel LF, Muller MS, Walls AB, Sickmann HM, Bak LK, Waagepetersen HS, Schousboe A (2012) Brain glycogen-new perspectives on its metabolic function and regulation at the subcellular level. Front Neuroenergetics 4:1–15

    Article  Google Scholar 

  54. Halse R, Bonavaud SM, Armstrong JL, McCormack JG, Yeaman SJ (2001) Control of glycogen synthesis by glucose, glycogen, and insulin in cultured human muscle cells. Diabetes 50:720–726

    Article  CAS  PubMed  Google Scholar 

  55. Krssak M, Brehm A, Bernroider E, Anderwald C, Nowotny P, Dalla Man C, Cobelli C, Cline GW et al (2004) Alterations in postprandial hepatic glycogen metabolism in type 2 diabetes. Diabetes 53:3048–3056

    Article  CAS  PubMed  Google Scholar 

  56. Tavoni TM, Obici S, de Castro RMA, Minguetti-Camara VC, Curi R, Bazotte RB (2013) Evaluation of liver glycogen catabolism during hypercortisolism induced by the administration of dexamethasone in rats. Pharmacol Rep 65:144–151

    Article  CAS  PubMed  Google Scholar 

  57. Allaman I, Pellerin L, Magistretti PJ (2004) Glucocorticoids modulate neurotransmitter-induced glycogen metabolism in cultured cortical astrocytes. J Neurochem 88:900–908

    Article  CAS  PubMed  Google Scholar 

  58. Tong Q, Ye CP, Jones JE, Elmquist JK, Lowell BB (2008) Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci 11:998–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wu Q, Boyle MP, Palmiter RD (2009) Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137:1225–1234

    Article  PubMed  PubMed Central  Google Scholar 

  60. van den Pol AN (2003) Weighing the role of hypothalamic feeding neurotransmitters. Neuron 40:1059–1061

    Article  PubMed  Google Scholar 

  61. Stricker-Krongrad A, Beck B, Nicolas JP, Burlet C (1992) Central effects of monosodium glutamate on feeding behavior in adult long-Evans rats. Pharmacol Biochem Behav 43:881–886

    Article  CAS  PubMed  Google Scholar 

  62. Stanley BG, Ha LH, Spears LC, Dee MG 2nd (1993) Lateral hypothalamic injections of glutamate, kainic acid, D,L-alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid or N-methyl-D-aspartic acid rapidly elicit intense transient eating in rats. Brain Res 613:88–95

    Article  CAS  PubMed  Google Scholar 

  63. Fukumoto K, Chaki S (2015) Involvement of serotonergic system in the effect of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test. J Pharmacol Sci 127:57–61

    Article  CAS  PubMed  Google Scholar 

  64. Schousboe A, Bak LK, Sickmann HM, Sonnewald U, Waagepetersen HS (2007) Energy substrates to support glutamatergic and GABAergic synaptic function: role of glycogen, glucose and lactate. Neurotox Res 12:263–268

    Article  CAS  PubMed  Google Scholar 

  65. Sickmann HM, Waagepetersen HS, Schousboe A, Benie AJ, Bouman SD (2012) Brain glycogen and its role in supporting glutamate and GABA homeostasis in a type 2 diabetes rat model. Neurochem Int 60:267–275

    Article  CAS  PubMed  Google Scholar 

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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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  1. Gitika Kharkwal

    Present address: ICMR Headquarters, Ansari Nagar, New Delhi, Delhi-110029, India

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India

    Ragitha Chruvattil, Shreya Banerjee, Sarmi Nath, Gitika Kharkwal & Sarita Gupta

  2. Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India

    Jatin Machhi & Mange Ram Yadav

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  1. Ragitha Chruvattil
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  2. Shreya Banerjee
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Correspondence to Sarita Gupta.

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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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