Injection of resistin into the paraventricular nucleus produces a cardiovascular response that may be mediated by glutamatergic transmission in the rostral ventrolateral medulla

Document Type : Original Article


1 Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

2 Department of Food Hygiene and Public Health, School of Veterinary Medicine, Shiraz University, Shiraz, Iran


Objective(s): High levels of resistin are associated with metabolic diseases and their complications, including hypertension. The paraventricular nucleus (PVN) is also involved in metabolic disorders and cardiovascular diseases, such as hypertension. Therefore, this study aimed to study cardiovascular (CV) responses evoked by the injection of resistin into the lateral ventricle (LV) and PVN and determine the mechanism of these responses in the rostral ventrolateral medulla (RVLM).
Materials and Methods: Arterial pressure (AP) and heart rate (HR) were evaluated in urethane-anesthetized male rats (1.4 g/kg intraperitoneally) before and after all injections. This study was carried out in two stages. Resistin was injected into LV at the first stage, and AP and HR were evaluated. After that, the paraventricular, supraoptic, and dorsomedial nuclei of the hypothalamus were chosen to evaluate the gene expression of c-Fos. Afterward, resistin was injected into PVN, and cardiovascular responses were monitored. Then to detect possible neural mechanisms of resistin action, agonists or antagonists of glutamatergic, GABAergic, cholinergic, and aminergic transmissions were injected into RVLM. 
Results: Resistin injection into LV or PVN could increase AP and HR compared to the control group and before injection. Resistin injection into LV also increases the activity of RVLM, paraventricular, supraoptic, and dorsomedial areas. Moreover, the CV reflex created by the administration of resistin in PVN is probably mediated by glutamatergic transmission within RVLM. 
Conclusion: It can be concluded that hypothalamic nuclei, including paraventricular, are important central areas for resistin actions, and glutamatergic transmission in RVLM may be one of the therapeutic targets for high AP in obese people or with metabolic syndrome.


Main Subjects

1. Verberne AJM, Owens NC. Cortical modulation of thecardiovascular system. Prog Neurobiol 1998; 54:149-168.
2. Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci 2006; 7:335-346.
3. Benarroch EE. Paraventricular nucleus, stress response, and cardiovascular disease. Clin Auton Res 2005; 15:254-263.
4. Hill JW. PVN pathways controlling energy homeostasis. Indian J Endocrinol Metab 2012; 16:S627-636.
5. Ferguson AV, Latchford KJ, Samson WK. The paraventricular nucleus of the hypothalamus-a potential target for integrative treatment of autonomic dysfunction. Expert Opin Ther Targets 2008; 12:717-727.
6. Rasoulinejad SA, Akbari A, Nasiri K. Interaction of miR-146a-5p with oxidative stress and inflammation in complications of type 2 diabetes mellitus in male rats: Anti-oxidant and anti-inflammatory protection strategies in type 2 diabetic retinopathy. Iran J Basic Med Sci 2021; 24:1078-1086.
7. Dampney RA, Michelini LC, Li D-P, Pan H-L. Regulation of sympathetic vasomotor activity by the hypothalamic paraventricular nucleus in normotensive and hypertensive states. Am J Physiol Heart Circ Physiol 2018; 315:H1200-H1214.
8. Shafton AD, Ryan A, Badoer E. Neurons in the hypothalamic paraventricular nucleus send collaterals to the spinal cord and to the rostral ventrolateral medulla in the rat. Brain Res 1998; 801:239-243.
9. Gabor A, Leenen FHH. Central neuromodulatory pathways regulating sympathetic activity in hypertension. J Appl Physiol 2012; 113:1294-1303.
10. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature 2001; 409:307-312.
11. Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun 2001; 285:561-564.
12. Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, Plumpton C, et al. Resistin is expressed in human macrophages and directly regulated by PPARγ activators. Biochem Biophys Res Commun 2003; 300:472-476.
13. Morash BA, Ur E, Wiesner G, Roy J, Wilkinson M. Pituitary resistin gene expression: effects of age, gender and obesity. Neuroendocrinology 2004; 79:149-156.
14. Ling C, Kindblom J, Wennbo H, Billig H. Increased resistin expression in the adipose tissue of male prolactin transgenic mice and in male mice with elevated androgen levels. FEBS Lett 2001; 507:147-150.
15. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Tumor necrosis factor α is a negative regulator of resistin gene expression and secretion in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2001; 288:1027-1031.
16. Butler J, Kalogeropoulos A, Georgiopoulou V, de Rekeneire N, Rodondi N, Smith AL, et al. Serum resistin concentrations and risk of new onset heart failure in older persons the health, aging, and body composition (Health ABC) study. Arterioscler Thromb Vasc Biol 2009; 29:1144-1149.
17. Frankel DS, Vasan RS, D’Agostino RB, Benjamin EJ, Levy D, Wang TJ, et al. Resistin, adiponectin, and risk of heart failure: the Framingham offspring study. J Am Coll Cardiol 2009; 53:754-762.
18. Bhalla V, Kalogeropoulos A, Georgiopoulou V, Butler J. Serum resistin: physiology, pathophysiology and implications for heart failure. Biomarkers 2010; 4:445-452.
19. Fisher JP, Young CN, Fadel PJ. Central sympathetic overactivity: maladies and mechanisms. Auton Neurosci 2009; 148:5-15.
20. Esler M, Rumantir M, Wiesner G, Kaye D, Hastings J, Lambert G. Sympathetic nervous system and insulin resistance: From obesity to diabetes. Am J hypertens 2001; 14:304S-309S.
21. Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, et al. FIZZ1, a novel cysteine‐rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J 2000; 19:4046-4055.
22. Benomar Y, Gertler A, De Lacy P, Crepin D, Ould Hamouda H, Riffault L, et al. Central resistin overexposure induces insulin resistance through Toll-like receptor 4. Diabetes 2013; 62:102-114.
23. Miao J, Benomar Y, Al Rifai S, Poizat G, Riffault L, Crepin D, et al. Resistin inhibits neuronal autophagy through Toll-like receptor 4. J Endocrinol 2018; 238:77-89.
24. Berghoff M, Hochberg A, Schmid A, Schlegel J, Karrasch T, Kaps M, et al. Quantification and regulation of the adipokines resistin and progranulin in human cerebrospinal fluid. Eur J Clin Invest 2016; 46:15-26.
25. Kos K, Harte AL, da Silva NF, Tonchev A, Chaldakov G, James S, et al. Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin receptors in the human hypothalamus. J Clin Endocrinol Metab 2007; 92:1129-1136.
26. Tovar S, Nogueiras R, Tung LYC, Castaneda TR, Vázquez MaJs, Morris A, et al. Central administration of resistin promotes short-term satiety in rats. Eur J Endocrinol 2005; 153:R1-R5.
27. Vazquez MJ, González CR, Varela L, Lage R, Tovar S, Sangiao-Alvarellos S, et al. Central resistin regulates hypothalamic and peripheral lipid metabolism in a nutritional-dependent fashion. Endocrinology 2008; 149:4534-4543.
28. Singhal NS, Lazar MA, Ahima RS. Central resistin induces hepatic insulin resistance via neuropeptide Y. J Neurosci 2007; 27:12924-12932.
29. Muse ED, Lam TKT, Scherer PE, Rossetti L. Hypothalamic resistin induces hepatic insulin resistance. J Clin Invest 2007; 117:1670-1678.
30. Akbari A, Jelodar G. Central administration of resistin into the paraventricular nucleus (PVN) produces significant cardiovascular responses. Physiol Pharmacol 2017; 21 216-224.
31. Akbari A, Jelodar G. Cardiovascular responses produced by resistin injected into paraventricular nucleus mediated by the glutamatergic and CRFergic transmissions within rostral ventrolateral medulla. Iran J Basic Med Sci 2020; 23:344-353.
32. Dampney R, Horiuchi J. Functional organisation of central cardiovascular pathways: Studies using c-fos gene expression. Prog Neurobiol 2003; 71:359-384.
33. Harris JA. Using c-fos as a neural marker of pain. Brain Res Bullet 1998; 45:1-8.
34. Kosari S, Rathner JA, Chen F, Kosari S, Badoer E. Centrally administered resistin enhances sympathetic nerve activity to the hindlimb but attenuates the activity to brown adipose tissue. Endocrinology 2011; 152:2626-2633.
35. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. Elsevier 2005:39-48.
36. Hahn JD, Swanson LW. Connections of the lateral hypothalamic area juxtadorsomedial region in the male rat. J Comp Neurol 2012; 520:1831-1890.
37. Habeeballah H, Alsuhaymi N, Stebbing MJ, Jenkins TA, Badoer E. Central administration of insulin and leptin together enhance renal sympathetic nerve activity and fos production in the arcuate nucleus. Front Physiol 2016; 7:672-681.
38. Kosari S, Rathner JA, Badoer E. Central resistin enhances renal sympathetic nerve activity via phosphatidylinositol 3‐kinase but reduces the activity to brown adipose tissue via extracellular signal‐regulated kinase 1/2. J Neuroendocrinol 2012; 24:1432-1439.
39. Rodriguez-Pacheco F, Vazquez-Martinez R, Martínez-Fuentes AJ, Pulido MR, Gahete MD, Vaudry H, et al. Resistin regulates pituitary somatotrope cell function through the activation of multiple signaling pathways. Endocrinol 2009; 150:4643-4652.
40. Shen YH, Zhang L, Gan Y, Wang X, Wang J, LeMaire SA, et al. Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells. J Biol Chem 2006; 281:7727-7736.
41. Badoer E, Kosari S, Stebbing MJ. Resistin, an Adipokine with Non-Generalized Actions on Sympathetic Nerve Activity. Front Physiol 2015; 6:321-321.
42. Takeishi Y, Niizeki T, Arimoto T, Nozaki N, Hirono O, Nitobe J, et al. Serum resistin is associated with high risk in patients with congestive heart failure a novel link between metabolic signals and heart failure. Circ J 2007; 71:460-464.
43. Busnardo C, Crestani CC, Tavares RF, Resstel LBM, Correa FMA. Cardiovascular responses to L-glutamate microinjection into the hypothalamic paraventricular nucleus are mediated by a local nitric oxide-guanylate cyclase mechanism. Brain Res 2010; 1344:87-95.
44. Busnardo C, Tavares RF, Corrêa FMA. Role of N‐methyl‐D‐aspartate and non‐N‐methyl‐D‐aspartate receptors in the cardiovascular effects of L‐glutamate microinjection into the hypothalamic paraventricular nucleus of unanesthetized rats. J Neurosci Res 2009; 87:2066-2077.
45. Kannan H, Niijima A, Yamashita H. Effects of stimulation of the hypothalamic paraventricular nucleus on blood pressure and renal sympathetic nerve activity. Brain Res Bullet 1988; 20:779-783.
46. Daftary SS, Boudaba C, Tasker JG. Noradrenergic regulation of parvocellular neurons in the rat hypothalamic paraventricular nucleus. Neurosci 2000; 96:743-751.
47. Wilkinson M, Wilkinson D, Wiesner G, Morash B, Ur E. Hypothalamic resistin immunoreactivity is reduced by obesity in the mouse: Co-localization with α-melanostimulating hormone. Neuroendocrinol 2005; 81:19-30.
48. Brunetti L, Orlando G, Recinella L, Michelotto B, Ferrante C, Vacca M. Resistin, but not adiponectin, inhibits dopamine and norepinephrine release in the hypothalamus. Eur J Pharmacol 2004; 493:41-44.
49. Deuchars SA, Lall VK. Sympathetic preganglionic neurons: Properties and inputs. Compr Physiol 2015; 5:829-869.
50. Hosoya Y, Sugiura Y, Okado N, Loewy AD, Kohno K. Descending input from the hypothalamic paraventricular nucleus to sympathetic preganglionic neurons in the rat. Exp Brain Res 1991;85:10-20.
51.Benarroch EE. Central autonomic control. Primer on the Autonomic Nervous System (Third Edition): Elsevier; 2012. p. 9-12.
52. Tjen-A-Looi SC, Guo Z-L, Fu L-W, Longhurst JC. Paraventricular nucleus modulates excitatory cardiovascular reflexes during electroacupuncture. Sci Rep 2016; 6:25910-25910.
53. Horiuchi J, Dampney R. Evidence for tonic disinhibition of RVLM sympathoexcitatory neurons from the caudal pressor area. Auton Neurosci 2002; 99:102-110.
54. Koganezawa T, Shimomura Y, Terui N. The role of the RVLM neurons in the viscero-sympathetic reflex: A mini review. Auton Neurosci 2008; 142:17-19.
55. Peng Y-J, Wang N, Gong Q-L, Li P. Caudal ventrolateral medulla mediates the depressor response elicited by the greater splanchnic nerve afferent stimulation in rats. Neurosci Lett 2002; 325:134-138.
56. Akine A, Montanaro M, Allen AM. Hypothalamic paraventricular nucleus inhibition decreases renal sympathetic nerve activity in hypertensive and normotensive rats. Auton Neurosci 2003; 108:17-21.
57. Menezes RC, Fontes MA. Cardiovascular effects produced by activation of GABA receptors in the rostral ventrolateral medulla of conscious rats. Neuroscience 2007; 144:336-343.
58. Kubo T, Hagiwara Y, Sekiya D, Chiba S, Fukumori R. Cholinergic inputs to rostral ventrolateral medulla pressor neurons from hypothalamus. Brain Res Bullet 2000; 53:275-282.
59. Kubo T, Taguchi K, Sawai N, Ozaki S, Hagiwara Y. Cholinergic mechanisms responsible for blood pressure regulation on sympathoexcitatory neurons in the rostral ventrolateral medulla of the rat. Brain Res Bullet 1997; 42:199-204.
60. Sun M, Guyenet PG. Hypothalamic glutamatergic input to medullary sympathoexcitatory neurons in rats. Am J Physiol 1986; 251:R798-R810.
61. Zhou W, Fu L-W, Tjen-A-Looi SC, Guo Z-l, Longhurst JC. Role of glutamate in a visceral sympathoexcitatory reflex in rostral ventrolateral medulla of cats. Am J Physiol Heart Circ Physiol 2006; 291:H1309-H1318.
62. Averill DB, Tsuchihashi T, Khosla MC, Ferrario CM. Losartan, nonpeptide angiotensin II-type 1 (AT1) receptor antagonist, attenuates pressor and sympathoexcitatory responses evoked by angiotensin II andL-glutamate in rostral ventrolateral medulla. Brain Res 1994; 665:245-252.
63. Ito S, Hiratsuka M, Komatsu K, Tsukamoto K, Kanmatsuse K, Sved AF. Ventrolateral medulla AT1 receptors support arterial pressure in Dahl salt-sensitive rats. Hypertension 2003; 41:744-750.