The effects of losartan on memory performance and leptin resistance induced by obesity and high-fat diet in adult male rats

Document Type : Original Article


1 Islamic Azad University, Kazerun Branch, Department of Physiology, Kazerun, Iran

2 Islamic Azad University, Zarghan Branch, Iran



Leptin is a hormone secreted by adipose tissue and is involved not only in the regulation of feeding and energy expenditure, but also its role in memory enhancement has been demonstrated as well. The partial transfer of leptin across the blood-brain barrier in obese individuals causes leptin resistance and prevents leptin reaching brain. On the other hand, studies have shown that angiotensin antagonists such as losartan can improve memory and learning abilities. The aim of this study was to evaluate the effects of losartan on improving memory and leptin resistance induced by high fat diet in obese rats.
Materials and Methods:
40 Wistar male rats were divided in 4 groups: control (C), losartan (LOS), high-fat diet (HFD) and high-fat diet and losartan (HFD and LOS). The spatial memory performances of the rats were assessed in the Morris water maze after 2 months of treatment. Then they were weighed and serum levels of leptin and triglyceride were measured.
In spite of receiving high-fat diet, no significant differences in body weight were observed in the (HFD & LOS) group. In the Morris water maze trial, the (LOS) and (HFD & LOS) groups also showed a significant reduction (P <0.05) in latency and path length. In addition, a significant decrease (P
<0.05) in serum levels of leptin and no significant difference in serum levels of triglyceride was observed in the (HFD & LOS) group.
Losartan can improve leptin resistance induced by obesity and high fat diet. At the same time, it modulates body weight and enhances learning and memory.


1. Breteler MMB, Claus JJ, Grobbee DE, Hofman A. Cardiovascular disease and distribution of cognitive function in elderly people: the Rotterdam study. BMJ 1994; 308:1604–1608.
Sharieh Hosseini et al Losartan, leptin resistance and memory performance
Iran J Basic Med Sci, Vol. 17, No. 1, Jan 2014 47
2. Elias MF, Wolf PA, D’Agostino RB, Cobb J, White LR. Untreated blood pressure level is inversely related to cognitive functioning: the Framingham study. Am J Epidemiol 1993; 138:353–364.
3. Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association between midlife blood pressure levels and late life cognitive function. JAMA 1995; 274:1846–1851.
4. Llorens-Cortes C, Mendelsohn FA. Organization and functional role of the brain angiotensin system. J Renin Angiotensin Aldosterone Syst 2002; 1:39-48
5. Allen AM , Oldfield BJ , Giles ME , Paxinos G , McKinley MJ, Mendelsohn FAO. Localization of angiotensin receptors in the nervous system. J Am Soc Nephrol 2000; 11:S23-29.
6. Bader M, Ganten D. It’s renin in the brain:Transgenic animals elucidate the brain renin–angiotensin system. Circ Res 2002; 90:8–10 .
7. Ciobica A, Bild W, Hritcu L, Haulica I. Brain renin-angiotensin system in cognitive function: pre-clinical findings and implications for prevention and treatment of dementia. Acta Neurol Belg 2009; 109:171-180.
8. Kerr DS, Bevilaqua LR, Bonini JS, Rossato JI, Kohler CA, Medina JH
, et al. Angiotensin II blocks memory consolidation through an AT2 receptor dependent mechanism. Psychopharmacology (Berl) 2005; 179:529-535.
9. Braszko JJ. AT (2) but not AT (1) receptor antagonism abolishes angiotensin II increase of the acquisition of conditioned avoidance responses in rats. Behav Brain Res 2002; 131:79-86.
10. Kerr DS, Bevilaqua LR, Bonini JS, Rossato JI, Kohler CA, Medina JH,
et al. Angiotensin II blocks memory consolidation through an AT2 receptor dependent mechanism. Psychopharmacology (Berl) 2005; 179:529-535.
11. Bonini JS, Bevilaqua LR, Zinn CG, Kerr DS, Medina JH, Izquierdo I,
et al. Angiotensin II disrupts inhibitory avoidance memory retrieval. Horm Behav 2006; 50:308-313.
12. Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1998; 1:619-625.
13. Campfield LA. The role of pharmacological agents in treatment of obesity. In:Weston LA, Savage LM. editors. In Obesity: Advances in Understanding and Treatment. Southborough: International Business Communications; Inc; 1996.p.432-441.
14.Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR,
et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334:292-295.
15. Guo ZH, Jiang HY, Xu XR, Duan WZ, Mattson MP. Leptin-mediated cell survival signaling in hippocampal neurons mediated by JAK STAT3 and mitochondrial stabilization. J Biol Chem 2008; 283:1754-1763.
16. Matochik JA, London ED, Yildiz BO, Ozata M, Caglayan S, DePaoli AM,
et al. Effect of leptin replacement on brain structure in genetically leptin-deficient adults. J Clin Endocrinol Metab 2005; 90:2851–2854.
17. Harvey J, Shanley LJ, O'Malley D, Irving AJ. Leptin: a potential cognitive enhancer? Biochem Soc Trans 2005; 33:1029-1032.
18. Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience 2002; 113:607-615.
19. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D,
et al. Weight-reducing effects of the plasma-protein encoded by the obese. Gene Sci 1995; 269:543–546 .
20. Campfield LA, Smith FJ. Overview: neurobiology of OB protein (leptin). Proc Nutr Soc 1998; 57:429-440.
21. Azam R, Parvaneh N, Mahdi H. Comparing effects of aerobics, pilates exercises and low calorie diet on leptin levels and lipid profiles in sedentary women. Iran J Basic Med Sci 2010; 14:256-263
22. Story DF, Ziogas J. Interaction of angiotensin with noradrenergic neuroeffector transmission. Trends Pharmacol Sci 1987; 8:269-271.
23. Wang Z, Zhou YT, Kakuma T, Lee Y, Kalra SP, Kalra PS,
et al. Leptin resistance of adipocytes in obesity: role of suppressors of cytokine signaling. Biochem Biophys Res Commun 2000; 277:20-26 .
24. Banks WA, Coon AB, Robinson SM, Moinuddin A, Shultz JM, Nakaoke R,
et al. Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes 2004; 53:1253–1260.
25. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR,
et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334:292–295.
26. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y,
et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1:1155–1161.
27. Horowitz JF, Klein S. Whole body and abdominal lipolytic sensitivity to epinephrine is suppressed in upper body obese women. Am J Physiol Endocrinol Metab 2000; 278:E1144-1152 .
28. Valet P, Grujic D, Wade J, Ito M, Zingaretti MC, Soloveva V,
et al. Expression of human alpha 2-adrenergic receptors in adipose tissue of beta 3-adrenergic receptor-deficient mice promotes dietinduced obesity. J Biol Chem 2000; 275:34797-34802 .
29. Phillips MI, De Oliveira EM. Brain renin angiotensin in disease. J Mol Med 2008; 86:715-22 .
30. Savaskan E, Hock C, Olivieri G, Bruttel S, Rosenberg C, Hulette C,
et al. Cortical alterations of angiotensin converting enzyme, angiotensin II and AT1 receptor in Alzheimer’s dementia. Neurobiol Aging 2001; 22:541-546.
31. Ge J, Barnes NM. Alterations in angiotensin AT1 and AT2 receptor subtype levels in brain regions from patients with neurodegenerative disorders. Eur J Pharmacol 1996; 297:299-306.
32. NRC (National Research Council). 1995a. Nutrient Requirements of Laboratory Animals, 4
th rev ed. Washington (D.C.): National Academy Press.
33. Rothwell NJ, Stock MJ. A role for brown adipose tissue in diet-induced thermogenesis. Nature (Lond.) 1979; 281:31-35.
34. Harris RB. The impact of high or low fat cafeteria foods on nutrient intake and growth of rats consuming a diet containing 30% energy as fat. Int J Obes Relat Metab Disord 1993; 17:307-315 .
Losartan, leptin resistance and memory performance Sharieh Hosseini et al
Iran J Basic Med Sci, Vol. 17, No. 1, Jan 2014 48
35. Rudi D’Hooge, Peter P De Deyn. Applications of the Morris water maze in the study of learning and Memory. Brain Res Rev 2001; 36:60–90.
36. Rahmouni K, Haynes WG, Morgan DA, Mark AL. Intracellular mechanisms involved in leptin regulation of sympathetic outflow. Hypertension 2003; 41:763–767.
37. Giacchetti G , Opocher G , Sarzani R , Rappelli A, Mantero F. Angiotensin II and the adrenal. Clin Exp Pharmacol Physiol 1996; 3:119-124.
38. Saxena PR. Interaction between the rennin-angiotensin-aldosterone and sympathetic nervous systems. J Cardiovasc Pharmacol 1992; 6:80-88.
39. Dicou E, Attoub S, Gressens P. Neuroprotective effects of leptin i
n vivo and in vitro. Neuroreport 2001; 12:3947–3951 .
40. Von Bohlen und Halbach O, Albrecht D. The CNS reninangiotensin system. Cell Tissue Res 2006; 326:599-616 .
41. Russo VC, Metaxas S, Kobayashi K, Harris M, Werther GA. Antiapoptotic effects of leptin in human neuroblastoma cells. Endocrinology 2004; 145:4103–4112.
42. Weng Z, Signore AP, Gao Y, Wang S, Zhang F, Hastings T,
et al. Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling. J Biol Chem 2007; 282:34479–34491.
43. Farr SA, Banks WA, Morley JE. Effects of leptin on memory processing. Peptides 2006; 27:1420-1425.
44. Oomura Y, Hori N, Shiraishi T, Fukunaga K, Takeda H, Tsuji M,
et al. Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats. Peptides 2006; 27:2738-2749.
45. Wayner MJ, Armstrong DL, Phelix CF, Oomura Y. Orexin-A (Hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats
in vivo. Peptides 2004; 25:991-996.
46. Shanley LJ, Irving AJ, Harvey J. Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. J Neurosci 2001; 21:RC186.
47. Bliss TV, Collingridge GL: A synaptic model of memory: longterm potentiation in the hippocampus. Nature 1993; 361:31-39.
48. Durakoglugil M, Irving AJ, Harvey J. Leptin induces a novel form of NMDA receptor-dependent long-term depression. J Neurochem 2005; 95:396-405.
49. Harvey J. Leptin regulation of neuronal excitability and cognitive function. Curr Opin Pharmacol 2007; 7:643–667.
50. Elias MF, Elias PK, Sullivan LM, Wolf PA, D’Agostino RB. Lower cognitive function in the presence of obesity and hypertension: the Framingham heart study. Int J Obes Relat Metab Disord 2003; 27:260–268.
51. Jeong SK, NamHS, Son MH, Son EJ, ChoK H. Interactive effect of obesity indexes on cognition. Dement Geriatr Cogn Disord 2005; 19:91–96.
52. Barnes NM, Costall B, Kelly ME, Murphy DA, Naylor RJ. Cognitive enhancing actions of PD123177 detected in a mouse habituation paradigm. Neuroreport 1991; 2:351-353.
53. DeNoble VJ, DeNoble KF, Spencer KR, Chiu AT, Wong PC, Timmermans PB. Non-peptide angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor: effect on a renin-induced deficit of a passive avoidance response in rats. Brain Res 1991; 561:230-235.
54. Indumathy S, Kavimani S, Raman KV. Role of renin Angiotensin system in memory enhancement. Int J Pharm Bio Sci 2010; 1.
55. Braszko JJ. AT(2) but not AT(1) receptor antagonism abolishes angiotensin II increase of the acquisition of conditioned avoidance responses in rats. Behav Brain Res 2002; 131:79-86
56. Davis CJ, Kramar EA, De A, Meighan PC, Simasko SM, Wright JW
, et al. AT4 receptor activation increases intracellular calcium influx and induces a non-N-methyl-D-aspartate dependent form of long-term potentiation . Neuroscience 2006; 137:1369-1379 .
57. Chai SY, Bastias MA, Clune EF, Matsacos DJ, Mustafa T, Lee JH,
et al. Distribution of angiotensin IV binding sites (AT4 receptor) in the human forebrain, midbrain and pons as visualized by in vitro receptor autoradiography. J Chem Neuroanat 2000; 20:339-348 .
58. Lee J, Chai SY, Mendelsohn FA, Morris MJ, Allen AM. Potentiation of cholinergic transmission in the rat hippocampus by angiotensin IV and LVV-hemorphin-7. Neuropharmacology 2001; 40:618-623.
59. Kramar EA, Armstrong DL, Ikeda S, Wayner MJ, Harding JW, Wright JW. The effects of angiotensin IV analogs on long-term potentiation within the CA1 region of the hippocampus in vitro. Brain Res 2001; 897:114-121.