[Home ] [Archive]    
:: Main :: Current Issue :: Archive :: Search :: Submit :: Contact ::
Main Menu
Journal Information::
Articles archive::
Indexing Sources::
For Authors::
Publication ethics::
Contact us::
Site Facilities::
Creative Commons License

This Journal under a

Creative Commons Attribution-NonCommercial 4.0 International License.

Open Access Policy




Registered in



:: Volume 5, Issue 2 (Apr-Jun 2018) ::
Nutr Food Sci Res 2018, 5(2): 3-10 Back to browse issues page
The Effect of Peripheral Injection of Leptin on Biomarkers of Aging in Calorie Restricted Rats
Mona Pourghaderi , Mohammad Javad Hosseinzadeh-Attar , Mahmoud Jalali , Fereydoun Siassi , Fatemeh Nabavizadeh , Mohammad Reza Eshraghian
Tehran University of Medical Sciences , mhosseinzade@tums.ac.ir
Abstract:   (4076 Views)

Background and Objectives: Calorie restriction (CR) is one of the proven methods of extending lifespan and slowing aging. Leptin is a nutritionally regulated adipokine that has been proposed as a possible key signal in the adaptive responses relevant to CR. Under CR, plasma leptin levels decrease, thus it was hypothesized that leptin administration may counteract CR-induced weight loss. Therefore, the effect of leptin administration on modulating CR-induced alterations in some biomarkers of aging was investigated in a rat model.
Materials and Methods: Fifty male Wistar rats were fed either ad libitum (AL) or 40% calorie restricted diet for 11 weeks. Then each group randomly assigned to receive 0.5 mg/kg/day intravenous leptin or saline, for 3 days. Fasting blood glucose, insulin, and leptin levels as well as body temperature were measured at the end of the treatment.
Results: After CR, all variables including body weight, BMI, body temperature, serum levels of glucose, insulin and leptin decreased significantly compared to the AL group. After 3 days of leptin treatment, no statistically significant differences were observed in body weight, BMI, serum glucose and insulin levels compared to the saline treatment. Body temperature did not change after leptin administration in CR subgroups, but it was significantly higher in AL-leptin compared to AL-saline group.
Conclusions: Based on these findings, administration of recombinant leptin was not effective in modulating the alterations of aging biomarkers induced by calorie restriction.

Keywords: Aging, Body temperature, Calorie restriction, Insulin, Leptin
Full-Text [PDF 209 kb]   (1495 Downloads)    
Article type: Research | Subject: Nutrition
Received: 2017/11/24 | Accepted: 2018/03/10 | Published: 2018/03/10
1. Smith PR. A Historical Perspective in Aging and Gerontology. In: The Collective Spirit of aging across cultures. 2014, Springer. P: 7-27. [DOI:10.1007/978-94-017-8594-5_2]
2. Fontana L, Excessive adiposity, calorie restriction, and aging. JAMA. 2006; 295(13): 1577-8. [DOI:10.1001/jama.295.13.1577]
3. Stenholm S, Metter EJ, Roth GS, Ingram DK, Mattison JA, Taub DD, and et al. Relationship between plasma ghrelin, insulin, leptin, interleukin 6, adiponectin, testosterone and longevity in the Baltimore Longitudinal Study of Aging. Aging Clin Exp Res. 2011; 23(2): 153-8. [DOI:10.1007/BF03351078]
4. Dean DJ, Gazdag AC, Wetter TJ, Cartee GD. Comparison of the effects of 20 days and 15 months of calorie restrictionan male Fischer-344 rats. Ageing. 1998; 10(4): 303–7.
5. Gredilla R, Barja G. Minireview: The role of oxidative stress in relation to calorie restriction and longevity. Endocrinology. 2005; 146(9): 3713-7. [DOI:10.1210/en.2005-0378]
6. Kealy RD, Lawler DE, Mantz SL, Biery DN, Greely Eh, Lust G, et al. Effects of diet restriction on lifespan and age-related changes in dogs. J Am Vet Med Assoc. 2002; 220(9): 1315-20. [DOI:10.2460/javma.2002.220.1315]
7. Mattison JA, Lane MA, Roth GS, Ingram DK. Calorie restriction in rhesus monkeys. Exp Gerontol. 2003; 38(1-2): 35–46. [DOI:10.1016/S0531-5565(02)00146-8]
8. Redman LM, Ravussin E. Caloric restriction in humans: impact on physiological, psychological, and behavioral outcomes. Antioxid Redox Signal. 2011; 15; 14(2): 275-6.
9. Yu BP. Why calorie restriction would work for human longevity. Biogerontol. 2006; 7)3): 179-82.
10. Ingram DK, Zhu M, Mamczarz J, Zou S, Lane MA, Roth GS and et al. Calorie restriction mimetics: an emerging research field. Aging Cell. 2006; 5(2):97-108. [DOI:10.1111/j.1474-9726.2006.00202.x]
11. Ahima RS, Osei SY. Leptin signaling. Physiol Behav. 2004; 81(2):223-41. [DOI:10.1016/j.physbeh.2004.02.014]
12. Bartfai T, Conti B. Molecules affecting hypothalamic control of core body temperature in response to calorie intake. Front Genet. 2012; 5; 3: 184.
13. Fogteloo J, Meinders E, Frolich M, McCamish M, Pijl H. The decline in plasma leptin in response to calorie restriction predicts the effects of adjunctive leptin treatment on body weight in humans. Eur J Inter Med 2003; 14(7): 415-8. [DOI:10.1016/j.ejim.2003.08.003]
14. Mitchell SE, Delville C, Konstantopedos P, Derous D, Green CL, Chen L, and et al. The effects of graded levels of calorie restriction: III. Impact of short term calorie and protein restriction on mean daily body temperature and torpor use in the C57BL/6 mouse. Oncotarget. 2015; 6(21): 18314-37. [DOI:10.18632/oncotarget.4506]
15. Fontana L, Klein S. Aging, adiposity, and calorie restriction. JAMA. 2007; 7; 297(9): 986-94.
16. Reeves PG, Nielsen FH, Fahey GC. AIN-93 purified diets for laboratory rodents: final report of the American institute of Nutrition AdHoc Writingn Committee on the reformulation of the AIN-76A rodent diet. J Nutr. 1993; 123(11): 1939-51. [DOI:10.1093/jn/123.11.1939]
17. Pugh TD, Klopp RG, Weindruch R. Controlling caloric consumption: protocols for rodents and rhesus monkeys. Neurobiol Aging. 1999; 20 (2): 157-65. [DOI:10.1016/S0197-4580(99)00043-3]
18. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature. 1996; 382(6588): 250-2. [DOI:10.1038/382250a0]
19. Komatso T, Chiba T, Yamaza H, To K, Toyama H, Higami Y, et al. Effect of leptin on hypothalamic gene expression in calorie-restricted rats. J Gerontol. 2006; 61(9): 890-8. [DOI:10.1093/gerona/61.9.890]
20. Halaas JL, Boozer C, Blair-West J, Fidahusein N, Friedman JM. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci USA. 1997; 94 (16): 8878–83. [DOI:10.1073/pnas.94.16.8878]
21. Engelbregt MJ, Weissenbruch M, Poop-snijders C, Lips P, Waal D. Body mass index, body composition, and leptin at onset of puberty in male and female rats after intrauterine growth retardation and after early postnatal food restriction. Pediatr Res. 2001; 50(4): 474–8. [DOI:10.1203/00006450-200110000-00009]
22. Morrison CD, Daniel JA, Holmberg BJ, Djiane J, Raver N, Gertler A, and et al. Central infusion of leptin into well-fed and undernourished ewe lambs: effects on feed intake and serum concentrations of growth hormone and luteinizing hormone. J Endocrinol. 2001; 168(2): 317-24. [DOI:10.1677/joe.0.1680317]
23. Cases JA, Gabriely I, Ma XH, Yang XM, Michaeli T, Fleischer N. Physiological increase in plasma leptin markedly inhibits insulin secretion in vivo. Diabetes. 2001; 50(2): 348-52. [DOI:10.2337/diabetes.50.2.348]
24. Ramsay TG, Bush JA, McMurtry JP, Thivierge MC, Davis TA. Peripheral leptin administration alters hormone and metabolite levels in the young pig. Comp Biochem Physiol A Mol Integr Physiol. 2004; 138(1):17-25. [DOI:10.1016/j.cbpb.2004.02.005]
25. Muzumdar R, Ma X, Yang X, Atzmon G, Bernstein J, Karkanias G. Physiologic effect of leptin on insulin secretion is mediated mainly through central mechanisms. FASEB J. 2003; 17(9):1130-2. [DOI:10.1096/fj.02-0991fje]
26. Park S, Hong SM, Sung SR, Jung HK. Long-term effects of central leptin and resist in on body weight, insulin resistance, and β-cell function and mass by the modulation of hypothalamic leptin and insulin signaling. Endocrinology. 2008; 149(2):445-54. [DOI:10.1210/en.2007-0754]
27. Denroche H C, Huynh F K, Kieffer T J. The role of leptin in glucose homeostasis. J Diabetes Investig. 2012 28; 3(2):115-29.
28. Hidaka S, Yoshimatsu H, Kondou S, Tsuruta Y, Oka K, Noguchi H. Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats. FASEB J. 2002; 16(6):509-18. [DOI:10.1096/fj.01-0164com]
29. Pelleymounter MA, Cullen MJ, Healy D, Hecht R, Winters D, McCaleb M. Efficacy of exogenous recombinant murine leptin in lean and obese 10-to 12-mo-old female CD-1 mice. Am J Physiol. 1998; 275(4 Pt 2): R950-9. [DOI:10.1152/ajpregu.1998.275.4.R950]
30. Fürnsinn C, Brunmair B, Furtmüller R, Roden M, Englisch R, Waldhäusl W. Failure of leptin to affect basal and insulin-stimulated glucose metabolism of rat skeletal muscle in vitro. Diabetologia. 1998; 41(5):524-9. [DOI:10.1007/s001250050941]
31. Zierath JR, Frevert EU, Ryder JW, Berggren PO, Kahn BB. Evidence against a direct effect of leptin on glucose transport in skeletal muscle and adipocytes. Diabetes. 1998; 47(1):1-4. [DOI:10.2337/diab.47.1.1]
32. Levin N, Nelson C, Gurney A, Vandlen R, de Sauvage F. Decreased food intake does not completely account for adiposity reduction after ob protein infusion. Proc Natl Acad Sci U S A. 1996 20; 93(4):1726-30.
33. Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature. 1997; 25; 389(6649): 374-7.
34. Park S, Ahn IS, Kim DS. Central infusion of leptin improves insulin resistance and suppresses β-cell function, but not β-cell mass, primarily through the sympathetic nervous system in a type 2 diabetic rat model. Life Sci. 2010 5; 86(23-24): 854-62.
35. Rossetti L, Massillon D, Barzilai N, Vuguin P, Chen W, Hawkins M. Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. J Biol Chem. 1997; 31; 272(44): 27758-63.
36. Cummings BP, Bettaieb A, Graham JL, Stanhope KL, Dill R, Morton GJ, and et al. Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats. Proc Natl Acad Sci U S A. 2011; 30; 108(35): 14670-5.
37. Lejeune MP, Hukshorn CJ, Saris WH, Westerterp-Plantenga MS. Effects of very low calorie diet induced body weight loss with or without human pegylated recombinant leptin treatment on changes in ghrelin and adiponectin concentrations. Physiol Behav. 2007; 91(2-3): 274-80. [DOI:10.1016/j.physbeh.2007.03.004]
38. Speakman JR, Mitchell SE. Mitchell, Caloric restriction. Mol Aspects Med. 2011; 32(3): 159-221. [DOI:10.1016/j.mam.2011.07.001]
39. Seeley RJ, van Dijk G, Campfield LA, Smith FJ, Burn P, Nelligan JA, and et al. Intraventricular leptin reduces food intake and body weight of lean rats but not obese Zucker rats. Horm Metab Res. 1996; 28(12): 664-8. [DOI:10.1055/s-2007-979874]
40. Luheshi GN, Gardner JD, Rushforth DA, Loudon AS, Rothwell NJ. Leptin actions on food intake and body temperature are mediated by IL-1. Proc Natl Acad Sci U S A. 1999; 96(12): 7047-52. [DOI:10.1073/pnas.96.12.7047]
41. Shimokawa I, Higami Y. Leptin signaling and aging: insight from caloric restriction. Mech Ageing Dev. 2001; 122(14): 1511-19. [DOI:10.1016/S0047-6374(01)00284-6]
42. Legradi G, Emerson CH, Ahima RS, Flier JS, Lechan RM. Leptin prevents fastinginduced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinol. 1997; 138(6): 2569-76. [DOI:10.1210/endo.138.6.5209]
43. Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE, Leibel RL. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol Metab 2002; 87(5): 2391-4. [DOI:10.1210/jcem.87.5.8628]
44. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995; 269(5223): 546-9. [DOI:10.1126/science.7624778]
45. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev. 2014; 94(2): 355-82. [DOI:10.1152/physrev.00030.2013]
Send email to the article author

Add your comments about this article
Your username or Email:


XML     Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Pourghaderi M, Hosseinzadeh-Attar M J, Jalali M, Siassi F, Nabavizadeh F, Eshraghian M R. The Effect of Peripheral Injection of Leptin on Biomarkers of Aging in Calorie Restricted Rats. Nutr Food Sci Res 2018; 5 (2) :3-10
URL: http://nfsr.sbmu.ac.ir/article-1-282-en.html

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Volume 5, Issue 2 (Apr-Jun 2018) Back to browse issues page
Nutrition and Food Sciences Research
Persian site map - English site map - Created in 0.05 seconds with 45 queries by YEKTAWEB 4642