Effect of exogenous leptin on serum levels of lipids, glucose, renal and hepatic variables in both genders of obese and streptozotocin-induced diabetic rats

Document Type: Original Article


1 Neurogenic Inflammation Research center, Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran

3 Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Neurocognitive Research Center, Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


Objective(s): Leptin exerts various effects on appetite and body weight. Disruption of the obesitygene is precedent to fatness. Insulin or glucose elevates leptin, but streptozotocin reduces it. However, controversial data exist for the effects of leptin on diabetes and leptin level in each gender. Leptin can damage the kidney function but little evidence exists for its hepatic effects. The aim of this study was to investigate the probable sex-dependent differences in blood sugar levels, lipid profile, and renal and hepatic biochemical factors in the obesity and streptozotocin-induced diabetic rats after leptin administration.
Materials and Methods: Wistar rats of both sexes were randomly divided into two groups, namely obese and diabetic rats. Each group was further divided into male and female subgroups. Extra fat and carbohydrate was added to the diet to induce obesity. Furthermore, streptozotocin (55 mg/kg, IP) was injected to induce diabetes. The treatment groups received leptin (0.1 mg/kg SC) for 10 days, and then, blood samples were taken from the orbital sinus for laboratory evaluations.
Results: Leptin resulted in a significant weight loss in both sexes (P<0.001), food intake reduction in male rats (P<0.05), LDL reduction in female rats (obese (P<0.05) and diabetic (P<0.001)), and glucose level decline in the female diabetic rats (P<0.001). However, total protein concentration, LFT (liver function tests), urea and creatinin concentrations among different groups did not show any significant changes.
Conclusion: Leptin caused some discrepant results, especially regarding the LDL and glucose levels in diabetic female rats.


1. Patel BK, Koenig JI, Kaplan LM, Hooi SC. Increase in plasma leptin and lep mRNA concentrations byfood intake is dependent on insulin. Metabolism 1998; 47:603–607.

2. Harvey J, Solovyova N, Irving A. Leptin and its role in hippocampal synaptic plasticity. Prog Lip Res 2006; 45:369–378.

3. Morrison CD. Leptin signaling in brain : A link between nutrition and cognition ? Biochem Biophys Acta [serial online] 2009; 1792:401–408. Available from: Elsevier B.V.Accessed 2008.12.004

4. Sivitz WI, Walsh S, Morgan D, Donohoue P, Haynes W, Leibel RL. Plasma leptin in diabetic and insulin-treated diabetic and normal rats. Metabolism 1998; 47:584–591.

5. Havel PJ, Uriu-hare JY, Liu T, Stanhope KL, Stern JS, Keen CL, et al. Marked and rapid decreases of circulating leptin in streptozotocin diabetic rats : reversal by insulin. Am J Physiol 1998; 274:1482–1491.

6. Kozłowska L, Rydzewski A, Grzechnik A, Rosołowska-huszcz D. Adiponectin, resistin and leptin response to dietary intervention in diabetic nephropathy. J Renal Nutr 2010; 20:255–262.

7. Ceddia RB, Koistinen HA, Zierath JR, Sweeney G. Analysis of paradoxical observations on the association between leptin and insulin resistance. FASEB J 2002; 16:1163–1176.

8. Javor ED, Moran SANN, Young JR, Cochran EK, Depaoli AM, Oral EA, et al. Proteinuric nephropathy in acquired and congenital generalizedlipodystrophy : baselinecharacteristics and course during recombinant leptin therapy. J Clin Endocrinol Metab 2004; 89:3199–3207.

9. Toya K, Bouchi R, Hanai K, Babazono T, Tanaka N, Mugishima M. Association of serum leptin levels with progression of diabetic kidney disease in patients with type 2 diabetes. Diabetes Care 2011; 34:11–13.

10. Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim S, et al. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 2011; 301:567–584.

11. Chan WB, Ma RCW, Chan NN, Ng MCY, Lee ZSK, Lai CWK, et al. Increased leptin concentrations and lack of gender difference in type 2 diabetic patients with nephropathy. Diabetes Res Clin Pract 2004; 64:93–98.

12. Couillard C, Maurie P, Prud D, Nadeau A, Tremblay A, Bouchard C, et al. Plasma leptin concentrations : gender differences and associations with metabolic risk factors for cardiovascular disease. Diabetologia 1997; 40:1178–1184.

13. Kennedy A, Gettys TW, Watson P, Wallace P, Ganaway E, Pan QIN, et al. The metabolic significance of leptin in humans : gender-based differences in relationship to adiposity , insulin sensitivity , and energy expenditure. J Clin Endocrinol Metab 2014; 82:1293–1300.

14. Murer SB, Kno BH, Aeberli I, Jung A, Wildhaber J, Wildhaber-brooks J, et al. Baseline leptin and leptin reduction predict improvements in metabolic variables and long-term fat loss in obese children and adolescents : a prospective study of an inpatient weight-loss program 1 – 3. Am J Clin Nutr 2011; 93:695–702.

15. Bruder ED, Jacobson L, Raff H. Plasma leptin and ghrelin in the neonatal rat: interaction of dexamethasone and hypoxia. J Endocrinol 2006; 185:477–484.

16. Gajda AM. High fat diets for diet-induced obesity models. Research Diets, Inc. 2008. p: 2008–2010.Available at: http://www.researchdiets.com.

17. Mingrone G, Manco M, Granato L, Calvani M, Scarfone A, Mora EV, et al. Leptin pulsatility in formerly obese women. FASEB J 2005; 24:1–24.

18. Bibak B, Khalili M, Rajaei Z, Soukhtanloo M, Hadjzadeh M. Effects of melatonin on biochemical factors and food and water consumption in diabetic rats. Adv Biomed Res 2014; 3:1–7.

19. Rasi S, Mohaddes G, Naghdi N, Ilkhani VH. Evaluation of the effect of peripheral injection of leptin on spatial memory. Internet J Neurol 2007; 8:1-10. 

20. Lee M, Orlov D, Sweeney G. Leptin induces rat glomerular mesangial cell hypertrophy , but does not regulate hyperplasia or apoptosis. Int J Obes 2005; 29:1395–1401.

21. Pit-Siu Lee M, Madani S, Sekula D,Sweeney G. Leptin increases expression and activity of matrix metalloproteinase-2 and does not alter collagen production in rat glomerular mesangial cells. Metab Syndr Relat Disord 2005; 31:27–37.

22. Papafragkaki D, Tolis G. Obesity and renal disease: A possible role of leptin. Hormones 2005; 4:90–95.

23. Tao Y, Wei-gang Z, Qi S, Yong F, Ying- yue D, Ya-xiu D,et al. Association between four adipokines and insulin sensitivity in patients with obesity, type 1 or type 2 diabetes mellitus, and in the general Chinese population. Chin Med J 2010; 123:2018–2022.25.

24. Karacabey K. The effect of exercise on leptin,insulin, cortisol andlipid profiles in obese children. J Int Med Res 2009; 37:1472–1478.

25. Sari R, Balci MK, Apaydin C. The relationship between plasmaleptin levels and chroniccomplication in patients with type 2 diabetes mellitus. Metab Syndr Relat Disord 2010; 8:499–503.

26. Bates SH, Kulkarni RN, Seifert M, Myers MG. Roles for leptin receptor/STAT3-dependent and independent signals in the regulation of glucose homeostasis. Cell Metab 2005; 1:169–178.

27.  Haghshenas R, Jafari M, Ravasi A, Kordi M, Gilani N, Shariatzadeh M, Hedayati M, et al. The effect of eight weeks endurance training and high-fat diet on appetite-regulating hormones in rat plasma. Iran J Basic Med Sci 2014; 17:237–243.

28. La Sorensen T, Soren M, Echwald J-CH. Leptin in obesity. Brit Med J 1996; 313:953–954.

29. Guevara R, Valle A, Gianotti M, Roca P, Oliver J. Gender-dependent differences in serum profiles of insulin and leptin in caloric restricted rats. Horm Metab Res 2008; 40:38–43.

30. Gao Q, Horvath TL. Cross-talk between estrogen and leptin signaling in the hypothalamus. Am J Physiol Endocrinol Metab 2008; 294:817–826.

31. Kanoski SE, Hayes MR, Greenwald HS, Fortin SM, Gianessi CA, Gilbert JR, et al. Hippocampal leptin signaling reduces food intake and modulates food-related memory processing. Neuropsycho-pharmacology [serial online]. Nature Publishing Group; 2011; 36:1859–1870. Available from: Nature Publishing Group.Accessed 2011.70

32. Lemieux I, Pascot A, Lamarche B, Prud D, Nadeau A, Bergeron J, et al. Is the gender difference in LDL size explained by the metabolic complications of visceral obesity ? Eur J Clin Invest 2002; 32:909–917.

33. Maingrette F. Leptin increases lipoprotein lipase secretion by macrophages : involvement of oxidative stress and protein kinase C. Diabetes 2003; 52:2121–2128.

34. Singh KA, Boozer CN, Vasselli JR, Kimberly A. Physiological regulation of appetite: acute insulin-induced elevations of circulating leptin and feeding inhibition in lean but not obese rats. Am J Physiol-Regul I 2005; 10025:373–379.

35. Shetty GK, Matarese G, Magkos F, Moon H, Liu X, Brennan AM. Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric diet. Eur J Endocrinol 2011; 165:249–254.

36. Moralejo DH, Hansen CT, Treuting P, Hessner MJ, Fuller JM, Yserloo B Van, et al. Differential effects of leptin receptor mutation on male and female BBDR . Gimap5Ϫ / Gimap5Ϫ spontaneously diabetic rats. Physiol Genomics 2010; 41:9–20.

37. Chiu C, Lu L, Yu T, Hung W, Chung F, Tsai I, et al. Increased levels of total p-cresylsulphate and indoxyl sulphate are associated with disease in patients with diabetic nephropathy. Rev Diabet Stud 2010; 7:275–284.

38. Chung FM, Tsai JC, Chang DM, Shin SJ, Lee YJ. Peripheral total and differential leukocyte count indiabetic nephropathy. Diabetes Care 2005; 28:1710–1717.

39. Han DC, Isono M, Chen S, Casaretto A, Hong SW, Wolf G, et al.  Leptin stimulates type I collagen production in db / db mesangial cells : glucose uptake and TGF- ␤ type II receptor expression. Kidney Int 2001; 59:1315–1323.

40. Gray B, Steyn F, Davies PS VL. Liver function parameters, cholesterol, and phospholipid α-linoleic acid are associated with adipokine levels in overweight and obese adults. Nutr Res 2014; 34:375–382.