The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Metformin Enhances Leptin Sensitivity in Aged Rats

  • Kim, Sae-Rom (Department of Internal Medicine, Daegu Fatima Hospital) ;
  • Park, So-Young (Department of Physiology, College of Medicine, Yeungnam Uniuersity) ;
  • Kim, Jong-Yeon (Department of Physiology, College of Medicine, Yeungnam Uniuersity) ;
  • Kim, Yong-Woon (Department of Physiology, College of Medicine, Yeungnam Uniuersity)
  • Published : 2006.02.21
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Abstract

To evaluate whether metformin restores leptin sensitivity in aged rats with leptin resistance, we measured leptin sensitivity in aged (2 year old) and adult (5 month old) rats after 4 weeks of treatment with metformin (300 mg/kg/D, mixing in drinking water), by measuring food intake, body weight and visceral fat losing effects. Leptin ($15{\mu}g/D$) was administered by intracerobroventricular (i.c.v.) infusion through osmotic minipump for 1 week. Metformin treatment decreased body weight and daily food intake in both adult and aged rats compared with their control rats, however, these effects were more prominent in aged rats than in adult rats. Anorexic and fat losing responses following i.c.v. leptin were attenuated in aged rats compared to adult rats. However, these responses of aged rats to leptin were restored by metformin treatment. Moreover, serum concentration of leptin in aged rats was significantly decreased by combined treatment with metformin and leptin. These results suggest that metformin enhances leptin sensitivity in aged rat model, and that combination therapy with metformin and leptin would be helpful for treatment of aging-associated obesity.

Keywords

References

  1. Cankurtaran M, Halil M, Yavuz BB, Dagli N, Oyan B, Ariogul S. Prevalence and correlates of metabolic syndrome (MS) in older adults. Arch Gerontol Geriatr 42: 35-45, 2006 https://doi.org/10.1016/j.archger.2005.05.004
  2. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF. Serum immunoreactive-leptin concentrations in normalweight and obese humans. N Engl J Med 334: 292-295, 1996 https://doi.org/10.1056/NEJM199602013340503
  3. Fruehwald-Schultes B, Oltmanns KM, Toschek B, Sopke S, Kern W, Born KJ, Fehm HL, Peters A. Short-term treatment with metformin decreases serum leptin concentration without affecting body weight and body fat content in normal-weight healthy men. Metabolism 51: 531-536, 2002 https://doi.org/10.1053/meta.2002.31332
  4. Fryer LG, Parbu-Patel A, Carling D. The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 277: 25226-25232, 2002 https://doi.org/10.1074/jbc.M202489200
  5. Glueck CJ, Fontaine RN, Wang P, Subbiah MTR, Weber K, Illig E, Streicher P, Sieve-Smith L, Tracy T, Kang JE, McCullough P. Metformin reduces weight, centropedal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism 50: 856-861, 2001 https://doi.org/10.1053/meta.2001.24192
  6. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin- induced resumption of normal mense in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism 48: 511-519, 1999 https://doi.org/10.1016/S0026-0495(99)90113-0
  7. Fernandez-Galaz C, Fernandez-Agullo T, Perez C, Peralta S, Arribas C, Andres A, Carrascosa JM, Ros M. Long-term food restriction prevents ageing-associated central leptin resistance in Wistar rats. Diabetologia 45: 997-1003, 2002 https://doi.org/10.1007/s00125-002-0851-4
  8. Halaas JL, Booze C, Blair-West J, Fidahusein N, Denton DA, Friedman JM. Physiological response to long term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci 94: 8878-8883, 1997
  9. Hawley SA, Gadalla AE, Olsen GS, Hardie DG. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 51: 2420-2425, 2002 https://doi.org/10.2337/diabetes.51.8.2420
  10. Hundal HG, Ramlal T, Reyes R, Leiter LA. Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells. Endocrinology 131: 1165-1173, 1992 https://doi.org/10.1210/en.131.3.1165
  11. Kay JP, Alemzadeh R, Langley G, D'Angelo L, Smith P, Holshouser S. Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism 50: 1457-1461, 2001 https://doi.org/10.1053/meta.2001.28078
  12. Kim YW, Choi DW, Park YH, Huh JY, Won KC, Choi KH, Park SY, Kim JY, Lee SK. Leptin-like effects of MTII are augmented in MSG-obese rats. Regul Pept 127: 63-70, 2005 https://doi.org/10.1016/j.regpep.2004.10.006
  13. Kim YW, Kim JY, Park YH, Park SY, Won KC, Choi KH, Huh JY, Moon KH. Metformin restores leptin sensitivity in high fat obese rats with leptin resistance. Diabetes 53(Suppl 2): A409, 2004
  14. Klip A, Guma A, Ramlal T, Bilan PJ, Lam L, Leiter LA. Stimulation of hexose transport by metformin in L6 muscle cells in culture. Endocrinology 130: 2535-2544, 1992 https://doi.org/10.1210/en.130.5.2535
  15. Kolodziejczyk B, Duleba AJ, Spaczynski RZ, Pawelczyk L. Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome. Fertil Steril 73: 1149-1154, 2000 https://doi.org/10.1016/S0015-0282(00)00501-X
  16. Levin BE, Dunn-Meynell AA. Reduced central leptin sensitivity in rats with diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 283: R941-R948, 2002 https://doi.org/10.1152/ajpregu.00245.2002
  17. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415: 339-343, 2002 https://doi.org/10.1038/415339a
  18. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428: 569- 574, 2004 https://doi.org/10.1038/nature02440
  19. Moghetti P, Castello R, Tosi F, Perrone F, Caputo M, Zanolin E, Muggeo M. Metformin effects on clinical features, endocrine and metabolic profiles and insulin sensitivity in polycystic ovary syndrome: a randomized, double blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 85: 139-146, 2000 https://doi.org/10.1210/jc.85.1.139
  20. Morin-Papunen LC, Koivunen RM, Tomas C, Ruokonen A, Martikainen HK. Decreased serum leptin concentrations during metformin therapy in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 83: 2566-2568, 1998 https://doi.org/10.1210/jc.83.7.2566
  21. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphine-induced ovulation in the polycystic ovary syndrome. N Engl J Med 338: 1876-1880, 1998 https://doi.org/10.1056/NEJM199806253382603
  22. Radziuk J, Bailey CJ, Wiernsperger NF, Yudkin JS. Metformin and its liver targets in the treatment of type 2 diabetes. Curr Drug Targets Immune Endocr Metab Disord 3: 151-169, 2003 https://doi.org/10.2174/1568008033340298
  23. Scarpace PJ, Matheny M, Moore RL, Tumer N. Impaired leptin responsiveness in aged rats. Diabetes 49: 431-435, 2000 https://doi.org/10.2337/diabetes.49.3.431
  24. Shek, EW, Scarpace PJ. Resistance to the anorexic and thermogenic effects of centrally administrated leptin in obese aged rats. Regul Pept 92(1-3): 65-71, 2000 https://doi.org/10.1016/S0167-0115(00)00151-8
  25. van den Brandt J, Kovacs P, Kloting I. Metabolic syndrome and aging in Wistar Ottawa Karlsburg W rats. Int J Obes Relat Metab Disord 26: 573-576, 2002 https://doi.org/10.1038/sj.ijo.0801966
  26. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43: 647-654, 1994 https://doi.org/10.1016/0026-0495(94)90209-7
  27. Wiernsperger NF, Bailey CJ. The antihyperglycemic effect of metformin: therapeutic and cellular mechanisms. Drugs 58: 31-39, 1999
  28. Zhou G, Myers R, li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated kinase in mechanism of metformin action. J Clin Invest 108: 1167-1174, 2001 https://doi.org/10.1172/JCI13505