Browse > Article

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)
Publication Information
The Korean Journal of Physiology and Pharmacology / v.10, no.1, 2006 , pp. 1-6 More about this Journal
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
Leptin resistance; Food intake; Aged rats; Visceral fat;
Citations & Related Records

Times Cited By SCOPUS : 0
연도 인용수 순위
  • Reference
1 Scarpace PJ, Matheny M, Moore RL, Tumer N. Impaired leptin responsiveness in aged rats. Diabetes 49: 431-435, 2000   DOI   ScienceOn
2 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   DOI
3 Wiernsperger NF, Bailey CJ. The antihyperglycemic effect of metformin: therapeutic and cellular mechanisms. Drugs 58: 31-39, 1999
4 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   DOI   ScienceOn
5 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   DOI   ScienceOn
6 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   DOI   ScienceOn
7 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   DOI   ScienceOn
8 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   DOI
9 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   DOI   ScienceOn
10 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   DOI   ScienceOn
11 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   DOI   ScienceOn
12 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   DOI   ScienceOn
13 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   DOI   ScienceOn
14 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
15 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   DOI
16 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
17 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   DOI   ScienceOn
18 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   DOI
19 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   DOI   ScienceOn
20 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   DOI   ScienceOn
21 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   DOI   ScienceOn
22 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   DOI   ScienceOn
23 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   DOI   ScienceOn
24 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   DOI
25 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   DOI   ScienceOn
26 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   DOI   ScienceOn
27 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   DOI   ScienceOn
28 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   DOI   ScienceOn