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Bae, Park, Kim, Park, Kim, Son, Huh, Won, and Kim: Naloxone Increases the Anorexic Effect of MTII in OLETF Rats
Original Article
Journal of Korean Endocrine Society

Journal of Korean Endocrine Society 2008; 23(1): 18-26.

Published online: 20 February 2008

DOI: https://doi.org/10.3803/jkes.2008.23.1.18

Naloxone Increases the Anorexic Effect of MTII in OLETF Rats

Jang Ho Bae, Yong Hoon Park2, Sung Ho Kim3, So Young Park1, Jong Yeon Kim1, Jo Young Son1, Jung Yoon Huh1, Kyu Chang Won4, Yong Woon Kim1

Department of Neurosurgery, Joeun Hospital, Korea.

1Department of Physiology, College of Medicine, Yeungnam University, Korea.

2Department of Pediatrics, College of Medicine, Yeungnam University, Korea.

3Department of Neurosurgery, College of Medicine, Yeungnam University, Korea.

4Department of Internal Medicine, College of Medicine, Yeungnam University, Korea.

Received 13 November 2007       Accepted 30 November 2007

Copyright © 2008 Korean Endocrine Society

Abstract

Background

Leptin, an adipocyte-derived hormone, inhibits obesity in lean subjects, but is not widely used because of leptin resistance. Thus, circumventing the arcuate nucleus of the hypothalamus, the site responsible for leptin resistance, has been evaluated for treatment of obesity. However, chronic treatment of melanotan II (MTII), a synthetic agonist of the melanocortin 3/4 receptor, induces tachyphylaxis. Here, we evaluated whether naloxone, a non-specific agouti-related peptide (AgRP) antagonist, increases the anorexic effect of MTII in Otsuka Long-Evans Tokushima Fatty (OLETF) rats.

Methods

We measured food intake following intracerebroventricular (i.c.v.) infusion of MTII and/or naloxone in OLETF rats. Sprague-Dawley rats were used as a normal control group.

Results

The anorexic effect of i.c.v. MTII infusion decreased with time in OLETF rats, indicating the development of tachyphylaxis. In normal control rats, naloxone alone decreased AgRP expression in the hypothalamus but failed to induce anorexia. Moreover, there was no additional anorexic effect with co-treatment of naloxone and MTII. In OLETF rats, naloxone alone did not show an anorexic effect despite increased POMC expression in the hypothalamus. However, naloxone sensitized the anorexic effect of MTII when treated together.

Conclusion

These results suggest that naloxone augmented the anorexic effect of MTII when treated together in OLETF rats, but had no effect alone. These results suggest that a combination therapy of naloxone and a melanocortin receptor activator would be an effective modality for treatment of obesity.

Keywords: OLETF rats, leptin resistance, MTII, naloxone, tachyphylaxis

Figures and Tables

Fig. 1
Effects of MTII and/or naloxone on daily food intake and total food intake in SD (A, C, respectively) and OLETF (B, D, respectively) rats. MTII (1 nm/day/rat) and/or naloxone (100 µg/day/rat) were infused for 7 days. Values are means ± SE of six rats per group. *P < 0.01, †P < 0.05, ‡P < 0.01 vs saline, §P < 0.05, ‖P < 0.05 vs naloxone, ¶P < 0.05 vs MTII.
jkes-23-18-g001
Fig. 2
Effects of MTII and/or naloxone on body weight changes in SD (A) and OLETF (B) rats. MTII (1 nm/day/rat) and/or naloxone (100 µg/day/rat) were infused for 7 days. Values are means ± SE of six rats per group. *P < 0.05, †P < 0.01.
jkes-23-18-g002
Fig. 3
Effects of MTII and/or naloxone on percent visceral fat mass in SD (A) and OLETF (B) rats. MTII (1 nm/day/rat) and/or naloxone (100 ug/day/rat) were infused for 7 days. Values are means±SE of six rats per group. *P < 0.01 vs saline, †P < 0.05, ‡P < 0.01 vs naloxone, §P < 0.05 vs MTII.
jkes-23-18-g003
Fig. 4
Expressions of POMC (A), NPY (B), AgRP (C), and MC4R (D) in the hypothalamus of saline-, naloxone-, MTII-, MTII plus naloxone-treated Sprague-Dawley rats. Values are means ± SE of six rats per group.
jkes-23-18-g004
Fig. 5
Expressions of POMC (A), NPY (B), AgRP (C), and MC4R (D) in the hypothalamus of saline-, naloxone-, MTII-, MTII plus naloxone-treated OLETF rats. Values are means ± SE of six rats per group. *P < 0.01 vs saline.
jkes-23-18-g005
Table 1
Body weights of the experimental groups
jkes-23-18-i001

Values are mean ± S.E. Number of cases is six per each group.

SD, Sprague-Dawley; OLETF, Otsuka Long-Evans Tokushima Fatty.

Table 2
Real-time PCR primer sequences
jkes-23-18-i002

POMC, proopiomelanocortin; NPY, neuropeptide Y; AgRP, agouti-related peptide; MC4R, melanocortin receptor 4.

References

1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994. 372:425–432.
2. Scarpace PJ, Tümer N. Peripheral and hypothalamic leptin resistance with age-related obesity. Physiol Behav. 2001. 74:721–727.
3. Shek EW, Scarpace PJ. Resistance to the anorexic and thermogenic effects of centrally administrated leptin in obese aged rats. Regul Pept. 2000. 92(1-3):65–71.
4. Van Heek M, Compton DS, France CF, Tedesco RP, Fawzi AB, Graziano MP, Sybertz EJ, Strader CD, Davis HR Jr. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest. 1997. 99:385–390.
5. Widdowson PS, Upton R, Buckingham R, Arch J, Williams G. Inhibition of food response to intracerebroventricular injection of leptin is attenuated in rats with diet-induced obesity. Diabetes. 1997. 46:1782–1785.
6. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV. Decraesed cerebrospinal-fluid/serum leptin ratio in obesity, a possible mechanism for leptin resistance. Lancet. 1996. 348:159–161.
7. Halaas JL, Boozer 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 USA. 1997. 94:8878–8883.
8. Jonsson L, Skarphedinsson JO, Skuladottir GV, Atlason PT, Eiriksdottir VH, Franzson L, Schiöth HB. Melanocortin receptor agonist transiently increases oxygen consumption in rats. Neuroreport. 2001. 12:3703–3708.
9. Scarpace PJ, Matheny M, Zolotukhin S, Tümer N, Zhang Y. Leptin-induced leptin resistant rats exhibit enhanced responses to the melanocortin agonist MT II. Neuropharmacology. 2003. 45:211–219.
10. Kim YW, Choi DW, Park YH, Huh JY, Won KC, Choi KH, Park SY, Kim JY, Lee SK. Leptin-like effect of MTII are augmented in MSG-obese rats. Regul Pept. 2005. 127:63–70.
11. Brugman S, Clegg DJ, Woods SC, Seeley RJ. Combined blockade of both micro- and kappa-opioid receptors prevents the acute orexigenic action of Agouti-related protein. Endocrinology. 2002. 143:4265–4270.
12. Dube MG, Horvath TL, Leranth C, Kalra PS, Kalra SP. Naloxone reduces the feeding evoked by intracerebroventricular galanin injection. Physiol Behav. 1994. 56:811–813.
13. Kim YW, Kim JY, Park YH, Park YH, Park SY, Won KC, Choi KH, Huh JY, Moon KH. Metformin Restores Leptin Sensitivity in High Fat Fed Obese Rats with Leptin Resistance. Diabetes. 2006. 55:716–724.
14. Covasa M, Ritter RC. Attenuated satiation response to intestinal nutrients in rats that do not express CCK-A receptors. Peptides. 2001. 22:1339–1348.
15. Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell. 2001. 104:531–543.
16. Li G, Zhang Y, Wilsey JT, Scarpace PJ. Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats. Diabetologia. 2005. 48:2376–2385.
17. Li G, Zhang Y, Cheng KY, Scarpace PJ. Lean rats with hypothalamic pro-opiomelanocortin overexpression exhibit greater diet-induced obesity and impaired central melanocortin responsiveness. Diabetologia. 2007. 50:1490–1499.
18. Fong TM, Mao C, MacNeil T, Kalyani R, Smith T, Weinberg D, Tota MR, Van der Ploeg LH. ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochem Biophys Res Commun. 1997. 237:629–631.
19. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997. 278:135–138.
20. Wortley KE, Anderson KD, Yasenchak J, Murphy A, Valenzuela D, Diano S, Yancopoulos GD, Wiegand SJ, Sleeman MW. Agouti-related protein-deficient mice display an age-related lean phenotype. Cell Metab. 2005. 2:421–427.
21. Rossi M, Kim MS, Morgan DG, Small CJ, Edwards CM, Sunter D, Abusnana S, Goldstone AP, Russell SH, Stanley SA, Smith DM, Yagaloff K, Ghatei MA, Bloom SR. A C-terminal fragment of agouti-related protein increases feeding and antagonizes the effect of α-melanocyte stimulating hormone in vivo. Endocrinology. 1998. 139:4428–4431.
22. Hagan MM, Rushing PA, Pritchard LM, Schwartz MW, Strack AM, Van der Ploeg LH, Woods SC, Seeley RJ. Long-term orexigenic effects of AgRP-(83-132) involve mechanisms other than melanocortin receptor blockade. Am J Physiol. 2000. 279:R47–R52.
23. Hagan MM, Rushing PA, Pritchard LM, Schwartz MW, Strack AM, Van der Ploeg HT, Woods SC, Seeley RJ. Long-term orexigenic effects of AgRP-(83-132) involve mechanisms other than melanocortin receptor blockade. Am J Physiol. 2000. 279:R47–R52.
24. Kotz CM, Grace MK, Briggs J, Levine AS, Billington CJ. Effects of opioid antagonists naloxone and naltrexone on neuropeptide Y-induced feeding and brown fat thermogenesis in the rat. Neural site of action. J Clin Invest. 1995. 96:163–170.
25. Tabarin A, Diz-Chaves Y, Carmona Mdel C, Catargi B, Zorrilla EP, Roberts AJ, Coscina DV, Rousset S, Redonnet A, Parker GC, Inoue K, Ricquier D, Pénicaud L, Kieffer BL, Koob GF. Resistance to diet-induced obesity in mu-opioid receptor-deficient mice: evidence for a "thrifty gene". Diabetes. 2005. 54(12):3510–3516.
26. Schusdziarra V, Zimmermann JP, Schick RR. Importance of orexigenic counter-regulation for multiple targeted feeding inhibition. Obes Res. 2004. 12:627–632.
27. MaLaughlin CL, Baile CA. Feeding behavior responses of Zucker rats to naloxone. Physiol Behav. 1984. 32:755–761.
28. Jarosz PA, Metzger BL. The effect of opioid antagonism on food intake behavior and body weight in a biobehavioral model of obese binge eating. Biol Res Nurs. 2002. 3:198–209.
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