Journal List > J Korean Endocr Soc > v.23(1) > 1003433

Bae, Park, Kim, Park, Kim, Son, Huh, Won, and Kim: Naloxone Increases the Anorexic Effect of MTII in OLETF Rats

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.

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.
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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.
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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.
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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.
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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.
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Table 1
Body weights of the experimental groups
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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.

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