J Korean Endocr Soc.  2008 Feb;23(1):18-26. 10.3803/jkes.2008.23.1.18.

Naloxone Increases the Anorexic Effect of MTII in OLETF Rats

• Bae JH
• Park YH
• Kim SH
• Park SY
• Kim JY
• Son JY
• Huh JY
• Won KC
• Kim YW

• KMID: 2063546
• DOI: http://doi.org/10.3803/jkes.2008.23.1.18

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.

Keyword

OLETF rats; leptin resistance; MTII; naloxone; tachyphylaxis

MeSH Terms

Animals
Anorexia
Arcuate Nucleus
Diethylpropion
Eating
Hypothalamus
Leptin
Naloxone
Obesity
Pro-Opiomelanocortin
Rats
Rats, Inbred OLETF
Rats, Sprague-Dawley
Receptors, Melanocortin
Tachyphylaxis
Diethylpropion
Leptin
Naloxone
Pro-Opiomelanocortin
Receptors, Melanocortin

Figure

• 

  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.

• 

  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.

• 

  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.

• 

  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.

• 

  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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