Effects of Acute and Chronic Administration of the Melanocortin Agonist MTII in Mice With Diet-Induced Obesity

  1. Dominique D. Pierroz,
  2. Mary Ziotopoulou,
  3. Linda Ungsunan,
  4. Stergios Moschos,
  5. Jeffrey S. Flier and
  6. Christos S. Mantzoros
  1. From the Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

    Abstract

    High-fat diet-induced obesity (DIO) in rodents is associated with hyperleptinemia and resistance to leptin, but the response to agents acting downstream of leptin receptors remains unknown. We assessed the response of mice with DIO to treatment with MTII, an α-melanocyte-stimulating hormone analog. MTII delivered four times daily by intraperitoneal injection to C57BL/6J mice produced a dose-responsive effect on food intake, body weight, leptin, corticosterone, insulin, and free fatty acids. In DIO mice, administration of MTII 100 μg q.i.d. i.p. markedly suppressed feeding during the first 4 days of treatment, with food intake returning to control levels at day 5. Progressive weight loss also occurred over the first 4 days, after which weight plateaued at a level below control. After 8 days of treatment, MTII-treated DIO mice had major suppression of both leptin and insulin levels. Central administration of MTII for 4 days (10 nmol/day) in DIO mice significantly suppressed food intake, induced weight loss, and increased energy expenditure. These results indicate that 1) MTII administration to DIO mice causes suppression of food intake and body weight loss, and decreased food intake is primarily responsible for weight loss; 2) peripheral MTII improves insulin resistance in DIO mice; 3) “tachyphylaxis” to the effect of chronic MTII treatment on food intake occurs; and 4) at least some of the effects of MTII are exerted centrally. In conclusion, treatment with a melanocortin agonist is a promising therapeutic approach to DIO and associated insulin resistance.

    Footnotes

    • Address correspondence and reprint requests to Dr. Jeffrey S. Flier, Division of Endocrinology 325, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave., Boston, MA 02215. E-mail: jflier{at}caregroup.harvard.edu.

      D.D.P. and M.Z contributed equally to the work presented here.

      Received for publication 20 July 2001 and accepted in revised form 12 February 2002.

      AgRP, agouti-related protein; CNS, central nervous system; DEXA, dual-energy X-ray absorptiometry; DIO, diet-induced obesity; ICV, intracerebroventricular; IRS-1, insulin receptor substrate-1; MC, melanocortin; α-MSH, α-melanocyte-stimulating hormone; POMC, pro-opiomelanocortin; RQ, respiratory quotient; TNF-α, tumor necrosis factor-α.

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