Biphasic effect of melanocortin agonists on metabolic rate and body temperature.

Abstract

The melanocortin system regulates metabolic homeostasis and inflammation. Melanocortin agonists have contradictorily been reported to both increase and decrease metabolic rate and body temperature. We find two distinct physiologic responses occurring at similar doses. Intraperitoneal administration of the nonselective melanocortin agonist MTII causes a melanocortin-4 receptor (Mc4r)-mediated hypermetabolism/hyperthermia. This is preceded by a profound, transient hypometabolism/hypothermia that is preserved in mice lacking any one of Mc1r, Mc3r, Mc4r, or Mc5r. Three other melanocortin agonists also caused hypothermia, which is actively achieved via seeking a cool environment, vasodilation, and inhibition of brown adipose tissue thermogenesis. These results suggest that the hypometabolic/hypothermic effect of MTII is not due to a failure of thermoregulation. The hypometabolism/hypothermia was prevented by dopamine antagonists, and MTII selectively activated arcuate nucleus dopaminergic neurons, suggesting that these neurons may contribute to the hypometabolism/hypothermia. We propose that the hypometabolism/hypothermia is a regulated response, potentially beneficial during extreme physiologic stress.

• Authors: Beth Lute, William Jou, Dalya M Lateef, Margalit Goldgof, Cuiying Xiao, Ramón A Piñol, Alexxai V Kravitz, Nicole R Miller, Yuning George Huang, Clemence Girardet, Andrew A Butler, Oksana Gavrilova, Marc L Reitman
• Journal: Cell metabolism (Cell Metab) Vol. 20 Issue 2 Pg. 333-45 (Aug 05 2014) ISSN: 1932-7420 [Electronic] United States
• PMID: 24981835 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Dopamine Antagonists
• Receptor, Melanocortin, Type 1
• Receptor, Melanocortin, Type 3
• Receptor, Melanocortin, Type 4
• Receptors, Melanocortin
• acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide
• melanocortin 5 receptor
• alpha-MSH

Topics

• Animals
• Arcuate Nucleus of Hypothalamus (metabolism)
• Body Temperature (drug effects)
• Dopamine Antagonists (pharmacology)
• Dopaminergic Neurons (drug effects, metabolism)
• Energy Metabolism (drug effects)
• Female
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptor, Melanocortin, Type 1 (agonists, genetics, metabolism)
• Receptor, Melanocortin, Type 3 (agonists, genetics, metabolism)
• Receptor, Melanocortin, Type 4 (agonists, genetics, metabolism)
• Receptors, Melanocortin (agonists, genetics, metabolism)
• alpha-MSH (analogs & derivatives, pharmacology)