Melanotan II causes hypothermia in mice by activation of mast cells and stimulation of histamine 1 receptors

Shalini Jain, Anna Panyutin, Naili Liu, Cuiying Xiao, Ramón A. Piñol, Priyanka Pundir, Clémence Girardet, Andrew A. Butler, Xinzhong Dong, Oksana Gavrilova, Marc L. Reitman

Research output: Contribution to journalArticlepeer-review

Abstract

Intraperitoneal administration of the melanocortin agonist melanotan II (MTII) to mice causes a profound, transient hypometabolism/hypothermia. It is preserved in mice lacking any one of melanocortin receptors 1, 3, 4, or 5, suggesting a mechanism independent of the canonical melanocortin receptors. Here we show that MTII-induced hypothermia was abolished in KitW-sh/W-sh mice, which lack mast cells, demonstrating that mast cells are required. MRGPRB2 is a receptor that detects many cationic molecules and activates mast cells in an antigen-independent manner. In vitro, MTII stimulated mast cells by both MRGPRB2-dependent and-independent mechanisms, and MTII-induced hypothermia was intact in MRGPRB2-null mice. Confirming that MTII activated mast cells, MTII treatment increased plasma histamine levels in both wild-type and MRGPRB2-null, but not in KitW-sh/W-sh, mice. The released histamine produced hypothermia via histamine H1 receptors because either a selective antagonist, pyrilamine, or ablation of H1 receptors greatly diminished the hypothermia. Other drugs, including compound 48/80, a commonly used mast cell activator, also produced hypothermia by both mast cell-dependent and-independent mechanisms. These results suggest that mast cell activation should be considered when investigating the mechanism of drug-induced hypothermia in mice.

Original languageEnglish (US)
Pages (from-to)E357-E366
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume315
Issue number3
DOIs
StatePublished - Sep 2018

Keywords

  • Histamine
  • Hypothermia
  • MRG-PRB2
  • Mast cell activation
  • Melanocortin

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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