Obesity is a huge and increasing medical problem, with inadequate therapeutic options. One approach to the treatment of obesity is long-term pharmacotherapy. One modestly effective drug, orlistat, has been marketed in the United States since 1999. More recently four other drugs have been approved by the FDA: lorcaserin and Qsymia (a combination of phentermine and topiramate) in 2012 and Contrave (a combination of buproprion and naltrexone) and liraglutide (high dose) in 2014. The limited efficacy of single agents has led to the idea that additional agents and combination therapy are required. Progress in FY2018 includes the following: MTII (melanotan II) is a peptide melanocortin agonist commonly used to probe the physiology of energy homeostasis. A peptide melanocortin agonist (setmelanotide) is currently in clinical development for the treatment of certain rare forms of obesity. We previously reported that intraperitoneal administration of MTII causes a profound, transient hypometabolism/hypothermia in mice. 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. In 2018 we published the mechanism by which MTII induces hypothermia. MTII directly activates mast cells. MTII did not produce hypothermia in mice lacking mast cells. Some of the mast cell activation may be via MRGPRB2, a receptor that detects many cationic molecules and activates in an antigen-independent manner. MTII treatment increased plasma histamine levels in both wild type mice and but not in mice lacking mast cells. The released histamine produced hypothermia via histamine H1 receptors, since either a selective antagonist, pyrilamine, or ablation of H1 receptors greatly diminished the hypothermia. These results suggest that mast cell activation should be considered when investigating the mechanism of drug-induced hypothermia in mice.
Showing the most recent 10 out of 26 publications
