Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways.
The burden of type 2 diabetes and its associated premature morbidity and mortality is rapidly growing, and the need for novel efficacious treatments is pressing. We report here that serotonin 2C receptor (5-HT(2C)R) agonists, typically investigated for their anorectic properties, significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes. Importantly, 5-HT(2C)R agonist-induced improvements in glucose homeostasis occurred at concentrations of agonist that had no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass. We determined that this primary effect on glucose homeostasis requires downstream activation of melanocortin-4 receptors (MC4Rs), but not MC3Rs. These findings suggest that pharmacological targeting of 5-HT(2C)Rs may enhance glucose tolerance independently of alterations in body weight and that this may prove an effective and mechanistically novel strategy in the treatment of type 2 diabetes.
Zhou
Ligang
L
Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QQ, UK.
Sutton
Gregory M
GM
Rochford
Justin J
JJ
Semple
Robert K
RK
Lam
Daniel D
DD
Oksanen
Laura J
LJ
Thornton-Jones
Zoe D
ZD
Clifton
Peter G
PG
Yueh
Chen-Yu
CY
Evans
Mark L
ML
McCrimmon
Rory J
RJ
Elmquist
Joel K
JK
Butler
Andrew A
AA
Heisler
Lora K
LK
D015502:Absorptiometry, Photon; D000818:Animals; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011333:Pro-Opiomelanocortin / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D007328:Insulin; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; D011333:Pro-Opiomelanocortin; D005947:Glucose; C015068:1-(3-chlorophenyl)piperazine