5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis.
Drugs activating 5-hydroxytryptamine 2C receptors (5-HT2CRs) potently suppress appetite, but the underlying mechanisms for these effects are not fully understood. To tackle this issue, we generated mice with global 5-HT2CR deficiency (2C null) and mice with 5-HT2CRs re-expression only in pro-opiomelanocortin (POMC) neurons (2C/POMC mice). We show that 2C null mice predictably developed hyperphagia, hyperactivity, and obesity and showed attenuated responses to anorexigenic 5-HT drugs. Remarkably, all these deficiencies were normalized in 2C/POMC mice. These results demonstrate that 5-HT2CR expression solely in POMC neurons is sufficient to mediate effects of serotoninergic compounds on food intake. The findings also highlight the physiological relevance of the 5-HT2CR-melanocortin circuitry in the long-term regulation of energy balance.
Xu
Yong
Y
Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Jones
Juli E
JE
Kohno
Daisuke
D
Williams
Kevin W
KW
Lee
Charlotte E
CE
Choi
Michelle J
MJ
Anderson
Jason G
JG
Heisler
Lora K
LK
Zigman
Jeffrey M
JM
Lowell
Bradford B
BB
Elmquist
Joel K
JK
D000818:Animals; D001066:Appetite / Q000187:drug effects / Q000235:genetics; D001067:Appetite Depressants / Q000494:pharmacology; D001069:Appetite Regulation / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics*; D006963:Hyperphagia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009434:Neural Pathways / Q000166:cytology / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism*
D001067:Appetite Depressants; D044405:Receptor, Serotonin, 5-HT2C; D012701:Serotonin; D011333:Pro-Opiomelanocortin