Deletion of the serotonin 2c receptor from transgenic mice overexpressing leptin does not affect their lipodystrophy but exacerbates their diet-induced obesity.
The binding of leptin to hypothalamic neurons elicits inhibition of orexigenic NPY/AgRP neurons and stimulation of anorexigenic POMC/CART neurons. Projections of serotonergic neurons onto POMC neurons suggest that leptin and serotonin converge onto POMC neurons to regulate body weight. We probed the interaction of these pathways by generating transgenic mice overexpressing leptin (LepTg) without 5HT2c receptors. On a chow diet, the lean phenotype of LepTg mice was unaffected by the absence of 5HT2c receptors, whereas on a high fat diet, LepTg/5HT2c receptors knockout mice showed an exacerbation of diet-induced obesity. POMC mRNA levels were low in LepTg, 5HT2c receptors knockout and LepTg/5HT2c receptors knockout mice, demonstrating that perturbations of the 5HT2c receptor and leptin pathways, either alone or in combination, negatively impact on POMC expression. Thus, on a chow diet, leptin action is independent of 5HT2c receptors whereas on a high fat diet 5HT2c receptors are required for the attenuation of obesity.
Wang
Biao
B
Department of Laboratory Medicine, University of California, San Francisco, CA 94143-1034, USA.
Chehab
Farid F
FF
D054369:Agouti-Related Protein; D000818:Animals; D001835:Body Weight; D004032:Diet; D007031:Hypothalamus / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D020738:Leptin / Q000096:biosynthesis* / Q000235:genetics; D008060:Lipodystrophy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000096:biosynthesis; D009479:Neuropeptides / Q000096:biosynthesis; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin
D054369:Agouti-Related Protein; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009478:Neuropeptide Y; D009479:Neuropeptides; D044405:Receptor, Serotonin, 5-HT2C; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D011333:Pro-Opiomelanocortin