Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene.
Brain serotonin and leptin signaling contribute substantially to the regulation of feeding and energy expenditure. Here we show that young adult mice with a targeted mutation of the serotonin 5-HT2C receptor gene consume more food despite normal responses to exogenous leptin administration. Chronic hyperphagia leads to a 'middle-aged'-onset obesity associated with a partial leptin resistance of late onset. In addition, older mice develop insulin resistance and impaired glucose tolerance. Mutant mice also responded more to high-fat feeding, leading to hyperglycemia without hyperlipidemia. These findings demonstrate a dissociation of serotonin and leptin signaling in the regulation of feeding and indicate that a perturbation of brain serotonin systems can predispose to type 2 diabetes.
Department of Psychiatry and Center for Neurobiology and Psychiatry, University of California at San Francisco, 94143-0984, USA.
K
K
Nonogaki
A M
AM
Strack
M F
MF
Dallman
L H
LH
Tecott
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D015984:Causality; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology*; D004041:Dietary Fats; D004435:Eating / Q000187:drug effects; D006706:Homeostasis; D006963:Hyperphagia / Q000209:etiology* / Q000235:genetics; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D020738:Leptin; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009765:Obesity / Q000209:etiology; D011506:Proteins / Q000494:pharmacology*; D044405:Receptor, Serotonin, 5-HT2C; D054411:Receptors, Leptin; D011985:Receptors, Serotonin / Q000235:genetics*
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D020738:Leptin; D011506:Proteins; D044405:Receptor, Serotonin, 5-HT2C; D054411:Receptors, Leptin; D011985:Receptors, Serotonin; C515447:leptin receptor, mouse