Lack of the serotonin transporter in mice reduces locomotor activity and leads to gender-dependent late onset obesity.
OBJECTIVE
Mice deficient of the serotonin transporter (5-HTT ko) mice have a reduced brain serotonin content and develop late-onset obesity. To elucidate the pathophysiology of this obesity, we analyzed the expression of the interrelated weight-regulatory molecules: brain-derived neurotrophic factor (BDNF) and leptin receptor (LR) in brain areas associated with nutrition and activity.


METHODS
We investigated feeding behavior, physical activity and metabolic parameters of 5-HTT ko and wild-type mice and measured the expression of BDNF and LR in brain areas associated with nutrition and activity using quantitative real-time PCR. The influence of age, gender and fasting was analyzed.


RESULTS
Male 5-HTT ko mice developed obesity without hyperphagia from the age of 5 months. Physical activity was reduced in old male, but not old female, 5-HTT ko mice. The BDNF gene expression in frontal cortex was elevated in young, but reduced in old 5-HTT ko mice. Fasting failed to increase the BDNF gene expression in frontal cortex of young 5 HTT ko mice and in the hypothalamus in old 5-HTT ko mice. The fasting-induced hypothalamic increase of LR was absent in both young and old 5-HTT ko mice.


CONCLUSIONS
We propose that low brain serotonin level due to the 5-HTT ko genotype leads to reduced physical activity and low BDNF, which together with the lack of fasting-induced hypothalamic BDNF and LR production results in late-onset obesity. Although lack of the 5-HTT is a genetic vulnerability factor for obesity, female gender is protective.
Uçeyler
N
N
Department of Neurology, University of Würzburg, Würzburg, Germany.
Schütt
M
M
Palm
F
F
Vogel
C
C
Meier
M
M
Schmitt
A
A
Lesch
K-P
KP
Mössner
R
R
Sommer
C
C
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000378:metabolism*; D005247:Feeding Behavior; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009765:Obesity / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D054411:Receptors, Leptin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors
D019208:Brain-Derived Neurotrophic Factor; D026901:Membrane Transport Proteins; D054411:Receptors, Leptin; D050486:Serotonin Plasma Membrane Transport Proteins; C515447:leptin receptor, mouse