Enhanced hypothalamic leptin signaling in mice lacking dopamine D2 receptors.
The dopamine D(2) receptor (D2R) plays a critical role in diverse neurophysiological functions. D2R knock-out mice (D2R(-/-)) show reduced food intake and body weight while displaying an increased basal energy expenditure level, compared with their wild type littermates. Thus, these mice show a lean phenotype. D2R(-/-) mice displayed increased leptin sensitivity, and leptin injection induced increased phosphorylation of the hypothalamic signal transducer and activator of transcription 3 (STAT3) in D2R(-/-) mice relative to wild type littermates. Using double immunofluorescence histochemistry, we have demonstrated that D2Rs are present in leptin-sensitive STAT3-positive cells in the arcuate nucleus of the hypothalamus and that leptin injection induces STAT3 phosphorylation in hypothalamic neurons expressing D2Rs. Stimulation of D2R by the D2R agonist quinpirole suppressed the leptin-induced STAT3 phosphorylation and nuclear trans-localization of phospho-STAT3 in the hypothalamus of wild type mice. However, this regulation was not detected in the D2R(-/-) mice. Treatment of D2R agonist and antagonist could modulate the leptin-induced food intake and body weight changes in wild type mice but not in D2R(-/-) mice. Together, our findings suggest that the interaction between the dopaminergic system and leptin signaling in hypothalamus is important in control of energy homeostasis.
Kim
Kyu Seok
KS
School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
Yoon
Ye Ran
YR
Lee
Hyo Jin
HJ
Yoon
Sehyoun
S
Kim
Sa-Yong
SY
Shin
Seung Woo
SW
An
Juan Ji
JJ
Kim
Min-Seon
MS
Choi
Se-Young
SY
Sun
Woong
W
Baik
Ja-Hyun
JH
D000818:Animals; D001823:Body Composition; D002467:Cell Nucleus / Q000378:metabolism; D003433:Crosses, Genetic; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization; D020738:Leptin / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D020738:Leptin; D017448:Receptors, Dopamine D2; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse