Hypothalamic apolipoprotein A-IV is regulated by leptin.
Apolipoprotein A-IV (apo A-IV) is a satiety factor involved in the control of food intake and body weight. Our previous studies demonstrated that apo A-IV is present in areas of the hypothalamus where leptin acts to influence energy homeostasis. In the present studies, we found that leptin-deficient obese (ob/ob) mice have significantly reduced hypothalamic apo A-IV mRNA levels. Intragastric infusion of a lipid emulsion significantly stimulated hypothalamic apo A-IV gene expression in lean controls but not in ob/ob mice. Daily ip administration of leptin (3 microg/g) for 5 d significantly increased hypothalamic apo A-IV mRNA levels of ob/ob mice relative to pair-fed controls. In addition, centrally administered leptin raised the reduced apo A-IV gene expression induced by fasting. Using immunohistochemistry, we demonstrated that apo A-IV is present in leptin-sensitive phosphorylated signal transducer and activator of transcription 3 (pSTAT3)-positive cells of the arcuate nucleus of the hypothalamus. Knockdown of STAT3 expression by small interfering RNA significantly attenuated the stimulatory effect of leptin on apo A-IV protein expression in cultured primary hypothalamic neurons, implying that the hypothalamic apo A-IV is regulated by leptin, at least partially, via the STAT3 signaling pathway. Third-ventricular (intracerebroventricular) administration of a subthreshold dose of leptin (1 microg) potentiated apo A-IV-induced (subthreshold dose, 0.5 microg) reduction of feeding, indicating the existence of a functional synergistic interaction between leptin and apo A-IV, leading to suppression of food intake.
Shen
Ling
L
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237-0507, USA.
Tso
Patrick
P
Woods
Stephen C
SC
Sakai
Randall R
RR
Davidson
W Sean
WS
Liu
Min
M
D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D004435:Eating / Q000187:drug effects; D004622:Embryo, Mammalian; D005215:Fasting / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D007031:Hypothalamus / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
D001054:Apolipoproteins A; D020738:Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C022205:apolipoprotein A-IV