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Hypothalamic Apolipoprotein A-IV Is Regulated by Leptin

Departments of Pathology and Laboratory Medicine (L.S., P.T., W.S.D., M.L.) and Psychiatry (S.C.W., R.R.S.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45237

Address all correspondence and requests for reprints to: Min Liu, Ph.D., Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237-0507. E-mail: lium{at}uc.edu.

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 µg/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 µg) potentiated apo A-IV-induced (subthreshold dose, 0.5 µg) reduction of feeding, indicating the existence of a functional synergistic interaction between leptin and apo A-IV, leading to suppression of food intake.