Fourth-ventricle leptin infusions dose-dependently activate hypothalamic signal transducer and activator of transcription 3.
Previous studies have shown that very low-dose infusions of leptin into the third or the fourth ventricle alone have little effect on energy balance, but simultaneous low-dose infusions cause rapid weight loss and increased phosphorylation of STAT3 (p-STAT3) in hypothalamic sites that express leptin receptors. Other studies show that injecting high doses of leptin into the fourth ventricle inhibits food intake and weight gain. Therefore, we tested whether fourth-ventricle leptin infusions that cause weight loss are associated with increased leptin signaling in the hypothalamus. In a dose response study 14-day infusions of increasing doses of leptin showed significant hypophagia, weight loss, and increased hypothalamic p-STAT3 in rats receiving at least 0.9 μg leptin/day. In a second study 0.6 μg leptin/day transiently inhibited food intake and reduced carcass fat, but had no significant effect on energy expenditure. In a final study, we identified the localization of STAT3 activation in the hypothalamus of rats receiving 0, 0.3, or 1.2 μg leptin/day. The high dose of leptin, which caused weight loss in the first experiment, increased p-STAT3 in the ventromedial, dorsomedial, and arcuate nuclei of the hypothalamus. The low dose that increased brown fat UCP1 but did not affect body composition in the first experiment had little effect on hypothalamic p-STAT3. We propose that hindbrain leptin increases the precision of control of energy balance by lowering the threshold for leptin signaling in the forebrain. Further studies are needed to directly test this hypothesis.
Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia ruharris@augusta.edu.
Ruth B S
RB
Harris
Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia.
Bhavna N
BN
Desai
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D020546:Fourth Ventricle; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D057967:Infusions, Intraventricular; D020738:Leptin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012249:Rhombencephalon / Q000187:drug effects / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000187:drug effects* / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000187:drug effects / Q000378:metabolism; D000071256:Uncoupling Protein 1 / Q000187:drug effects / Q000378:metabolism
D020738:Leptin; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D019869:Phosphatidylinositol 3-Kinases; D058539:Phosphatidylinositol 3-Kinase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516610:Ptpn1 protein, rat
body composition; energy expenditure; food intake; rats