Neural site of leptin influence on neuropeptide Y signaling pathways altering feeding and uncoupling protein.
Inhibition of a signal that produces positive energy balance involving neuropeptide Y (NPY) projection from arcuate nucleus (Arc; site of NPY synthesis) to paraventricular nucleus (PVN; site of NPY release) is one potential mechanism of leptin action. NPY in the PVN increases feeding and decreases uncoupling protein (UCP) activity in brown fat, whereas leptin decreases NPY biosynthesis in the Arc, which presumably decreases PVN NPY. It is hypothesized that decreased NPY activity is necessary for the satiety and thermogenic effects of leptin. To test this, we first determined the effect of leptin on feeding in two paradigms: satiated rats and food-deprived rats. Leptin was effective in decreasing feeding in the satiated rats but ineffective in the food-deprived rats. Next, we determined that leptin decreases NPY and increases UCP gene expression. Finally, we injected leptin intracerebroventricularly before specific PVN NPY microinjection. We found that repletion of NPY in PVN by specific NPY microinjection reverses the feeding-inhibitory and thermogenic effects of centrally administered leptin, the first functional evidence indicating that leptin acts on the Arc-PVN feeding-regulatory pathway.
Minnesota Obesity Center, University of Minnesota, Saint Paul 55108, USA.
C M
CM
Kotz
J E
JE
Briggs
J D
JD
Pomonis
M K
MK
Grace
A S
AS
Levine
C J
CJ
Billington
D000704:Analysis of Variance; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D005508:Food Deprivation; D005786:Gene Expression Regulation / Q000187:drug effects*; D007276:Injections, Intraventricular; D007473:Ion Channels; D020738:Leptin; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D024101:Mitochondrial Proteins; D009478:Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology*; D011506:Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009478:Neuropeptide Y; D011506:Proteins; D000071256:Uncoupling Protein 1