Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity.
Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at the PI3K pathway, we directly addressed the role of phosphatidylinositol3,4,5-trisphosphate-mediated (PIP3-mediated) signals in hypothalamic proopiomelanocortin (POMC) neurons by inactivating the gene for the PIP3 phosphatase Pten specifically in this cell type. Here we show that POMC-specific disruption of Pten resulted in hyperphagia and sexually dimorphic diet-sensitive obesity. Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of POMC cell-restricted Pten knockout (PPKO) mice, it failed to significantly inhibit food intake in vivo. POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (KATP) channel activity. Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3K inhibitor LY294002 and the KATP blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice. Moreover, icv administration of tolbutamide abolished hyperphagia in PPKO mice. These data indicate that PIP3-mediated signals are critical regulators of the melanocortin system via modulation of KATP channels.
Plum
Leona
L
Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne and Center of Molecular Medicine Cologne (CMMC), Cologne, Germany.
Ma
Xiaosong
X
Hampel
Brigitte
B
Balthasar
Nina
N
Coppari
Roberto
R
Münzberg
Heike
H
Shanabrough
Marya
M
Burdakov
Denis
D
Rother
Eva
E
Janoschek
Ruth
R
Alber
Jens
J
Belgardt
Bengt F
BF
Koch
Linda
L
Seibler
Jost
J
Schwenk
Frieder
F
Fekete
Csaba
C
Suzuki
Akira
A
Mak
Tak W
TW
Krone
Wilhelm
W
Horvath
Tamas L
TL
Ashcroft
Frances M
FM
Brüning
Jens C
JC
D000818:Animals; D002867:Chromones / Q000378:metabolism; D004032:Diet; D004435:Eating / Q000187:drug effects; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015221:Potassium Channels / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology*; D014044:Tolbutamide / Q000494:pharmacology
D002867:Chromones; D007004:Hypoglycemic Agents; D007328:Insulin; D020738:Leptin; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015221:Potassium Channels; D011333:Pro-Opiomelanocortin; D014044:Tolbutamide; C060974:phosphatidylinositol 3,4,5-triphosphate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C487757:Pten protein, mouse