Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice.
Normal food intake and body weight homeostasis require the direct action of leptin on hypothalamic proopiomelanocortin (POMC) neurons. It has been proposed that leptin action requires PI3K activity. We therefore assessed the contribution of PI3K signaling to leptin's effects on POMC neurons and organismal energy balance. Leptin caused a rapid depolarization of POMC neurons and an increase in action potential frequency in patch-clamp recordings of hypothalamic slices. Pharmacologic inhibition of PI3K prevented this depolarization and increased POMC firing rate, indicating a PI3K-dependent mechanism of leptin action. Mice with genetically disrupted PI3K signaling in POMC cells failed to undergo POMC depolarization or increased firing frequency in response to leptin. Insulin's ability to hyperpolarize POMC neurons was also abolished in these mice. Moreover, targeted disruption of PI3K blunted the suppression of feeding elicited by central leptin administration. Despite these differences, mice with impaired PI3K signaling in POMC neurons exhibited normal long-term body weight regulation. Collectively, these results suggest that PI3K signaling in POMC neurons is essential for leptin-induced activation and insulin-induced inhibition of POMC cells and for the acute suppression of food intake elicited by leptin, but is not a major contributor to the regulation of long-term organismal energy homeostasis.
Hill
Jennifer W
JW
Division of Hypothalamic Research, Department of Internal Medicine and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Williams
Kevin W
KW
Ye
Chianping
C
Luo
Ji
J
Balthasar
Nina
N
Coppari
Roberto
R
Cowley
Michael A
MA
Cantley
Lewis C
LC
Lowell
Bradford B
BB
Elmquist
Joel K
JK
D000818:Animals; D001835:Body Weight; D004435:Eating; D004734:Energy Metabolism; D006706:Homeostasis; D006801:Humans; D007031:Hypothalamus / Q000166:cytology*; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D020738:Leptin; D011333:Pro-Opiomelanocortin; D019869:Phosphatidylinositol 3-Kinases