title: The acute effects of leptin require PI3K signaling in the hypothalamic ventral premammillary nucleus.
abstract: Evidence suggests that the role played by the adipocyte-derived hormone leptin in female reproductive physiology is mediated in part by neurons located within the ventral premammillary nucleus (PMV). Leptin activates PMV neurons; however, the intracellular signaling pathway and channel(s) involved remain undefined. Notably, leptin's excitatory and inhibitory effects within hypothalamic and brainstem nuclei share the intracellular signaling cascade phosphoinositide 3 kinase (PI3K). Therefore, we assessed whether PI3K signaling is required for the acute effect of leptin to alter cellular activity of PMV neurons that express leptin receptors (LepR PMV neurons). Leptin caused a rapid depolarization in the majority of LepR PMV neurons in patch-clamp recordings of hypothalamic slices, while a subset of LepR PMV neurons were hyperpolarized in response to leptin. Data were obtained from both male and female mice and results demonstrate that the acute effect of leptin on LepR PMV neurons was identical for both sexes. Pharmacological inhibition of PI3K prevented the acute leptin-induced change in neuronal activity of LepR PMV neurons, indicating a PI3K-dependent mechanism of leptin action. Similarly, mice with genetically disrupted PI3K signaling in LepR PMV neurons failed to alter cellular activity in response to leptin. Moreover, the leptin-induced depolarization was dependent on a putative TRPC channel. In contrast, the leptin-induced-hyperpolarization required the activation of a putative Katp channel. Collectively, these results suggest that PI3K signaling in LepR PMV neurons is essential for leptin-induced alteration in cellular activity, and these data may suggest a cellular correlate in which leptin contributes to the initiation of reproductive development.
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. Kevin.Williams@UTSouthwestern.edu
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Williams
authors.forename: Jong-Woo
authors.initials: JW
authors.lastname: Sohn
authors.forename: Jose
authors.initials: J
authors.lastname: Donato
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Lee
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Carol F
authors.initials: CF
authors.lastname: Elias
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D054086:KATP Channels / Q000502:physiology; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021122:Protein Subunits / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D001896:Boron Compounds; D002867:Chromones; D007093:Imidazoles; D054086:KATP Channels; D020738:Leptin; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021122:Protein Subunits; D050052:TRPC Cation Channels; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C109986:2-aminoethoxydiphenyl borate; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole