title: Appropriate inhibition of orexigenic hypothalamic arcuate nucleus neurons independently of leptin receptor/STAT3 signaling.
abstract: Leptin directly suppresses the activity of orexigenic neurons in the hypothalamic arcuate nucleus (ARC). We examined c-Fos-like immunoreactivity (CFLIR) as a marker of ARC neuronal activity in db/db mice devoid of the signaling form of the leptin receptor (LRb) and s/s mice that express LRb(S1138) [which is defective for STAT3 (signal transducer and activator of transcription) signaling]. Both db/db and s/s animals are hyperphagic and obese. This analysis revealed that CFLIR in agouti related peptide-expressing orexigenic ARC neurons is basally elevated in db/db but not s/s mice. Consistent with these observations, electrophysiologic evaluation of a small number of neurons in s/s animals suggested that leptin appropriately suppresses the frequency of IPSCs on ARC proopiomelanocortin (POMC) neurons that are mediated by the release of GABA from orexigenic ARC neurons. CFLIR in POMC neurons of s/s mice was also increased compared with db/db animals. Thus, these data suggest that, although LRb-->STAT3 signaling is crucial for the regulation of feeding, it is not required for the acute or chronic regulation of orexigenic ARC neurons, and the activation of STAT3-mediated transcription by leptin is not required for the appropriate development of leptin responsiveness in these neurons.
authors.affiliation: Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Münzberg
authors.forename: Erin E
authors.initials: EE
authors.lastname: Jobst
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Bates
authors.forename: Justin
authors.initials: J
authors.lastname: Jones
authors.forename: Eneida
authors.initials: E
authors.lastname: Villanueva
authors.forename: Rebecca
authors.initials: R
authors.lastname: Leshan
authors.forename: Marie
authors.initials: M
authors.lastname: Björnholm
authors.forename: Joel
authors.initials: J
authors.lastname: Elmquist
authors.forename: Mark
authors.initials: M
authors.lastname: Sleeman
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cowley
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D011956:Receptors, Cell Surface / Q000378:metabolism*; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C515447:leptin receptor, mouse