title: Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus.
abstract: The hypothalamic arcuate nucleus (ARH) is a brain region critical for regulation of food intake and a primary area for the action of leptin in the CNS. In lean mice, the adipokine leptin inhibits neuropeptide Y (NPY) and agouti-related peptide (AgRP) neuronal activity, resulting in decreased food intake. Here we show that diet-induced obesity in mice is associated with persistent activation of NPY neurons and a failure of leptin to reduce the firing rate or hyperpolarize the resting membrane potential. However, the molecular mechanism whereby diet uncouples leptin's effect on neuronal excitability remains to be fully elucidated. In NPY neurons from lean mice, the Kv channel blocker 4-aminopyridine inhibited leptin-induced changes in input resistance and spike rate. Consistent with this, we found that ARH NPY neurons have a large, leptin-sensitive delayed rectifier K(+) current and that leptin sensitivity of this current is blunted in neurons from diet-induced obese mice. This current is primarily carried by Kv2-containing channels, as the Kv2 channel inhibitor stromatoxin-1 significantly increased the spontaneous firing rate in NPY neurons from lean mice. In HEK cells, leptin induced a significant hyperpolarizing shift in the voltage dependence of Kv2.1 but had no effect on the function of the closely related channel Kv2.2 when these channels were coexpressed with the long isoform of the leptin receptor LepRb. Our results suggest that dynamic modulation of somatic Kv2.1 channels regulates the intrinsic excitability of NPY neurons to modulate the spontaneous activity and the integration of synaptic input onto these neurons in the ARH.
authors.affiliation: Department of Physiology, Department of Anatomy and Neurobiology, and Neuroscience Institute, University of Tennessee Health Science Center, Memphis, Tennessee 38163, and Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Baver
authors.forename: Kevin
authors.initials: K
authors.lastname: Hope
authors.forename: Shannon
authors.initials: S
authors.lastname: Guyot
authors.forename: Christian
authors.initials: C
authors.lastname: Bjørbaek
authors.forename: Catherine
authors.initials: C
authors.lastname: Kaczorowski
authors.forename: Kristen M S
authors.initials: KM
authors.lastname: O'Connell
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology*; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000139:chemically induced*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051669:Shab Potassium Channels / Q000378:metabolism
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D020738:Leptin; D009478:Neuropeptide Y; D026902:Potassium Channel Blockers; D051669:Shab Potassium Channels; D049452:Green Fluorescent Proteins
keywords: Kv channels; Kv2.1; arcuate nucleus; hypothalamus; leptin; neuropeptide Y
references.citation: Neuron. 2012 Feb 9;73(3):511-22
references.pmid: 22325203
references.citation: J Neurosci. 2006 Sep 20;26(38):9609-18
references.pmid: 16988031
references.citation: Neuron. 2011 Jul 14;71(1):142-54
references.pmid: 21745644
references.citation: J Neurosci. 2012 Jan 25;32(4):1244-52
references.pmid: 22279209
references.citation: J Neurosci. 2006 Jan 11;26(2):685-95
references.pmid: 16407566
references.citation: J Clin Invest. 2011 Apr;121(4):1424-8
references.pmid: 21364278
references.citation: J Comp Neurol. 2010 Nov 1;518(21):4298-310
references.pmid: 20853508
references.citation: Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):200-6
references.pmid: 19910644
references.citation: Cell Metab. 2007 Mar;5(3):181-94
references.pmid: 17339026
references.citation: Channels (Austin). 2009 Jan-Feb;3(1):46-56
references.pmid: 19276663
references.citation: Neuron. 1990 Oct;5(4):433-43
references.pmid: 2206531
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12351-6
references.pmid: 20566856
references.citation: J Neurosci. 2008 May 7;28(19):4982-94
references.pmid: 18463252
references.citation: Am J Physiol Endocrinol Metab. 2010 Feb;298(2):E193-201
references.pmid: 19671839
references.citation: Neuron. 2003 Feb 20;37(4):649-61
references.pmid: 12597862
references.citation: Nat Med. 2011 Aug 28;17(9):1121-7
references.pmid: 21873987
references.citation: J Physiol. 2000 Jan 1;522 Pt 1:19-31
references.pmid: 10618149
references.citation: Mol Biol Cell. 2006 Oct;17(10):4330-42
references.pmid: 16870705
references.citation: J Biol Chem. 2003 May 9;278(19):17509-14
references.pmid: 12615930
references.citation: Endocrinology. 2004 Nov;145(11):4880-9
references.pmid: 15271881
references.citation: Science. 2005 Oct 28;310(5748):683-5
references.pmid: 16254186
references.citation: Nat Neurosci. 2011 Mar;14(3):351-5
references.pmid: 21209617
references.citation: J Neurophysiol. 1999 Sep;82(3):1512-28
references.pmid: 10482766
references.citation: Physiol Rev. 2010 Jan;90(1):291-366
references.pmid: 20086079
references.citation: FASEB J. 2003 Apr;17(6):720-2
references.pmid: 12586735
references.citation: Annu Rev Physiol. 2008;70:537-56
references.pmid: 17937601
references.citation: Trends Neurosci. 2001 Sep;24(9):517-26
references.pmid: 11506885
references.citation: Neuropharmacology. 2003 Jan;44(1):1-7
references.pmid: 12559116
references.citation: Cell. 2011 Sep 16;146(6):992-1003
references.pmid: 21925320
references.citation: J Biol Chem. 2011 Apr 1;286(13):11707-15
references.pmid: 21270124
references.citation: J Neurosci. 2006 Dec 27;26(52):13505-14
references.pmid: 17192433
references.citation: J Cell Sci. 2005 May 15;118(Pt 10):2155-66
references.pmid: 15855232
references.citation: Cell Metab. 2007 Sep;6(3):229-35
references.pmid: 17767909
references.citation: Nat Neurosci. 2000 Aug;3(8):757-8
references.pmid: 10903566
references.citation: Endocrinology. 2005 Mar;146(3):1043-7
references.pmid: 15591135
references.citation: Nat Neurosci. 2004 Jul;7(7):691-2
references.pmid: 15220926
references.citation: Science. 2004 Apr 2;304(5667):110-5
references.pmid: 15064421
references.citation: J Proteome Res. 2012 Feb 3;11(2):1018-26
references.pmid: 22106938
references.citation: Mol Pharmacol. 2002 Jul;62(1):48-57
references.pmid: 12065754
references.citation: J Biol Chem. 2008 Oct 17;283(42):28066-73
references.pmid: 18718905
references.citation: Nat Neurosci. 2004 May;7(5):493-4
references.pmid: 15097991
references.citation: Nat Neurosci. 2004 Jul;7(7):711-8
references.pmid: 15195093
references.citation: Neuroscience. 1993 Aug;55(3):613-20
references.pmid: 8413924
references.citation: Nature. 2012 Aug 9;488(7410):172-7
references.pmid: 22801496
references.citation: J Neurosci. 2011 Aug 17;31(33):11825-35
references.pmid: 21849543
references.citation: Nature. 1997 Dec 4;390(6659):521-5
references.pmid: 9394003
references.citation: Neuron. 1999 Aug;23(4):775-86
references.pmid: 10482243
references.citation: Neuroscience. 2012 Aug 16;217:56-66
references.pmid: 22554782
references.citation: J Neurosci. 2001 Dec 15;21(24):RC186
references.pmid: 11734601
references.citation: J Neurosci. 2011 Sep 14;31(37):13147-56
references.pmid: 21917798
references.citation: J Biol Chem. 2010 May 14;285(20):15048-15055
references.pmid: 20202934
references.citation: J Neurosci. 2009 Apr 8;29(14):4622-39
references.pmid: 19357287
references.citation: Cardiovasc Res. 2004 Apr 1;62(1):9-33
references.pmid: 15023549
references.citation: Int J Obes (Lond). 2008 Dec;32 Suppl 7:S8-12
references.pmid: 19136996
references.citation: Chem Res Toxicol. 2003 Oct;16(10):1217-25
references.pmid: 14565763
references.citation: Nature. 2001 May 24;411(6836):480-4
references.pmid: 11373681
references.citation: BMC Neurosci. 2004 Dec 06;5:54
references.pmid: 15581426
references.citation: J Neurosci. 2005 Nov 30;25(48):11184-93
references.pmid: 16319318
references.citation: Neurosci Lett. 2010 Dec 10;486(2):60-7
references.pmid: 20600597