Artículo

Cowley, M.A.; Smart, J.L.; Rubinstein, M.; Cerdán, M.G.; Diano, S.; Horvath, T.L.; Cone, R.D.; Low, M.J. "Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus" (2001) Nature. 411(6836):480-484
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Abstract:

The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (γ-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.

Registro:

Documento: Artículo
Título:Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus
Autor:Cowley, M.A.; Smart, J.L.; Rubinstein, M.; Cerdán, M.G.; Diano, S.; Horvath, T.L.; Cone, R.D.; Low, M.J.
Filiación:Vollum Institute, Oregon Health Sciences University, Portland, OR 97201-3098, United States
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Department of Biology, University of Buenos Aires, 1428, Argentina
Reproductive Neurosciences Unit, Department of Obstetrics and Gynecology, Yale Medical School, New Haven, CT 06520, United States
Department of Neurobiology, Yale Medical School, New Haven, CT 06520, United States
Palabras clave:Electrophysiology; Hormones; Metabolism; Proteins; Neurons; Neural networks; 4 aminobutyric acid; cation channel; green fluorescent protein; leptin; neuropeptide Y; proopiomelanocortin; action potential; animal cell; animal experiment; arcuate nucleus; article; controlled study; depolarization; embryo; gene expression; gene targeting; male; mouse; nerve cell; nerve cell network; nonhuman; priority journal; regulatory mechanism; transgenic mouse; Action Potentials; Animals; Animals, Genetically Modified; Anorexia; Arcuate Nucleus; Electrophysiology; Evoked Potentials; gamma-Aminobutyric Acid; Green Fluorescent Proteins; Leptin; Luminescent Proteins; Male; Mice; Mice, Inbred C57BL; Nerve Net; Neural Inhibition; Neurons; Neuropeptide Y; Pro-Opiomelanocortin; Animalia; Mus musculus
Año:2001
Volumen:411
Número:6836
Página de inicio:480
Página de fin:484
DOI: http://dx.doi.org/10.1038/35078085
Título revista:Nature
Título revista abreviado:Nature
ISSN:00280836
CODEN:NATUA
CAS:gamma-Aminobutyric Acid, 56-12-2; Green Fluorescent Proteins, 147336-22-9; Leptin; Luminescent Proteins; Neuropeptide Y; Pro-Opiomelanocortin, 66796-54-1
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00280836_v411_n6836_p480_Cowley

Referencias:

  • Zhang, Y., Positional cloning of the mouse obese gene and its human homologue (1994) Nature, 372, pp. 425-432
  • Erratum (1995) Nature, 374, p. 479
  • Farooqi, I.S., Effects of recombinant leptin therapy in a child with congenital leptin deficiency (1999) N. Engl. J. Med., 341, pp. 879-884
  • Campfield, L.A., Smith, F.J., Guisez, Y., Devos, R., Burn, P., Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks (1995) Science, 269, pp. 546-549
  • Kim, M.S., The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin (2000) J. Clin. Invest., 105, pp. 1005-1011
  • Haynes, W.G., Morgan, D.A., Walsh, S.A., Mark, A.L., Sivitz, W.I., Receptor-mediated regional sympathetic nerve activation by leptin (1997) J. Clin. Invest., 100, pp. 270-278
  • Haynes, W.G., Morgan, D.A., Djalali, A., Sivitz, W.I., Mark, A.L., Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic (1999) Hypertension, 33, pp. 542-547
  • Hakansson, M.L., Brown, H., Ghilardi, N., Skoda, R.C., Meister, B., Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus (1998) J. Neurosci., 18, pp. 559-572
  • Kalra, S.P., Interacting appetite-regulating pathways in the hypothalamic regulation of body weight (1999) Endocr. Rev., 20, pp. 68-100
  • Cone, R.D., The central melanocortin system and energy homeostasis (1999) Trends Endocrinol. Metab., 10, pp. 211-216
  • Elias, C.F., Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area (1999) Neuron, 23, pp. 775-786
  • Glaum, S.R., Leptin, the obese gene product, rapidly modulates synaptic transmission in the hypothalamus (1996) Mol. Pharmacol., 50, pp. 230-235
  • Spanswick, D., Smith, M.A., Groppi, V.E., Logan, S.D., Ashford, M.L., Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels (1997) Nature, 390, pp. 521-525
  • Lee, K., Dixon, A.K., Richardson, P.J., Pinnock, R.D., Glucose-receptive neurones in the rat ventromedial hypothalamus express KATP channels composed of Kir6.1 and SUR1 subunits (1999) J. Physiol. (Lond.), 515, pp. 439-452
  • Shiraishi, T., Sasaki, K., Niijima, A., Oomura, Y., Leptin effects on feeding-related hypothalamic and peripheral neuronal activities in normal and obese rats (1999) Nutrition, 15, pp. 576-579
  • Bagnol, D., Anatomy of an endogenous antagonist: Relationship between Agouti-related protein and proopiomelanocortin in brain (1999) J. Neurosci., , http://www.jneurosci.org/cgi/content/full/19/18/RC26, cited 25 Aug. 99
  • Butler, A.A., A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse (2000) Endocrinology, 141, pp. 3518-3521
  • Young, J.I., Authentic cell-specific and developmentally regulated expression of pro-opiomelanocortin genomic fragments in hypothalamic and hindbrain neurons of transgenic mice (1998) J. Neurosci., 18, pp. 6631-6640
  • Franklin, K.B.J., Paxinos, G., (1997) The Mouse Brain in Stereotaxic Coordinates, , Academic, San Diego
  • Kelly, M.J., Loose, M.D., Ronnekleiv, O.K., Opioids hyperpolarize β-endorphin neurons via μ-receptor activation of a potassium conductance (1990) Neuroendocrinology, 52, pp. 268-275
  • Slugg, R.M., Hayward, M.D., Ronnekleiv, O.K., Low, M.J., Kelly, M.J., Effect of the μ-opioid agonist DAMGO on medial basal hypothalamic neurons in β-endorphin knock-out mice (2000) Neuroendocrinology, 72, pp. 208-217
  • Powis, J.E., Bains, J.S., Ferguson, A.V., Leptin depolarizes rat hypothalamic paraventricular nucleus neurons (1998) Am. J. Physiol., 274, pp. R1468-R1472
  • Horvath, T.L., Bechmann, I., Naftolin, F., Kalra, S.P., Leranth, C., Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations (1997) Brain Res., 756, pp. 283-286
  • Broberger, C., Landry, M., Wong, H., Walsh, J.N., Hokfelt, T., Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus (1997) Neuroendocrinology, 66, pp. 393-408
  • King, P.J., Widdowson, P.S., Doods, H.N., Williams, G., Regulation of neuropeptide Y release by neuropeptide Y receptor ligands and calcium channel antagonists in hypothalamic slices (1999) J. Neurochem., 73, pp. 641-646
  • Grieco, P., Balse, P.M., Weinberg, D., MacNeil, T., Hruby, V.J., D-Amino acid scan of gamma-melanocyte-stimulating hormone: Importance of Trp(8) on human MC3 receptor selectivity (2000) J. Med. Chem., 43, pp. 4998-5002
  • Csiffary, A., Gorcs, T.J., Palkovits, M., Neuropeptide Y innervation of ACTH-immunoreactive neurons in the arcuate nucleus of rats: A correlated light and electron microscopic double immunolabeling study (1990) Brain Res., 506, pp. 215-222
  • Horvath, T.L., Naftolin, F., Leranth, C., GABAergic and catecholaminergic innervation of mediobasal hypothalamic beta-endorphin cells projecting to the medial preoptic area (1992) Neuroscience, 51, pp. 391-399
  • Cowley, M.A., Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: Evidence of a cellular basis for the adipostat (1999) Neuron, 24, pp. 155-163
  • Halaas, J.L., Physiological response to long-term peripheral and central leptin infusion in lean and obese mice (1997) Proc. Natl Acad. Sci. USA, 94, pp. 8878-8883

Citas:

---------- APA ----------
Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdán, M.G., Diano, S., Horvath, T.L., Cone, R.D.,..., Low, M.J. (2001) . Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature, 411(6836), 480-484.
http://dx.doi.org/10.1038/35078085
---------- CHICAGO ----------
Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdán, M.G., Diano, S., Horvath, T.L., et al. "Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus" . Nature 411, no. 6836 (2001) : 480-484.
http://dx.doi.org/10.1038/35078085
---------- MLA ----------
Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdán, M.G., Diano, S., Horvath, T.L., et al. "Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus" . Nature, vol. 411, no. 6836, 2001, pp. 480-484.
http://dx.doi.org/10.1038/35078085
---------- VANCOUVER ----------
Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdán, M.G., Diano, S., Horvath, T.L., et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411(6836):480-484.
http://dx.doi.org/10.1038/35078085