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Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus

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Abstract

The administration of leptin1 to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity2,3. 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 activity4,5,6. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus7 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 metabolism8,9. 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.

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Figure 1: Generation of transgenic mice expressing EGFP in ARC POMC neurons.
Figure 2: Activation of MOP-Rs hyperpolarizes the EGFP-labelled POMC neurons by opening G-protein-coupled inwardly rectifying potassium channels.
Figure 3: Leptin depolarizes POMC neurons through a nonspecific cation channel, and decreases the GABA-mediated tone onto POMC cells.
Figure 4: The GABA-mediated inputs to POMC cells are from NPY neurons that co-express GABA.

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Acknowledgements

We wish to thank V. J. Hruby for the d-Trp8-γMSH, O. K. Ronnekliev, R. G. Allen and M. R. Brown for antisera and J. T. Williams and J. M. Brundege for advice. This work was supported by the NIH, a Fogarty International Research Collaborative Award, the International Scholar Program of the Howard Hughes Medical Institute, and Agencia Nacional de Promoción Cientifica y Technológica.

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  1. Michael A. Cowley, James L. Smart and Tamas L. Horvath: These authors contributed equally to this work

Authors and Affiliations

  1. The Vollum Institute, Oregon Health Sciences University, Portland, 97201-3098, Oregon, USA

    Michael A. Cowley, James L. Smart, Roger D. Cone & Malcolm J. Low

  2. CONICET and Department of Biology, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, School of Sciences, University of Buenos Aires, 1428, Argentina

    Marcelo Rubinstein & Marcelo G. Cerdán

  3. Department of Obstetrics and Gynecology, Reproductive Neurosciences Unit,

    Sabrina Diano & Tamas L. Horvath

  4. Department of Neurobiology, Yale Medical School, New Haven, 06520, Connecticut, USA

    Tamas L. Horvath

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  1. Michael A. Cowley
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  2. James L. Smart
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  7. Roger D. Cone
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Correspondence to Roger D. Cone.

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Cowley, M., Smart, J., Rubinstein, M. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001). https://doi.org/10.1038/35078085

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