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

Author

Listed:
  • Michael A. Cowley

    (The Vollum Institute, Oregon Health Sciences University)

  • James L. Smart

    (The Vollum Institute, Oregon Health Sciences University)

  • Marcelo Rubinstein

    (Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, School of Sciences, University of Buenos Aires)

  • Marcelo G. Cerdán

    (Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, School of Sciences, University of Buenos Aires)

  • Sabrina Diano

    (Reproductive Neurosciences Unit)

  • Tamas L. Horvath

    (Reproductive Neurosciences Unit
    Yale Medical School)

  • Roger D. Cone

    (The Vollum Institute, Oregon Health Sciences University)

  • Malcolm J. Low

    (The Vollum Institute, Oregon Health Sciences University)

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.

Suggested Citation

  • Michael A. Cowley & James L. Smart & Marcelo Rubinstein & Marcelo G. Cerdán & Sabrina Diano & Tamas L. Horvath & Roger D. Cone & Malcolm J. Low, 2001. "Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus," Nature, Nature, vol. 411(6836), pages 480-484, May.
  • Handle: RePEc:nat:nature:v:411:y:2001:i:6836:d:10.1038_35078085
    DOI: 10.1038/35078085
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    Cited by:

    1. Mingming Xing & Yang Li & Yuqi Zhang & Juemou Zhou & Danting Ma & Mengqi Zhang & Minglei Tang & Ting Ouyang & Fumiao Zhang & Xiaofeng Shi & Jianyuan Sun & Zuxin Chen & Weiping J. Zhang & Shuli Zhang &, 2024. "Paraventricular hypothalamic RUVBL2 neurons suppress appetite by enhancing excitatory synaptic transmission in distinct neurocircuits," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    2. Sheng Qiu & Qinan Wu & Hao Wang & Dongfang Liu & Chen Chen & Zhiming Zhu & Hongting Zheng & Gangyi Yang & Ling Li & Mengliu Yang, 2024. "AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Stephan Dodt & Noah V. Widdershooven & Marie-Luise Dreisow & Lisa Weiher & Lukas Steuernagel & F. Thomas Wunderlich & Jens C. Brüning & Henning Fenselau, 2024. "NPY-mediated synaptic plasticity in the extended amygdala prioritizes feeding during starvation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Alena A. Nikanorova & Nikolay A. Barashkov & Sergey S. Nakhodkin & Vera G. Pshennikova & Aisen V. Solovyev & Georgii P. Romanov & Sargylana S. Kuzmina & Nikolay N. Sazonov & Tatyana E. Burtseva & Jon , 2020. "The Role of Leptin Levels in Adaptation to Cold Climates," IJERPH, MDPI, vol. 17(6), pages 1-13, March.
    5. Hancheng Mao & Geun Hyang Kim & Linxiu Pan & Ling Qi, 2024. "Regulation of leptin signaling and diet-induced obesity by SEL1L-HRD1 ER-associated degradation in POMC expressing neurons," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. Hongli Li & Yuanzhong Xu & Yanyan Jiang & Zhiying Jiang & Joshua Otiz-Guzman & Jessie C. Morrill & Jing Cai & Zhengmei Mao & Yong Xu & Benjamin R. Arenkiel & Cheng Huang & Qingchun Tong, 2023. "The melanocortin action is biased toward protection from weight loss in mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    7. Stéphane Leon & Vincent Simon & Thomas H. Lee & Lukas Steuernagel & Samantha Clark & Nasim Biglari & Thierry Lesté-Lasserre & Nathalie Dupuy & Astrid Cannich & Luigi Bellocchio & Philippe Zizzari & Ca, 2024. "Single cell tracing of Pomc neurons reveals recruitment of ‘Ghost’ subtypes with atypical identity in a mouse model of obesity," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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