Insulin regulates POMC neuronal plasticity to control glucose metabolism

Garron T Dodd, Natalie J Michael, Robert S. Lee-Young, Salvatore P. Mangiafico, Jack T Pryor, Astrid C Munder, Stephanie E Simonds, Jens Claus Brüning, Zhong-Yin Zhang, Michael A Cowley, Sofianos Andrikopoulos, Tamas L Horvath, David Spanswick, Tony Tiganis

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18 Citations (Scopus)

Abstract

Hypothalamic neurons respond to nutritional cues by altering gene expression and neuronal excitability. The mechanisms that control such adaptive processes remain unclear. Here we define populations of POMC neurons in mice that are activated or inhibited by insulin and thereby repress or inhibit hepatic glucose production (HGP). The proportion of POMC neurons activated by insulin was dependent on the regulation of insulin receptor signaling by the phosphatase TCPTP, which is increased by fasting, degraded after feeding and elevated in diet-induced obesity. TCPTP-deficiency enhanced insulin signaling and the proportion of POMC neurons activated by insulin to repress HGP. Elevated TCPTP in POMC neurons in obesity and/or after fasting repressed insulin signaling, the activation of POMC neurons by insulin and the insulin-induced and POMC-mediated repression of HGP. Our findings define a molecular mechanism for integrating POMC neural responses with feeding to control glucose metabolism.

Original languageEnglish
Article numbere38704
Number of pages30
JournaleLife
Volume7
DOIs
Publication statusPublished - 19 Sep 2018

Keywords

  • cellular signalling
  • glucose metabolism
  • human biology
  • hypothalamus
  • insulin
  • medicine
  • mouse
  • neuroscience
  • POMC neurons
  • protein tyrosine phosphatase

Cite this

Dodd, G. T., Michael, N. J., Lee-Young, R. S., Mangiafico, S. P., Pryor, J. T., Munder, A. C., Simonds, S. E., Brüning, J. C., Zhang, Z-Y., Cowley, M. A., Andrikopoulos, S., Horvath, T. L., Spanswick, D., & Tiganis, T. (2018). Insulin regulates POMC neuronal plasticity to control glucose metabolism. eLife, 7, [e38704]. https://doi.org/10.7554/eLife.38704