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

Research output: Contribution to journalArticleResearchpeer-review

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, Garron T ; Michael, Natalie J ; Lee-Young, Robert S. ; Mangiafico, Salvatore P. ; Pryor, Jack T ; Munder, Astrid C ; Simonds, Stephanie E ; Brüning, Jens Claus ; Zhang, Zhong-Yin ; Cowley, Michael A ; Andrikopoulos, Sofianos ; Horvath, Tamas L ; Spanswick, David ; Tiganis, Tony. / Insulin regulates POMC neuronal plasticity to control glucose metabolism. In: eLife. 2018 ; Vol. 7.
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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.",
keywords = "cellular signalling, glucose metabolism, human biology, hypothalamus, insulin, medicine, mouse, neuroscience, POMC neurons, protein tyrosine phosphatase",
author = "Dodd, {Garron T} and Michael, {Natalie J} and Lee-Young, {Robert S.} and Mangiafico, {Salvatore P.} and Pryor, {Jack T} and Munder, {Astrid C} and Simonds, {Stephanie E} and Br{\"u}ning, {Jens Claus} and Zhong-Yin Zhang and Cowley, {Michael A} and Sofianos Andrikopoulos and Horvath, {Tamas L} and David Spanswick and Tony Tiganis",
year = "2018",
month = "9",
day = "19",
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Dodd, GT, Michael, NJ, Lee-Young, RS, Mangiafico, SP, Pryor, JT, Munder, AC, Simonds, SE, Brüning, JC, Zhang, Z-Y, Cowley, MA, Andrikopoulos, S, Horvath, TL, Spanswick, D & Tiganis, T 2018, 'Insulin regulates POMC neuronal plasticity to control glucose metabolism', eLife, vol. 7, e38704. https://doi.org/10.7554/eLife.38704

Insulin regulates POMC neuronal plasticity to control glucose metabolism. / Dodd, Garron T; Michael, Natalie J; Lee-Young, Robert S.; Mangiafico, Salvatore P.; Pryor, Jack T; Munder, Astrid C; Simonds, Stephanie E; Brüning, Jens Claus; Zhang, Zhong-Yin; Cowley, Michael A; Andrikopoulos, Sofianos; Horvath, Tamas L; Spanswick, David; Tiganis, Tony.

In: eLife, Vol. 7, e38704, 19.09.2018.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Dodd, Garron T

AU - Michael, Natalie J

AU - Lee-Young, Robert S.

AU - Mangiafico, Salvatore P.

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AU - Munder, Astrid C

AU - Simonds, Stephanie E

AU - Brüning, Jens Claus

AU - Zhang, Zhong-Yin

AU - Cowley, Michael A

AU - Andrikopoulos, Sofianos

AU - Horvath, Tamas L

AU - Spanswick, David

AU - Tiganis, Tony

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KW - glucose metabolism

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KW - neuroscience

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KW - protein tyrosine phosphatase

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