Insulin regulates POMC neuronal plasticity to control glucose metabolism

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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.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Garron T Dodd

Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Natalie J Michael

Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9032-0862
Robert S Lee-Young

Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Salvatore P Mangiafico

Department of Medicine, University of Melbourne, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Jack T Pryor

Department of Physiology, Monash University, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Astrid C Munder

Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Stephanie E Simonds

Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Jens Claus Brüning

Department of Neuronal Control of Metabolism, Max Plank Institute for Metabolism Research, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Zhong-Yin Zhang

Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, United States

Competing interests
The authors declare that no competing interests exist.
Michael A Cowley

Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Sofianos Andrikopoulos

Department of Medicine, University of Melbourne, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Tamas L Horvath

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7522-4602
David Spanswick

Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia

For correspondence
David.Spanswick@monash.edu

Competing interests
The authors declare that no competing interests exist.
Tony Tiganis

Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia

For correspondence
Tony.Tiganis@monash.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8065-9942

Funding

National Health and Medical Research Council

David Spanswick
Tony Tiganis

National Health and Medical Research Council

Michael A Cowley

National Institutes of Health

Tamas L Horvath

National Institutes of Health

Zhong-Yin Zhang

National Health and Medical Research Council

Sofianos Andrikopoulos

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Experiments were approved by the Monash University School of Biomedical Sciences Animal EthicsCommittee (MARP2013/137).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.