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.
All data generated or analysed during this study are included in the manuscript and supporting files.
- David Spanswick
- Tony Tiganis
- Michael A Cowley
- Tamas L Horvath
- Zhong-Yin Zhang
- Sofianos Andrikopoulos
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Experiments were approved by the Monash University School of Biomedical Sciences Animal EthicsCommittee (MARP2013/137).
- Richard D Palmiter, Howard Hughes Medical Institute, University of Washington, United States
© 2018, Dodd et al.
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