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Cell. 2016 Mar 24;165(1):125-138. doi: 10.1016/j.cell.2016.02.044.

AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue.

Author information

1
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
2
Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Biocenter, Institute for Zoology, University of Cologne, Zülpicher Strasse 47b, 50674 Cologne, Germany.
3
Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
4
Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
5
Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Department II of Internal Medicine, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
6
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany.
7
Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 55242, USA.
8
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; National Center for Diabetes Research (DZD) Ingolstädter Land Strasse 1, 85764 Neuherberg, Germany. Electronic address: bruening@sf.mpg.de.

Abstract

Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation. Optogenetic circuitry mapping reveals that feeding and insulin sensitivity are controlled by both distinct and overlapping projections. Stimulation of AgRP → LHA projections impairs insulin sensitivity and promotes feeding while activation of AgRP → anterior bed nucleus of the stria terminalis (aBNST)vl projections, distinct from AgRP → aBNSTdm projections controlling feeding, mediate the effect of AgRP neuron activation on BAT-myostatin expression and insulin sensitivity. Collectively, our results suggest that AgRP neurons in mice induce not only eating, but also insulin resistance by stimulating expression of muscle-related genes in BAT, revealing a mechanism by which these neurons rapidly coordinate hunger states with glucose homeostasis.

Comment in

PMID:
27015310
PMCID:
PMC5157157
DOI:
10.1016/j.cell.2016.02.044
[Indexed for MEDLINE]
Free PMC Article

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