DREADDing proglucagon neurons: a fresh look at metabolic regulation by the brain
Jonathan E. Campbell, David A. D’Alessio
Jonathan E. Campbell, David A. D’Alessio
Published February 20, 2017
Citation Information: J Clin Invest. 2017;127(3):793-795. https://doi.org/10.1172/JCI92845.
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Commentary

DREADDing proglucagon neurons: a fresh look at metabolic regulation by the brain

Abstract

Glucagon-like peptide 1 receptor (GLP-1R) signaling in the CNS has been linked to reduced food intake, lower body weight, improved glucose homeostasis, and activation of CNS stress axes. GLP-1 is produced by cells that express proglucagon (GCG); however, the stimuli that activate GCG+ neurons are not well known, which has made understanding the role of this neuronal population in the CNS a challenge. In this issue of the JCI, Gaykema et al. use designer receptors exclusively activated by designer drugs (DREADD) technology to specifically activate GCG+ neurons in mouse models. While activation of GCG+ neurons did reduce food intake, and variably decreased hepatic glucose production, other GLP-1–associated effects were not observed — e.g., activation of stress axes or stimulation of insulin secretion — in response to GCG+ neuron activation. The authors have provided a valuable model to study this set of neurons in vivo, and their results provide new insights into the function of GCG+ neural activity in the brain and raise questions that will move research on this clinically relevant neural system forward.

Authors

Jonathan E. Campbell, David A. D’Alessio

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Figure 1

Comparison of the physiological effects of activating GCG+ neurons versus peripheral or systemic activation of GLP-1R.

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Comparison of the physiological effects of activating GCG+ neurons versu...
Clozapine N-oxide (CNO) activation of Gαq receptors expressed exclusively in GCG+ neurons leads to a decrease in food intake. The neurotransmitter responsible, as well as the projection sites of the GCG+ neurons, is unclear. Support for GLP-1 as a key neurotransmitter secreted by GCG+ neurons is provided by the idea that GLP-1 is likely a product of the cells and also that GCG+ neurons project on to GLP-1R+ cell bodies in the hypothalamus, a key CNS site that controls many of the physiological actions outlined here. However, the fact that activation of GCG+ neurons fails to elicit previously demonstrated effects of CNS GLP-1 leaves open the question as to which neurotransmitter these cells express. It still remains to be seen whether these discrepancies arise due to differences in methodology (i.e., physiology versus pharmacology) or if activation of GCG+ neurons provides more precise activation of biological events (i.e., only food intake). OXM, oxyntomodulin; Ach, acetylcholine; NE, norepinephrine.