Activation of murine pre-proglucagon–producing neurons reduces food intake and body weight
Ronald P. Gaykema ... Kevin W. Williams, Michael M. Scott
Ronald P. Gaykema ... Kevin W. Williams, Michael M. Scott
Published March 1, 2017
Citation Information: J Clin Invest. 2017;127(3):1031-1045. doi:10.1172/JCI81335.
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Categories: Research Article Metabolism Neuroscience

Activation of murine pre-proglucagon–producing neurons reduces food intake and body weight

Abstract

Peptides derived from pre-proglucagon (GCG peptides) act in both the periphery and the CNS to change food intake, glucose homeostasis, and metabolic rate while playing a role in anxiety behaviors and physiological responses to stress. Although the actions of GCG peptides produced in the gut and pancreas are well described, the role of glutamatergic GGC peptide–secreting hindbrain neurons in regulating metabolic homeostasis has not been investigated. Here, we have shown that chemogenetic stimulation of GCG-producing neurons reduces metabolic rate and food intake in fed and fasted states and suppresses glucose production without an effect on glucose uptake. Stimulation of GCG neurons had no effect on corticosterone secretion, body weight, or conditioned taste aversion. In the diet-induced obese state, the effects of GCG neuronal stimulation on gluconeogenesis were lost, while the food intake–lowering effects remained, resulting in reductions in body weight and adiposity. Our work suggests that GCG peptide–expressing neurons can alter feeding, metabolic rate, and glucose production independent of their effects on hypothalamic pituitary-adrenal (HPA) axis activation, aversive conditioning, or insulin secretion. We conclude that GCG neurons likely stimulate separate populations of downstream cells to produce a change in food intake and glucose homeostasis and that these effects depend on the metabolic state of the animal.

Authors

Ronald P. Gaykema, Brandon A. Newmyer, Matteo Ottolini, Vidisha Raje, Daniel M. Warthen, Philip S. Lambeth, Maria Niccum, Ting Yao, Yiru Huang, Ira G. Schulman, Thurl E. Harris, Manoj K. Patel, Kevin W. Williams, Michael M. Scott

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Characterization of Gcg-Cre mice. (A) Cre recombinase was inserted into ...

Figure 1

Characterization of Gcg-Cre mice.

(A) Cre recombinase was inserted into the Gcg gene locus of BAC RP23-242F22 at the ATG start codon. Red boxes, 5′ and 3′ untranslated regions; white boxes, Gcg exons; lines, intronic DNA. (B–I) Cre recombinase expression within GCG neurons was visualized by crossing Gcg-Cre mice with tdTomato reporter animals. tdTomato fluorescence (NTS in C; VLM in F) is restricted to GLP-1–expressing cells (B and E) in the NTS (D) and the VLM (G). Specificity of Cre recombinase expression is high, with virtually all tdTomato-labeled cells in the NTS (99%) and more than 92% in the VLM showing GLP-1 immunofluorescence (H). The majority of GLP-1–labeled neurons show Cre recombinase activity, with efficacy ranging from 84% in the VLM to 93% in the NTS (I). The few GLP-1–positive neurons that lack tdTomato signal are marked with green asterisks (in B, D, E, and G). (J and K) PVH and arcuate nuclei (Arc) neurons did not show expression, but tdTomato-labeled axons and terminals originating from brainstem GCG neurons were readily observed. AHE, anterior hypothalamic nucleus; ME, median eminence. (L–O) GCG-Gq DREADD transgenic mice exhibit normal body weight (L), daily chow food intake (M), and normal fed (N) and fasting (O) glucose levels. Scale bars in B–G, J, and K are in micrometers.