Activation of murine pre-proglucagon–producing neurons reduces food intake and body weight
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
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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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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Figure 2

Activation of GCG neurons transfected with Gq DREADD.

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Activation of GCG neurons transfected with Gq DREADD. Microinjection of ...
Microinjection of AAV2/5-hSyn-DIO-hM3Dq (Gq)-mCherry (A) resulted in Gq DREADD expression exclusively in GLP-1–immunoreactive neurons of the NTS (B) and the VLM (C); GLP-1, black precipitate; mCherry, brown precipitate. ITR, inverted terminal repeat. Some GLP-1–labeled cells lacked DsRed labeling (marked with asterisks in B). (D–F) Functional Gq DREADD expression was demonstrated by intense Fos induction within DsRed-labeled neurons of the NTS (D) and VLM (E) 2 hours following CNO injection. Strong Fos IR was seen in DsRed-labeled neurons (F). CNO treatment induced intense Fos staining largely limited to neurons displaying GLP-1 IR in the NTS (G) and the VLM (H). Most GCG neurons showed strong Fos staining in both NTS and VLM (I). Two saline-injected GCG-Gq DREADD mice showed a complete lack of Fos IR within DsRed- (J) and GLP-1–immunolabeled neurons (K). (L) Distribution of GCG neurons in the caudal medulla. (M–R) A small but significant increase in CNO-induced Fos staining was seen in the PVH (M, N, and O) and the arcuate nucleus (Arc; P, Q, and R), when GCG-Gq DREADD mice (M and P) were compared with controls (N and Q). n = 4 animals per group; all comparisons made using t test, *P < 0.05, **P < 0.01. Scale bars are in micrometers.