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 February 20, 2017
Citation Information: J Clin Invest. 2017;127(3):1031-1045. https://doi.org/10.1172/JCI81335.
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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 6

GCG neuronal activation alters metabolic rate and fasting locomotion, but has no effect on conditioned taste aversion, corticosterone levels, or anxiety-related behaviors.

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GCG neuronal activation alters metabolic rate and fasting locomotion, bu...
(A–C) GCG stimulation produces a small change in energy metabolism, with no effect on carbohydrate and fat utilization. CNO injection increased metabolic rate during the 3 hours after dark onset (A, VO2, paired t test n = 8, t = 2.661, *P = 0.0324; and VCO2, paired t test t = 2.273, P = 0.05), with no change in RER (B, paired t test, t = 0.1026, P = 0.9212). Activity was reduced (beam break counts in C; paired t tests t = 3.12 and 3.18, *P = 0.017 and 0.016, for X and Y ambulations, respectively). (D) Ucp1, Pparg, and Pgc1a gene expression was unchanged in iBAT dissected from CNO- and saline-treated animals Ucp1 (t test t = 0.94, P = 0.398), Pparg (t test, t = 0.462, P = 0.66), Pgc1a (t test, t = 0.07, P = 0.94). (E) Fourteen days of HCD feeding followed by CNO injections every 8 hours for 48 hours did not produce a change in body weight (2-way repeated measures ANOVA, F1,6 = 1.336, P = 0.292). (F) CNO did not affect saccharin preference (paired t test, t = 0.7649, P = 0.4733). Positive control LiCl produced a strong conditioned taste aversion (paired t test, t = 5.816, P = 0.0011). (G) CNO did not increase serum corticosterone levels at 70 and 90 minutes, despite producing a reduction in food intake (shown in Figure 4A) (ANOVA, F2,35 = 0.1134, P = 0.3834). (H–J) CNO injection did not change performance in the elevated plus maze (H, t test, open arms t = 0.7684, P = 0.4534; closed arms t = 0.6968, P = 0.4954), open field (I, time spent in open field, t test, center t = 0.1924, P = 0.8509, border t = 0.3785, P = 0.7123; J, locomotor activity reflected in distance traveled in both border and central zones, t test, border t = 0.5473, P = 0.5991, central t = 0.02015, P = 0.9844).