Vital to our bodies, preproglucagon otherwise known as GCG peptides act in both the periphery and the CNS to change food intake, glucose homeostasis, and metabolic rate. Although the actions of GCG peptides produced in the gut and pancreas are well described, the role of GGC peptide–secreting neurons in regulating metabolism has not been investigated. Now, a study from the University of Virginia investigates how stimulation of GGC peptide–secreting neurons can control appetite and glucose levels in mice. The team states they selectively excited GGC peptide–secreting neurons in the hypothalamus of mice to reduce the animals’ food intake and suppress glucose levels. The opensource study is published in the Journal of Clinical Investigation.
Previous studies show drugs targeting signaling by GGC peptides in the gut and pancreas are commonly used to regulate hypoglycemia in patients with type 2 diabetes. However, these drugs are associated with a number of unpleasant side effects that may be linked to other targets of GGC peptide signaling. A subset of neurons in the brain also produces GGC peptides, however, it is unclear how brain-mediated GGC peptide signaling influences metabolism and appetite.
The current study develops a transgenic mouse line to develop a clearer understanding of GCG neuron function. Through the expression of a synthetic receptor, the lab activated the GCG neurons to reduce food intake, metabolic rate, and glucose production in lean animals. Results show in diet-induced obese mice, the effect of neurostimulation on glucose production was lost, while the decrease in food intake remained, resulting in the reduction of body weight and adiposity.
The team states neurostimulation’s effects on glucose handling varied between lean and obese mice; with stimulation of GGC peptide–secreting neurons suppressing appetite without changing glucose levels in obese mice. In lean mice, these neurons were shown to modulate food intake while having no effect on corticosterone secretion, conditioned taste aversion, or exploratory behavior, with minimal effects on glucose handling or insulin secretion. They conclude their findings suggest distinct pathways exist with different sensitivities to individual metabolic states which may mediate the behavioral and physiological effects of GGC peptide signaling.
The team surmises they have successfully activated GCG neurons to produce a change in food intake and glucose homeostasis, dependent on the metabolic state of the animal. For the future, the researchers state their findings suggest a moderate level of GCG neuron activation may produce an inhibition or termination of feeding, or a reduction in glucose production.
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