Neurons used to successfully regulate appetite and glucose levels in mice.

It is known that 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 glutamatergic GGC peptide–secreting neurons in regulating metabolism has not been investigated.  Now, a study from the University of Virginia investigates how stimulation of glucagon-like peptide (GLP-1)-producing neurons can control appetite and glucose levels in mice. The team state that they selectively excited GLP-1 neurons in the hypothalamus of mice and found that the neurostimulation reduced the animals’ food intake and suppressed glucose from energy reserves.  The opensource study is published in the Journal of Clinical Investigation.

Previous studies show that drugs that target signaling by GLP-1 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 GLP-1 signaling.  A subset of neurons in the brain also produces GLP-1 and related peptides, however, it is unclear how brain-mediated GLP-1 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 designer receptor exclusively activated by designer drugs (DREADD), the lab activated GCG neurons. Results show that this targeted neurostimulation reduces food intake, metabolic rate, and glucose production in lean animals. The group note that no effect was observed on corticosterone secretion, anxiety-like behaviour, conditioned taste aversion, or body weight homeostasis.  Data findings show that in diet-induced obese mice, the effect of neurostimulation on glucose production was lost, while the food intake–lowering effect remained, resulting in the reduction of body weight and adiposity.

The team state that the neurostimulation’s effects on glucose handling varied between lean and obese mice; with stimulation of GLP-1 neurons suppressing appetite without changing glucose levels in obese mice.  These neurons are sufficient in lean mice to modulate food intake while having no effect on corticosterone secretion, conditioned taste aversion, or exploratory behaviour, with minimal effects on glucose handling or insulin secretion.  They conclude that their findings suggest distinct pathways exist with different sensitivities to individual metabolic states which may mediate the behavioural and physiological effects of GLP-1 signaling.

The team surmise that they have successfully stimulated GCG neurons to show they 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.  For the future, the researchers state that their findings suggest a moderate level of GCG neuron activation may produce an inhibition or termination of feeding and reduction in glucose production.

Source: University of Virginia Health System


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