Gut peptides are hormones secreted by the gut that act on the brain to regulate digestion and appetite. The function of gut peptides is a promising area of research for the treatment of type-2 diabetes and obesity.
In the last ten years, glucagon-like peptide (GLP-1) agonists have reached clinical use to treat type-2 diabetes. This class of drugs can cause side effects such as nausea and vomiting, so the maximum tolerable dose is limited. A combination of gut peptide agonists might allow better patient outcomes at lower doses of each drug.
New Studies Using Combination
Recently, a team of researchers sought to understand the effects of combining a GLP-1 agonist with a cholecystokinin (CCK) agonist. They gave mice a GLP-1 agonist and a CCK agonist by injection and measured the mice’s food intake in the short and the long term. Mice on the GLP-1/CCK1 agonist combination ate less and lost more body weight than mice on either agonist alone. The researchers also tested the effect of the GLP-1/CCK1 agonist combination on mice that had become obese by eating a high-fat diet. The obese mice had a similar but smaller response.
Impact on Brain
The researchers wanted to know what effect the agonist combination had on the mouse brain. They immunostained mouse brains for a marker of brain metabolic activity and found that activity was stimulated the most in the nucleus solitary tract, a part of the brain stem.
They did a further test for neuron RNA expression. Neurons that were activated by the GLP-1/CCK1 agonist combination had increased expression of a receptor for calcitonin gene-related peptide (CGRP). Neurons that were inhibited by the GLP-1/CCK1 agonist combination had increased expression of a receptor for pituitary adenylate cyclase-activating peptide (PACAP). The results of these studies suggest that CGRP and PACAP are themselves worth studying for their effects on type-2 diabetes and obesity.
Roth E, Benoit S, Quentin B, et al. Behavioral and neurochemical mechanisms underpinning the feeding-suppressive effect of GLP-1/CCK combinatorial therapy. Molecular Metabolism. 2021 Jan;43:101118. PMID: 33221554 doi.org/10.1016/j.molmet.2020.101118