Catestatin decreases duodenal hypermotility to improve glucose homeostasis in diabetic male mice
Anne Abot, Céline El Samrout, Milena Barcza Stockler-Pinto, Jean Monlong, Sarah Djebali, Cédric Moro, Patrice D Cani, Claude KnaufObjective
Enterosynes are bioactive molecules that control gut motility via the enteric nervous system. The large majority of these molecules target nitrergic enteric neurons, stimulating intestinal nitric oxide (NO) release. NO is a neurotransmitter that inhibits intestinal smooth muscle cells, thereby improving glucose homeostasis through gut–brain axis-mediated systemic effects. In this work, we investigated the effect of catestatin, a peptide known to inhibit acetylcholine signalling, a major stimulatory neurotransmitter of gut motility that also plays a key role in glycaemic control.
Design
We assessed the effects of catestatin on gut motility, intestinal NO release, glucose homeostasis and messenger RNA expression of metabolic markers in different tissues (intestine, brain, liver, adipose tissue and muscle) in male mice fed a high-fat diet. The effects of catestatin were measured after 1-week and 6-week oral administration.
Results
We demonstrate that acute or 1-week chronic treatments of catestatin decrease duodenal hypermotility in diabetic mice. This effect is associated with improved glucose tolerance and reduced glucose-stimulated insulin secretion. This enhanced blood glucose control in obese/diabetic mice under catestatin is accompanied by favourable transcriptomic changes in metabolic tissues. Long-term (6 weeks) oral treatment with catestatin in mice fed a high-fat diet decreases body weight gain and improves glucose tolerance. These effects are associated with a significant reduction of hepatic triglycerides in the liver.
Conclusion
We discovered that catestatin exerts an enterosyne-like effect on gut motility and glucose metabolism without stimulating intestinal NO. This result highlights a promising approach for improving hyperglycaemia in metabolic disorders.