Abstract

Glucagon-like peptide-1 (GLP-1) is a well-known incretin hormone secreted from enteroendocrinal L cells in response to nutrients, such as glucose and dietary fat, and controls glycemic homeostasis. However, the detailed intracellular mechanisms of how L cells control GLP-1 secretion in response to nutrients still remain unclear. Here, we report that bone morphogenetic protein (BMP) signaling pathway plays a pivotal role to control GLP-1 secretion in response to nutrient replenishment in well-established mouse enteroendocrinal L cells (GLUTag cells). Nutrient starvation dramatically reduced cellular respiration and GLP-1 secretion in GLUTag cells. Transcriptome analysis revealed that nutrient starvation remarkably reduced gene expressions involved in BMP signaling pathway, whereas nutrient replenishment rescued BMP signaling to potentiate GLP-1 secretion. Transient knockdown of inhibitor of DNA binding (ID)1, a well-known target gene of BMP signaling, remarkably reduced GLP-1 secretion. Consistently, LDN193189, an inhibitor of BMP signaling, markedly reduced GLP-1 secretion in L cells. In contrast, BMP4 treatment activated BMP signaling pathway and potentiated GLP-1 secretion in response to nutrient replenishment. Altogether, we demonstrated that BMP signaling pathway is a novel molecular mechanism to control GLP-1 secretion in response to cellular nutrient status. Selective activation of BMP signaling would be a potent therapeutic strategy to stimulate GLP-1 secretion in order to restore glycemic homeostasis.

Highlights

  • Obesity and type II diabetes (T2D) are the most common metabolic syndromes that are prevalent worldwide

  • It has been demonstrated that bile acids activated bile acid receptors, including farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1; known as TGR5), to potentiate Glucagon-like peptide-1 (GLP-1) secretion in L cells, suggesting that bile acid signaling pathway would be a plausible molecular mechanism to control GLP-1 secretion in response to nutrient status in L cells [13,14,15]

  • We demonstrated that bone morphogenetic protein (BMP) signaling pathway is a novel molecular mechanism to control GLP-1 secretion in response to cellular nutrient status

Read more

Summary

Introduction

Obesity and type II diabetes (T2D) are the most common metabolic syndromes that are prevalent worldwide. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that strongly potentiates insulin secretion, promotes the growth and survival of pancreatic β cells, and controls physiological glycemic homeostasis [5,6]. Given that GLP-1 controls glycemic controls, there are common views demonstrating that T2D patients often exhibit impaired. Previous reports have demonstrated that GLP-1 secretion is modulated by various nutrients, such as glucose, glutamine, and protein ligand signals [11,12]. It has been demonstrated that bile acids activated bile acid receptors, including farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1; known as TGR5), to potentiate GLP-1 secretion in L cells, suggesting that bile acid signaling pathway would be a plausible molecular mechanism to control GLP-1 secretion in response to nutrient status in L cells [13,14,15]. The detailed molecular mechanisms of how GLP-1 secretion is controlled in L cells in response to nutritional stress still remains unclear

Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call