ID1-Mediated BMP Signaling Pathway Potentiates Glucagon-Like Peptide-1 Secretion in Response to Nutrient Replenishment.

Younhee Ko,Jiwoo Lee,Hyunkyung Kim,Jae Woong Jeong,Hae-Kyung Lee,Minki Kim,Sungsoon Fang

doi:10.3390/ijms21113824

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

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

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Conclusion