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

Int J Mol Sci. 2020 May 28;21(11):3824. doi: 10.3390/ijms21113824.


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.

Keywords: L cells; bone morphogenetic protein 4; glucagon-like peptide-1; incretin; inhibitor of DNA binding 1.

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Line
  • Enteroendocrine Cells / metabolism
  • Gastric Inhibitory Polypeptide / metabolism
  • Gene Expression Regulation
  • Glucagon-Like Peptide 1 / metabolism*
  • Homeostasis
  • Incretins / metabolism*
  • Inhibitor of Differentiation Protein 1 / metabolism*
  • Insulin / metabolism
  • Mice
  • Mitochondria / metabolism
  • Nutrients / metabolism
  • Oxygen Consumption
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • RNA, Small Interfering / metabolism
  • Signal Transduction*


  • Blood Glucose
  • Bone Morphogenetic Proteins
  • Idb1 protein, mouse
  • Incretins
  • Inhibitor of Differentiation Protein 1
  • Insulin
  • LDN 193189
  • Pyrazoles
  • Pyrimidines
  • RNA, Small Interfering
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1