GLP1R MOA: Regulate Blood Glucose and Appetite through Several Mechanisms

GLP1R: A key regulator of metabolic homeostasis and its therapeutic intervention in obesity and diabetes

• Gene Information: The glucagon-like peptide 1 receptor (GLP1R) gene encodes a G protein-coupled receptor (GPCR) belonging to the class B glucagon receptor subfamily. 
• Protein Expression: GLP1R is a cell surface protein widely expressed in the brain, small intestine, heart, and lung. 
• Signaling Pathway: By binding to endogenous GLP-1 and GLP-1 analogs, GLP1R plays a pivotal role in driving the signaling cascades that govern insulin secretion. 
• Therapeutic Method: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent a novel class of anti-diabetic agents that lower blood glucose and promote weight loss by activating the GLP-1R. Mechanistically, they stimulate insulin secretion, inhibit glucagon release, slow gastric emptying, and decrease food intake through central appetite suppression.

GLP1R 

• Part of exon 2 and exon 3 of mouse Glp1r were replaced by the P2A and human CDS of GLP1R. 
• The promoter, 5’UTR, mouse exon 1, and intron 1 were retained. 
• The GLP1R protein expression will be driven by the endogenous mouse Glp1r promoter.
• The mouse Glp1r gene transcription and translation will be disrupted. 

• Human GLP1R mRNA was detected in homozygous B-hGLP1R mice plus, but not in wild-type mice. 
• Mouse Glp1r mRNA was detectable only in wild-type C57BL/6JNifdc mice.

Strain-specific analysis of GLP1R mRNA expression in wild-type C57BL/6JNifdc mice and B-hGLP1R mice plus by RT-PCR. Brain tissue RNA was isolated from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-hGLP1R mice plus (H/H), then cDNA libraries were synthesized by reverse transcription, followed by PCR with mouse or human GLP1R primers. Mouse Glp1r mRNA was detectable only in wild-type C57BL/6JNifdc mice. Human GLP1R mRNA was detectable only in homozygous B-hGLP1R mice plus but not in wild-type mice.