Description

Retatrutide – Advanced Biochemical Mechanism Profile

(GLP-1 / GIP / Glucagon Receptor Tri-Agonist – Peptide Analog)

Retatrutide is a long-acting synthetic peptide that acts as a triple agonist at:

1. GLP-1 receptor (GLP-1R)

2. GIP receptor (GIPR)

3. Glucagon receptor (GCGR)

All three are Class B G-protein–coupled receptors (GPCRs) that primarily signal through Gs-mediated cAMP accumulation, initiating PKA-dependent phosphorylation and downstream transcriptional programs. The molecule is engineered for prolonged receptor engagement and slow enzymatic degradation.

✅ 1. GLP-1 Receptor Signaling (GLP-1R)

Receptor: Class B GPCR — Gs-coupled
Primary pathway: Adenylate cyclase → ↑ cAMP → PKA activation → CREB phosphorylation

Key biochemical outputs

• ↑ cAMP and PKA activity

• EPAC2 activation

• MAPK signaling (ERK1/2)

• Calcium channel regulation in endocrine and neuronal cells

Gene targets commonly studied

• POMC, BDNF, CART (neuronal satiety genes)

• IRS2, PDX1 (metabolic signaling)

• CREB-responsive transcriptional programs

✅ 2. GIP Receptor Signaling (GIPR)

Receptor: GIPR (Gs-coupled GPCR)

Signaling cascades

• Gs → adenylate cyclase → cAMP → PKA

• PI3K → Akt phosphorylation

• mTOR-dependent nutrient signaling

• ERK1/2 MAPK pathway

Gene-level regulation in research models

• INS, GLUT2, GCK in metabolic cell lines

• Anti-apoptotic signaling via Akt → FoxO transcription factors

• Mitochondrial biogenesis markers (PGC-1α)

✅ 3. Glucagon Receptor Signaling (GCGR)

Receptor: GCGR (Gs-coupled GPCR on hepatocytes and metabolic tissues)

Enzymes & pathways

• Adenylate cyclase → ↑ cAMP → PKA

• Phosphorylation of CREB in hepatic nuclei

• Activation of PEPCK and G6PC gene promoters in gluconeogenesis research

• Mobilization of fatty-acid oxidation genes via PPAR-α

Gene targets in hepatic studies

• PCK1 (PEPCK)

• G6PC

• CPT1A (β-oxidation)

• ACOX1 (peroxisomal fatty acid oxidation)

✅ Integrated Tri-Agonist Signaling

Because Retatrutide stimulates three metabolic GPCRs, research focuses on:

Shared second messengers

• ↑ cAMP

• ↑ PKA-mediated phosphorylation

• ↑ CREB nuclear transcription

• ERK1/2 and Akt cross-talk

• Calcium influx signaling in endocrine cells

Shared gene programs

• CRE-containing metabolic genes

• Neuropeptide transcription (POMC, CART)

• Mitochondrial and oxidative metabolism genes (PGC-1α, CPT1A)

• Hepatic cAMP-responsive elements (PCK1, G6PC)

✅ Key Molecular Targets (Condensed Table)

Research-Only Classification

Retatrutide is supplied solely for controlled in-vitro laboratory research.
It is not approved for human or animal use, ingestion, injection, or diagnostic/therapeutic application.