Description
Mazdutide – Technical Biochemical Mechanism Profile
(Dual GLP-1R / GCGR Agonist – Research Use Only)
Mazdutide (also known as IBI362) is a synthetic peptide-based dual-agonist targeting both the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR).
In vitro studies show that Mazdutide activates Gs-coupled GPCR signaling, driving adenylate cyclase, cAMP accumulation, and downstream phosphorylation of PKA, CREB, and AMPK-linked metabolic regulators. Dual receptor activation produces coordinated effects on glucose metabolism, fatty-acid utilization, and hepatocellular gene expression.
✅ 1. Primary Molecular Targets
Mazdutide binds and activates:
| Receptor | Research Role |
|---|---|
| GLP-1R | cAMP-PKA signaling, insulinotropic transcription, neuroendocrine effects |
| GCGR | Hepatic fatty-acid oxidation, AMPK activation, gluconeogenic gene modulation |
Both receptors belong to class B GPCR family and signal primarily via Gs-protein activation → adenylate cyclase → cAMP.
✅ 2. Core Signaling Pathways
A. Gs → Adenylate Cyclase → cAMP → PKA
Mazdutide stimulation results in:
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↑ intracellular cAMP
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PKA phosphorylation
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CREB transcription factor activation
Representative CREB-regulated genes:
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PCK1 (PEPCK)
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G6PC
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PPARGC1A (PGC-1α)
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INS gene transcription in β-cell models
B. AMPK Metabolic Pathway (GCGR Axis)
GCGR activation stimulates:
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↑ cAMP-PKA–dependent AMPK signaling
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↑ β-oxidation and mitochondrial oxidative metabolism
Typical gene targets monitored in vitro:
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CPT1A, CPT2 (fatty-acid transport)
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ACOX1, ACADL (fatty-acid oxidation)
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NRF1, TFAM (mitochondrial biogenesis)
C. PI3K/Akt Crosstalk (GLP-1R Axis)
GLP-1R agonism can induce PI3K/Akt phosphorylation, especially in pancreatic and neuronal cell lines.
Downstream targets include:
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mTOR, GSK3β
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BCL2 family (cell-survival pathways)
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FOXO1 transcriptional control
✅ 3. Hepatic Gene Regulation
Dual GLP-1R/GCGR activation alters liver transcriptional programs:
| Functional Category | Gene Examples |
|---|---|
| Gluconeogenesis | PCK1, G6PC |
| Mitochondrial Oxidation | CPT1A, ACADL, ACOX1 |
| Cholesterol & Lipid Transport | ABCG5, ABCG8, SREBF1 |
| Mitochondrial Biogenesis | NRF1, TFAM |
Research frequently notes a shift toward fatty-acid oxidation over lipid storage.
✅ 4. Neuroendocrine Signaling (GLP-1R)
In neuronal culture systems:
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cAMP/PKA → CREB → POMC transcription
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Reduced NPY / AgRP gene activity
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Potential modulation of hypothalamic metabolic circuits
✅ 5. Second Messengers & Enzymes
| Component | Role in Mazdutide Mechanism |
|---|---|
| cAMP | Primary intracellular second messenger |
| PKA | Phosphorylation of CREB, ACC, GSK3β |
| CREB | Transcription factor for metabolic gene networks |
| ACC (acetyl-CoA carboxylase) | PKA-mediated inhibition → ↑ fatty-acid oxidation |
| AMPK | Energy-sensing kinase activated indirectly via GCGR |
✅ 6. Representative Measured Outcomes in Lab Models
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↑ p-CREB, p-AMPK, p-Akt
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↑ mitochondrial gene transcription (NRF1, TFAM)
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↑ fatty-acid oxidation gene expression (CPT1A, ACOX1)
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Changes in neuropeptide gene signaling (↑ POMC, ↓ AgRP/NPY)
✅ Mechanistic Summary
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Synthetic dual GLP-1R/GCGR agonist
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Strong cAMP-PKA-CREB activation
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Crosstalk with AMPK and PI3K/Akt pathways
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Modulation of metabolic gene clusters governing:
-
gluconeogenesis,
-
fatty-acid oxidation,
-
mitochondrial biogenesis,
-
neuroendocrine signaling
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✅ Research-Only Classification
Mazdutide is offered exclusively for controlled in-vitro laboratory research.
Not for human or animal use, ingestion, injection, or therapeutic application.