GLP3 (retatrutide): research background
What the compound is
The term "GLP3" appears in different contexts across scientific literature, referring to distinct entities. One context is an investigational triple GIP/GLP-1/glucagon receptor agonist known as retatrutide, which is not described in these abstracts. Another refers to a novel proglucagon-derived peptide found in chondrichthyans, such as the Pacific spiny dogfish (PMID 38346454). Additionally, "GLP3" can refer to a specific form of glypican-3, a protein (PMID 36165051). Polysaccharides derived from *Gracilaria lemaneiformis* are also denoted as GLPs, with GLP3 specifically referring to one with a molecular weight of 10.5 kDa (PMID 36900548). Furthermore, a gene identified in chickpea is referred to as GLP3 (PMID 38078944). A water-soluble polysaccharide from *Ganoderma leucocontextum* fruiting bodies was purified and termed GLP-3, with a molecular weight of 159.7 kDa, primarily composed of glucose (PMID 32933694). Finally, in the context of *Plasmodium falciparum*, GLP3 denotes a glutaredoxin-like protein (PMID 15843145).
How it is thought to work
The chondrichthyan glucagon-like peptide 3 (GLP-3) appears to influence hepatic ketone metabolism in the Pacific spiny dogfish. When perfused at 10 nM for 15 minutes in a liver, it switched ketone flux from net production to consumption and increased mRNA transcript abundance of putative ketone transporters and the activity of β-hydroxybutyrate dehydrogenase (animal study, PMID 38346454).
Glypican-3 (GPC3) overexpression has been identified as a poor prognostic factor in hepatocellular carcinoma (human study, PMID 36165051).
A water-soluble polysaccharide, GLP-3, from *Ganoderma leucocontextum* appears to exert immunomodulatory effects. It was recognized by toll-like receptor 2 (TLR2) and activated mitogen-activated protein kinases (MAPKs), phosphatidylinositol-3-kinase (PI3K)/Akt, and nuclear factor-κB (NF-κB) signaling pathways in RAW 264.7 macrophages (cell study, PMID 32933694).
In *Plasmodium falciparum*, Pf Glp3 (a glutaredoxin-like protein) possesses a thioredoxin fold in its C-terminal domain with conserved residues presumably for glutathione binding (cell study, PMID 15843145).
Laboratory and animal studies report
In the Pacific spiny dogfish (*Squalus suckleyi*), perfusion with 10 nM GLP-3 for 15 minutes altered hepatic ketone metabolism by shifting net ketone flux from production to consumption. It also led to increased mRNA for ketone transporters and heightened activity of β-hydroxybutyrate dehydrogenase in the liver. No effects were observed on glucose or oleic acid acquisition in the spiral valve or on glucose transport or glycolysis in the liver (animal study, PMID 38346454).
Polysaccharides from *Gracilaria lemaneiformis*, including GLP3 (Mw=10.5 kDa), influenced calcium oxalate (CaOx) crystal growth in laboratory experiments. GLP3, along with other GLPs, inhibited the growth of calcium oxalate monohydrate (COM) and induced the formation of calcium oxalate dihydrate (COD). The GLPs increased the absolute value of the Zeta potential on the crystal surface, reducing aggregation. In HK-2 cells, CaOx crystals regulated by GLPs showed reduced toxicity, with GLP7 (smallest Mw) demonstrating the least toxicity and highest SOD activity, lowest ROS and MDA levels, and lowest OPN expression (cell study, PMID 36900548).
In chickpea, GLP3 was identified as a probable candidate gene associated with lateral root traits when the plant was grown in soil with specific bulk densities (animal study, PMID 38078944).
A water-soluble polysaccharide, GLP-3, from *Ganoderma leucocontextum* had a molecular weight of 159.7 kDa and consisted mainly of glucose. Structural analysis showed a backbone of →4)-α-D-Glcp-(1→4,6)-β-D-Glcp-(1→ with a β-Glcp-(1→ branch. Atomic force microscopy and Congo red experiments suggested a globular structure with a triple-helix conformation in water (laboratory study, PMID 32933694).
*Plasmodium falciparum* Glp3 is one of three identified glutaredoxin-like proteins, containing a conserved cysteine in a CKYS-motif. Molecular models suggest a thioredoxin fold for its C-terminal domain, with residues for glutathione binding (laboratory study, PMID 15843145).
Human evidence so far
Overexpression of glypican-3 (GPC3) was found to be an independent risk factor for survival and a poor prognostic factor in 152 patients diagnosed with hepatocellular carcinoma (HCC) after hepatectomy, lobectomy, or liver transplantation. Patients with GPC3 overexpression (>10%) had significantly lower survival. Hepatitis C, alpha-fetoprotein (AFP) levels, tumor number, tumor focality, and portal vein tumor thrombosis were also identified as independent risk factors (human study, PMID 36165051).
Open questions and limitations
For the chondrichthyan GLP-3, it remains to be fully elucidated whether the distinct physiological actions on hepatic metabolism are due to the particular metabolic dependency on ketone bodies in chondrichthyans or a differential function of a novel GLP (PMID 38346454). The specific GLP3, retatrutide, is listed as an investigational triple agonist, but no research findings specific to this compound are presented in the provided abstracts.
Key terms explained
**Chondrichthyans**: A class of fish that includes sharks, rays, and chimaeras (PMID 38346454).
**Hepatic ketone metabolism**: The process of creating or using ketone bodies in the liver, which are alternative fuel sources for the body (PMID 38346454).
**Hepatocellular carcinoma (HCC)**: A common type of liver cancer (PMID 36165051).
**Glypican-3 (GPC3)**: A protein that can be a marker for HCC, with overexpression linked to poorer outcomes (PMID 36165051).
**Molecular weight (Mw)**: A measure of the mass of a molecule (PMID 36900548).
**Antioxidant activity**: The ability to prevent or slow damage to cells caused by free radicals (PMID 36900548).
**Calcium oxalate (CaOx)**: The main component of kidney stones, which can form crystals (PMID 36900548).
**Immunomodulatory activity**: The ability to modify the immune system's response (PMID 32933694).
**RAW 264.7 macrophages**: A type of mouse cell line commonly used in immunological research to study immune responses (PMID 32933694).
**Glutaredoxin-like proteins**: A subgroup of proteins similar to glutaredoxins, which are involved in maintaining cellular redox balance (PMID 15843145).
Studies cited in this section
Summarised from the PubMed abstracts listed above. Educational reference only — not medical advice or instructions.
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