Faculty Opinions recommendation of 2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy]-N-(methylsulfonyl)acetamide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug.

Long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RA), such as exendin-4 (Ex4), promote weight loss. On the basis of a newly discovered interaction between GLP-1 and oleoylethanolamide (OEA), we tested whether OEA enhances GLP-1RA-mediated anorectic signaling and weight loss. We analyzed the effect of GLP-1+OEA and Ex4+OEA on canonical GLP-1R signaling and other proteins/pathways that contribute to the hypophagic action of GLP-1RA (AMPK, Akt, mTOR, and glycolysis). We demonstrate that OEA enhances canonical GLP-1R signaling when combined with GLP-1 but not with Ex4. GLP-1 and Ex4 promote phosphorylation of mTOR pathway components, but OEA does not enhance this effect. OEA synergistically enhanced GLP-1- and Ex4-stimulated glycolysis but did not augment the hypophagic action of GLP-1 or Ex4 in lean or diet-induced obese (DIO) mice. However, the combination of Ex4+OEA promoted greater weight loss in DIO mice than Ex4 or OEA alone during a 7-day treatment. This was due in part to transient hypophagia and increased energy expenditure, phenotypes also observed in Ex4-treated DIO mice. Thus, OEA augments specific GLP-1RA-stimulated signaling but appears to work in parallel with Ex4 to promote weight loss in DIO mice. Elucidating cooperative mechanisms underlying Ex4+OEA-mediated weight loss could, therefore, be leveraged toward more effective obesity therapies.

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Novel GLP-1 Fusion Chimera as Potent Long Acting GLP-1 Receptor Agonist

PLoS ONE ◽

10.1371/journal.pone.0012734 ◽

2010 ◽

Vol 5 (9) ◽

pp. e12734 ◽

Cited By ~ 26

Author(s):

Qinghua Wang ◽

Kui Chen ◽

Rui Liu ◽

Fang Zhao ◽

Sandeep Gupta ◽

...

Keyword(s):

Receptor Agonist ◽

Long Acting

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OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes

10.21203/rs.3.rs-223237/v1 ◽

2021 ◽

Author(s):

Ashref Kayed ◽

Simone Melander ◽

Kim Andreassen ◽

Morten Karsdal ◽

Kim Henriksen

Keyword(s):

Type 2 Diabetes ◽

Receptor Agonist ◽

Therapeutic Option ◽

Treatment Options ◽

Potential Candidate ◽

Alcoholic Fatty Liver ◽

Glucagon Like Peptide 1 ◽

Treatment Of Obesity ◽

Long Acting

Abstract Obesity-related metabolic disorders, including non-alcoholic fatty liver disease and its more progressive form non-alcoholic steatohepatitis, are causing an increased health burden, especially due to the lack of approved treatment options. Using preclinical models of NASH, obesity, and type 2 diabetes, we investigated the effects of a long-acting glucagon-like peptide-1(GLP-1) and glucagon (GCG) receptor agonist OXM-104 head to head with once-daily GLP-1/GCG receptor agonist cotadutide and once-weekly GLP-1 receptor agonist semaglutide. OXM-104, cotadutide, and semaglutide elicited marked reductions in body weight and improved glucose control. In contrast, hepatoprotective effects, i.e., reductions in steatosis and fibrosis, as well as liver fibrosis biomarkers, were more prominent with OXM-104 and cotadutide than effects seen with semaglutide. This is demonstrated by improved NAFLD activity score (NAS) by OXM-104 and cotadutide which underlines the importance of the GCG receptor. Thus, these results underline the potential of OXM-104 as a promising therapeutic option for the resolution of NASH, but also as a therapeutic option for type 2 diabetes and obesity.

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