AM-879, a PPARy non-agonist and Ser273 phosphorylation blocker, promotes insulin sensitivity without adverse effects in mice

AM-879, a PPARy non-agonist and Ser273 phosphorylation blocker, promotes insulin sensitivity without adverse effects in mice

Obesity is one of the main risk factors for type 2 diabetes, and peroxisome proliferator-activated receptor γ (PPARγ) is considered a promising pathway on insulin sensitivity and adipose tissue metabolism. The search for molecules acting as insulin sensitizers have increased, especially for molecule...

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Bibliographic Details
Published in:Metabolism open Vol. 17; p. 100221
Main Authors: Terra, M.F., García-Arévalo, M., Avelino, T.M., Degaki, K.Y., Malospirito, C.C., de Carvalho, M., Torres, F.R., Saito, Â., Figueira, A.C.M.
Format: Journal Article
Language:English
Published: England Elsevier Inc 01-03-2023
Elsevier
Subjects:
Diabetes
Non-agonist
Obesity
Original Research Paper
Phosphorylation
PPARγ
Obesity
Phosphorylation
Diabetes
PPARγ
Non-agonist
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Summary:Obesity is one of the main risk factors for type 2 diabetes, and peroxisome proliferator-activated receptor γ (PPARγ) is considered a promising pathway on insulin sensitivity and adipose tissue metabolism. The search for molecules acting as insulin sensitizers have increased, especially for molecules that block PPARγ-Ser273 phosphorylation, without reaching full agonism. We evaluated the in vivo effects of AM-879, a PPARγ non-agonist, and found that AM-879 exerts different effects in mice depending on the dose. At lower doses, this ligand decreased BAT, increased leptin and Crh expression. However, at a higher dose, it promoted improvement on insulin sensitivity, ameliorates expression of metabolism-related genes, decreased the expression of genes related to liver toxicity, maintaining body weight and adipocyte size. These results present a new lead molecule to ameliorates insulin resistance and confirm AM-879 as a PPARγ non-agonist which blocks Ser273 phosphorylation as a good strategy to modulate insulin sensitivity without developing the adverse effects promoted by PPARγ full agonists. •AM-879 is a promising insulin sensitizer.•AM-879 promotes improvement on insulin sensitivity, ameliorates expression of metabolism related genes, maintained body weight, and the adipocyte size.•AM-879 is a non agonist of PPARγ
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ISSN:2589-9368
2589-9368
DOI:10.1016/j.metop.2022.100221