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Recent evidence suggests a sinister link between hypoadiponectinemia and development of insulin resistance\/type 2 diabetes (T2D). Adiponectin's insulin\u2010sensitizing property is mediated through the specific adiponectin receptors R1 and R2, which activate the AMP\u2010activated protein kinase (AMPK) and peroxisome proliferator\u2010activated receptor (PPAR) \u03b1 pathways. AdipoAI is a novel synthetic analogue of endogenous adiponectin with possibly similar pharmacological effects. Thus, there is a need of orally active small molecules that activate Adipoq subunits, and their downstream signaling, which could ameliorate obesity related type 2 diabetes. In the study we aim to investigate the effects of AdipoAI on obesity and T2D. Through in\u2010vitro and in\u2010vivo analyses, we investigated the antidiabetic potentials of AdipoAI and compared it with AdipoRON, another orally active adiponectin receptors agonist. Our results showed that in\u2010vitro treatment of AdipoAI (0\u20135\u2009\u00b5M) increased adiponectin receptor subunits AdipoR1\/R2 with increase in AMPK and APPL1 protein expression in C2C12 myotubes. Similarly, in\u2010vivo, oral administration of AdipoAI (25\u2009mg\/kg) observed similar effects as that of AdipoRON (50\u2009mg\/kg) with improved control of blood glucose and insulin sensitivity in diet\u2010induced obesity (DIO) mice models. Further, AdipoAI significantly reduced epididymal fat content with decrease in inflammatory markers and increase in PPAR\u2010\u03b1 and AMPK levels and exhibited hepatoprotective effects in liver. Further, AdipoAI and AdipoRON also observed similar results in adipose tissue. Thus, our results suggest that low doses of orally active small molecule agonist of adiponectin AdipoAI can be a promising therapeutic target for obesity and T2D.<\/jats:p>","DOI":"10.1002\/cbf.3910","type":"journal-article","created":{"date-parts":[[2024,1,4]],"date-time":"2024-01-04T00:39:05Z","timestamp":1704328745000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Antidiabetic features of AdipoAI, a novel AdipoR agonist"],"prefix":"10.1002","volume":"42","author":[{"given":"Akash","family":"Ahuja","sequence":"first","affiliation":[{"name":"Department of Periodontology Tufts University School of Dental Medicine,\u00a0Division of Oral Biology Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elissa","family":"Zboinski","sequence":"additional","affiliation":[{"name":"Department of Periodontology Tufts University School of Dental Medicine,\u00a0Division of Oral Biology 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