Antidiabetic features of AdipoAI, a novel AdipoR agonist

Adiponectin is an antidiabetic endogenous adipokine that plays a protective role against the unfavorable metabolic sequelae of obesity. Recent evidence suggests a sinister link between hypoadiponectinemia and development of insulin resistance/type 2 diabetes (T2D). Adiponectin's insulin-sensitizing property is mediated through the specific adiponectin receptors R1 and R2, which activate the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR) alpha 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-vitro and in-vivo analyses, we investigated the antidiabetic potentials of AdipoAI and compared it with AdipoRON, another orally active adiponectin receptors agonist. Our results showed that in-vitro treatment of AdipoAI (0-5 mu M) increased adiponectin receptor subunits AdipoR1/R2 with increase in AMPK and APPL1 protein expression in C2C12 myotubes. Similarly, in-vivo, oral administration of AdipoAI (25 mg/kg) observed similar effects as that of AdipoRON (50 mg/kg) with improved control of blood glucose and insulin sensitivity in diet-induced obesity (DIO) mice models. Further, AdipoAI significantly reduced epididymal fat content with decrease in inflammatory markers and increase in PPAR-alpha 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. Obesity is a global health concern, having doubled in more than 70 countries and resulting in an escalation of obesity-related diseases, such as type 2 diabetes (T2D). The adiponectin receptors (AdipoR1 and AdipoR2) have emerged as important targets for controlling inflammation, obesity and T2D. To maximize the potential of adiponectin receptors in targeting the fundamental etiopathology of obesity and T2D, we have designed, synthesized, Adiponectin receptor agonist named AdipoAI (standing for anti-inflammation) which in our preclinical trials on high fat diet (HFD) observed reduced glucose resistance, insulin tolerance, promoted adiponectin signaling in liver and adipose tissues of obese mice, and resulted decrease liver inflammation. Thus, our trial has affirmed AdipoAI as a potent adiponectin agonist with antidiabetic, hepatoprotective, and anti-inflammatory properties.