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. 2024 Jan;42(1):e3910.
doi: 10.1002/cbf.3910.

Antidiabetic features of AdipoAI, a novel AdipoR agonist

Akash Ahuja  1 , Elissa Zboinski  1 , Siddhartha das  1 , Xiaofang Zhu  1 , Qian Ma  1   2 , Ying Xie  1   3 , Qisheng Tu  1 , Jake Chen  1   4
Affiliations

Antidiabetic features of AdipoAI, a novel AdipoR agonist

Akash Ahuja et al. Cell Biochem Funct. 2024 Jan.

Abstract

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) α 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 µM) 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-α 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.

Keywords: AdipoAI; adiponectin; diet induced obesity; inflammation; obesity; type 2 diabetes.

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Conflict of interest statement

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1:
Figure 1:
Comparative in vitro studies of AdipoAI and AdipoRON to determine cellular toxicity and mRNA gene expression levels: (A) Cellular toxicity and behavioral patterns of C2C12 myotubes treated with AdipoAI and AdipoRON (0-10 mM) after 24 hrs incubation by using CCK8 assay; determined at 450 nm absorbance spectra. Cell cytotoxicity test reveals IC50 values of AdipoAI and AdipoRON. Quantitative gene expression analysis of (B) AdipoR1 (C) AdipoR2 (D) Ppargc1a in C2C12 myotubes treated with AdipoAI and AdipoRON (0-5 uM) after 1.5 hours of treatment. (E) Adiponectin signaling in differentiated C2C12 myotubes treated with different concentrations of AdipoAI and AdipoRON for 1.5 hours with respect to controls (untreated). Statistical significance was calculated based on ordinary one-way analysis of variance (ANOVA) with multiple comparison using GraphPad Prism 9.4.1 software and all the values are presented as mean ± SD with three independent experiments sets with *p<0.05; **p<0.001.Figure 2. Oral Glucose tolerance (OGTT) and Insulin tolerance test (ITT) test at 20 and 21 weeks in diet induced obesity (DIO) mice models for accessing AdipoAI efficacy. (A) Oral glucose tolerance test tested at 20 weeks in DIO mice treated with CMC (0.5%), AdipoAI (25 mg/kg) and AdipoRON (50 mg/kg). (B) Insulin tolerance test tested at 21 weeks in DIO mice treated with CMC (0.5%), AdipoAI (25 mg/kg) and AdipoRON (50 mg/kg). Data are represented as mean ± SD of 6 mice per group.; *p<0.05, **p<0.001 compared to CMC vehicle.
Figure 2.
Figure 2.
Body and adipocyte weight of DIO mice treated with CMC, AdipoAI and AdipoRON for 4 weeks (A) Concept strategy of in vivo trial (B) Comparative Body weights measured from 18-21 weeks in DIO mice treated with CMC (0.5%), AdipoAI (25 mg/kg) and AdipoRON (50 mg/kg) (C & D) changes in fat Inguinal and epididymal fat contents for gauging comparative adipose tissue biology in DIO mice models (E) liver weights of DIO mice with respective treated groups recorded at 21 weeks. Data were analyzed by using ordinary 1-way followed by Šidák’s post hoc test. all the values are presented as mean ± SD with three independent experiments sets with *p<0.05; **p<0.01.
Figure 3.
Figure 3.
Oral Glucose tolerance (OGTT) and Insulin tolerance test (ITT) test at 20 and 21 weeks in diet induced obesity (DIO) mice models for accessing AdipoAI efficacy (A) Mice were starved overnight, and oral administration of glucose (1mg/kg) were given blood glucose levels were evaluated prior to dosing (0-15 min), and carefully monitored every 15 minutes time interval for a period of 120 mins, following oral administration. The AdipoAI (25 mg/kg) exposed mice models revealed a decreased in blood glucose levels and have similar profile of OGTT with respect to another established bioactive molecule such as AdipoRon (50 mg/kg). (B) Insulin tolerance test (0.75 IU insulin per kg body weight) was performed in AdipoAI and AdipoRON treated DIO mice models after 6 hours of fasting. Blood glucose was monitored at specific time interval (0-120 mins) by using a sensitive glucometer depicting comparable curves of AdipoAI and AdipoRON. Data are represented as mean ± SD of 6 mice per group.; *p<0.05, **p<0.001 compared to CMC vehicle.
Figure 4.
Figure 4.
Effect of AdipoAI treatment on adiponectin subunits expression and hepatic microarchitecture in liver tissues. (A, B & C) mRNA Gene expression profiles of Ppargc1a, AdipoR2 in liver of 21 weeks old DIO mice treated with CMC (0.5%), AdipoAI (25 mg/kg) and AdipoRON (50 mg/kg) administered biweekly respectively (D) Western blot analysis phosphorylation of AMPK in liver samples treated with indicated amount of AdipoAI and AdipoRON (E) Immunohistochemistry staining profiles of p-AMPK levels in liver tissues from mice study models showing increase AMPK localization in AdipoAI treated groups (E, F and G) mRNA expression of inflammatory cytokines IL-6, TNF-a, IL-1B in liver tissues treated with CMC, AdipoAI, AdipoRON biweekly for four weeks (H) Hematoxylin and eosin staining depict improved hepatic details compared to control. Data were analyzed by using ordinary 1-way followed by multiple comparison between groups. all the values are presented as mean ± SD with three independent experiments sets with *p<0.05; **p<0.01, ***p<0.001.
Figure 5.
Figure 5.
AdipoAI activates adiponectin receptor subunit AdipoR1. (A, B, C & D) A tissue distribution of AdipoR1, AdipoR2, Ppargc1a, Ppara was assessed by mRNA expression in WAT adipose tissue of DIO mice treated with CMC (0.5%), AdipoAI (25mg/kg) and AdipoRON (50 mg/kg). Data were analyzed by using ordinary 1-way followed by multiple comparison between groups. all the values are presented as mean ± SD with three independent experiments sets with *p<0.05; **p<0.01, ***p<0.001.
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