Isorhapontigenin Improves Diabetes in Mice via Regulating the Activity and Stability of PPARγ in Adipocytes

Abstract

Isorhapontigenin is a natural bioactive stilbene isolated from various plants and fruits. It has been reported to exhibit several physiological activities including anticancer and anti-inflammation activity in vitro and in experimental animal models. This study aimed to investigate whether isorhapontigenin exerts antidiabetic effects in vivo. To this end, diabetic db/db mice were treated with either 25 mg kg–1 of isorhapontigenin or vehicle intraperitoneally for a period of 5 weeks. The results show that isorhapontigenin treatment significantly reduced postprandial levels of glucose, insulin, as well as free fatty acid, three markers of diabetes. Further studies show that isorhapontigenin treatment markedly improves insulin sensitivity and glucose tolerance of db/db mice as shown by ITT and GTT. Together, these physiological results show that isorhapontigenin possesses antidiabetic properties in vivo. Mechanistically, the isorhapontigenin-mediated antidiabetic effect is caused by favorable changes in adipose tissue, including reductions in adipocyte diameter and improved adipose insulin sensitivity. Further studies with 3T3-L1 cells show that isorhapontigenin treatment promotes preadipocyte differentiation by upregulation of the activity of the master adipogenic regulator PPARγ and deceleration of its proteasomal degradation. Together, our results establish for the first time an important role of isorhapontigenin as a potential nutraceutical agent for diabetes treatment.

Discovery of natural products capable of inducing porcine host defense peptide gene expression using cell-based high throughput screening

“…Isorhapontigenin is a natural derivative of stilbene, which is present in numerous plant species. It has prominent anti-inflammatory, anti-cancer, and anti-diabetic potential [38][39][40]. As a resveratrol analog, isorhapontigenin is a tetrahydroxylated stilbenoid with a methoxy group.…”

More Than Resveratrol: New Insights into Stilbene-Based Compounds

“…It has been reported that ISO exerts the anti-diabetic activity confirmed by in vivo study [26]. ISO treatment among mice at the dose of 25 mg/kg b.w.…”

“…As a result, changes in adipose tissue reduction were observed, and adipose insulin sensitivity was also improved. What is more, the mRNA expression levels of PPARγ (peroxisome proliferator-activator receptor gamma) were higher in white adipose tissue among mice treated by ISO comparing to the control group [26].…”

“…For many years, the stilbene scaffold has been known as an excellent structure in terms of biological potential. To date, both natural and synthetic compounds build on the stilbene scaffold demonstrated a plethora of biological activity such as anticancer [14], anti-inflammatory [22], antimicrobial [23], antifungal [24], and neuroprotective [25] properties and potential agents for diabetes [26] and obesity [27] treatment. Interestingly, in 2006, Li et al synthesized new stilbene derivatives with substituted hydroxyl groups and found that two of these compounds (E)-2 ,3,5 ,5-tetrathydroxystilbene and (E)-3 ,5,5 ,6-tetrahydroxystilbene-2-nitrogen inhibited SARS coronavirus replication using in vitro model [28].…”

Network-Based Identification and Experimental Validation of Drug Candidates Toward SARS-CoV-2 via Targeting Virus–Host Interactome

“…In total, four promising candidates including hesperidin, isorhapontigenin, salmeterol, and gallocatechin-7-gallate were demonstrated to show inhibitory activity on SARS-CoV-2 virus-infected Vero cells. As presented in Figure 7 , hesperidin (a flavanone glycoside isolated from various citrus fruits, such as orange; Küçükler et al, 2021 ) restrained the growth of the SARS-CoV-2 virus with an EC 50 value of 1.25 μg/ml ( Figure 7B ) while isorhapontigenin (originated from plants and fruits, such as Chinese herb Gnetum cleistostachyum; Chu et al, 2020 ) inhibited the replication of virus with an EC 50 value of 0.3 μg/ml ( Figure 7C ). As a citrus bioflavonoid, hesperidin possesses a variety of biological activities such as antioxidant, anti-inflammatory, and antivirus properties ( Ding et al, 2018 ; Afzal et al, 2020 ).…”