Ursolic acid ameliorates adipose tissue insulin resistance in aged rats via activating the Akt‑glucose transporter 4 signaling pathway and inhibiting inflammation

Abstract

Ageing often results in insulin resistance (IR) and chronic inflammation, and adipose is one of the tissues in which inflammation and IR occur earliest during this process. The present study investigated the effect and underlying mechanisms of ursolic acid (UA) on adipose IR and inflammation in ageing rats. Specific pathogen-free male Sprague-Dawley rats were randomly divided into 4 groups: i) Young normal (young); ii) untreated ageing (aged); and groups supplemented with UA either iii) low-UA 10 mg/kg (UA-L) or iv) high-50 mg/kg (UA-H). Animals in the UA-treated groups received 10 or 50 mg/kg UA (suspended in 5% Gum Arabic solution). The rats in the corresponding aged group and young groups received vehicle (5% Gum Arabic) alone. All rats were intragastrically treated once daily by oral gavage for 7 weeks. The day before the experiment terminated, overnight fasting blood (~700 µl) was collected and plasma was prepared to measure biochemical indicators; western blotting was performed to analyze the expression of insulin signaling proteins [(insulin receptor substrate 1 (IRS-1), phosphorylated (p)-IRS-1, PI3K, glucose transporter 4 (GLUT4), Akt and p-Akt)] and inflammatory factors (NF-κB, IL-6 and IL-1β) in the epididymis white adipose tissue (eWAT). The results revealed that treatment with UA-H decreased eWAT weight, the ratio of eWAT weight/body weight, fasted insulin and triglyceride levels, the homeostasis model assessment of insulin resistance and adipose tissue insulin resistance index in ageing rats, indicating the amelioration of systemic and adipose tissue IR, compared with the aged group. Mechanistically, UA-H administration upregulated p-protein kinase B, the ratio of p-Akt to protein kinase B and total and cellular membrane GLUT4 protein levels in eWAT of ageing rats. Conversely, UA inhibited the increase in NF-κB expression and proinflammatory cytokines IL-6 and IL-1β. However, these alterations were not observed in the rats of the aged group. Taken together, the findings of the present study indicated that UA may ameliorate adipose IR, which is associated with activation of the Akt-GLUT4 signaling pathway and inhibition of inflammation in ageing rats. These data provide a basis for the development of effective and safe drugs or functional substances, such as UA, for the prevention and treatment of metabolic diseases.

Ursolic acid inhibits glioblastoma through suppressing TGFβ-mediated epithelial-mesenchymal transition (EMT) and angiogenesis

“…Ursolic acid (UA), identified in a wide range of traditional medicinal herbs as a pentacyclic triterpenic acid, has diverse biological activities such as anti-inflammatory, antioxidant, and anticancer properties through several pathways [ [27] , [28] , [29] ]. For example, UA has been shown to reduce inflammation in fat tissue by triggering the Akt-GLUT4 signaling pathway in elderly rats [ 30 ]. Moreover, combining UA with empagliflozin has proven effective in mitigating diabetic nephropathy through the reduction of oxidative stress [ 31 ].…”

Recent progress in the development of ursolic acid derivatives as anti‐diabetes and anti‐cardiovascular agents

“…As for anti‐diabetes, UA amplifies insulin signaling by enhancing insulin resistant β (IRβ) subunit phosphorylation and P13K/Akt to achieve hypoglycemic effects. Activated P13 and Akt in humans promote the fusion of glucose transporter protein 4 (GLUT4) to the cell membrane thereby increasing the uptake of glucose at the membrane surface (Wang et al, 2021). Inhibiting protein tyrosine phosphatase 1B (PTP1B) and α‐glucosidase by UA is also an effective way to raise insulin sensitivity for reducing the blood sugar level.…”

“…In addition, UA also exhibits the function of regulating blood sugar levels by targeting forehead box protein O1 and glucose 6 phosphates (Camer et al, 2014). As for anti‐cardiovascular disease, UA is observed to inhibit the overexpression of pro‐inflammatory factor tumor necrosis factor‐alpha (TNF‐α), which is one of the most important factors of atherosclerosis (Wang et al, 2021). UA inhibits the formation of atherosclerosis by enhancing macrophage autophagy, which is an important pathway of UA to prevent cardiovascular disease (Leng et al, 2016).…”