Abstract
The progressive increase of metabolic diseases underscores the necessity for developing effective therapies. Although we found Tian-Huang formula (THF) could alleviate metabolic disorders, the underlying mechanism remains to be fully understood. In the present study, firstly, male Sprague-Dawley rats were fed with high-fat diet plus high-fructose drink (HFF, the diet is about 60% of calories from fat and the drink is 12.5% fructose solution) for 14 weeks to induce hepatosteatosis and glucose intolerance and then treated with THF (200 mg/kg) for 4 weeks. Then, metabolomics analysis was performed with rat liver samples and following the clues illustrated by Ingenuity Pathway Analysis (IPA) with the metabolomics discoveries, RT-qPCR and Western blotting were carried out to validate the putative pathways. Our results showed that THF treatment reduced the body weight from 735.1 ± 81.29 to 616.3 ± 52.81 g and plasma triglyceride from 1.5 ± 0.42 to 0.88 ± 0.33 mmol/L; meanwhile, histological examinations of hepatic tissue and epididymis adipose tissue showed obvious alleviation. Compared with the HFF group, the fasting serum insulin and blood glucose level of the THF group were improved from 20.77 ± 6.58 to 9.65 ± 5.48 mIU/L and from 8.96 ± 0.56 to 7.66 ± 1.25 mmol/L, respectively, so did the serum aspartate aminotransferase, insulin resistance index, and oral glucose tolerance (p = 0.0019, 0.0053, and 0.0066, respectively). Furthermore, based on a list of 32 key differential endogenous metabolites, the molecular networks generated by IPA suggested that THF alleviated glucose intolerance and hepatosteatosis by activating phosphatidylinositol-3 kinase (PI3K) and low-density lipoprotein receptor (LDL-R) involved pathways. RT-qPCR and Western blotting results confirmed that THF alleviated hepatic steatosis and glucose intolerance partly through protein kinase B- (AKT-) sterol regulatory element-binding protein (SREBP) nexus. Our findings shed light on molecular mechanisms of THF on alleviating metabolic diseases and provided further evidence for developing its therapeutic potential.
Highlights
Obesity and its close consequences, dyslipidemia, impaired glucose tolerance, and insulin resistance, are more common than ever in human history [1]. e progressive increase of the above conditions leads to the rising incidence of type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and metabolic syndrome [2]
In order to evaluate the protective effects of Tian-Huang formula (THF), rats undergoing HFF diet were treated with THF (200 mg/kg) or vehicle
Choi et al [39] reported that CCA exerted antiadipogenic activity on 3T3-L1 adipocytes 2 by downregulating C/EBP-α and PPAR-c; Yang et al [40] revealed that CCA may help alleviate hyperglycemia in diabetes by promoting glucose uptake by skeletal muscles; and Li et al [41] concluded that CCA prevent diabetic cognitive deficits most likely by ameliorating disorder of glucose and lipid metabolism, attenuating A-β deposition, and enhancing insulin signaling
Summary
Obesity and its close consequences, dyslipidemia, impaired glucose tolerance, and insulin resistance, are more common than ever in human history [1]. e progressive increase of the above conditions leads to the rising incidence of type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and metabolic syndrome [2]. Noninvasive drugs have been regarded as promising approaches to address the deficit of lifestyle intervention and reduce the severity of bariatric surgery [2, 6, 7]. Varying in their efficacy and side effect profiles, the existing available approved drugs targeting obesity and its close consequences and medical comorbidities are inadequate. Erefore, developing novel therapeutics from natural herbal extracts is a promising strategy to address the global health problem of obesity and its consequences; further studies on the precise role and mechanism of potential drugs against the development of diet-induced metabolic diseases will provide better support for their clinical usage [10]
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