Abstract
Objective: To evaluate the therapeutic efficacy and underlying molecular mechanisms of Bauhiniastatin-1 (BSTN1) to alleviate adiposity in diet-induced obese rodent model and in 3T3-L1 cells. Methods: BSTN1 was purified and confirmed through HPLC. In-vitro experiments such as MTT assay, Oil Red-O (ORO) stain, cellular lipid content, glycerol release and RT-PCR analysis were performed in 3T3-L1 cells in the presence and absence of BSTN1. In animal experiments, rats were divided into Group-I: normal pellet diet-fed, Group-II: HFD-fed, Groups-III, IV and V: HFD-fed BSTN1 (1.25, 2.5, and 5 mg/kg.b.wt./day/rat)-treated and Group-VI: HFD-fed Orlistat-treated. The rats were fed either normal diet or high fat diet (HFD) for 18 weeks and water ad-libitum. BSTN1 was orally administered from 13th week onwards to the selected HFD-fed groups. Body composition parameters, biochemical assays, histopathology examination and western blot analysis were performed to identify the predicted targets related to obesity. Molecular docking studies threw light on the binding interactions of BSTN1 against PPAR-γ, FAS and AMPK. Results: BSTN1 at 20 μM significantly (p < 0.001) inhibited adipocyte differentiation and lipid accumulation in 3T3-L1 cells. A conspicuous down-regulation in the mRNA expression levels of PPAR-γ, FAS and SREBP1 was observed but AMPK expression remained unchanged in BSTN1 treated 3T3-L1 cells. A substantial decrease in body weight gain, fat percent, total body fat, serum and liver lipid profile (except high-density lipoprotein), glucose, insulin and insulin resistance in BSTN1 treated rats was noticed in a dose dependent manner. In BSTN1 (5 mg/kg.b.wt.)-treated groups significantly (p < 0.01) elevated plasma adiponectin level but reduced leptin level as well as fall in serum AST and ALT were noticed. Further, the disturbed structural integrity and architecture of adipose and hepatic tissues due to high fat diet feeding were considerably recovered with BSTN1 treatment. Down-regulation in the protein expression level of PPAR-γ and activation of AMPK through phosphorylation was observed in BSTN1 treated rats than the untreated. Molecular docking studies revealed strong binding interactions of BSTN1 against PPAR-γ and AMPK and thus supported the experimental results. Conclusion: Taken together, the results suggest that BSTN1 could be a promising pharmacological molecule in the treatment of obesity and dyslipidemia.
Highlights
The epidemic of obesity has become a public health issue in both developed and developing countries as it strongly predisposes to type-2 diabetes, dyslipidemia, hypertension, cardiovascular diseases (CVDs), non-alcoholic fatty liver disease (NAFLD), sleep apnea, infertility and certain types of cancers (Hurt et al, 2010)
The effect of BSTN1 on cell viability of 3T3-L1 cells and cytotoxicity was analyzed in the dose range of 10–160 μM, at 48 h using MTT assay
(p < 0.01) high level of glycerol release was observed in adipocytes treated with BSTN1 than untreated cells and the maximum lipolytic activity was noticed at a concentration of 20 μM (Figure 2C)
Summary
The epidemic of obesity has become a public health issue in both developed and developing countries as it strongly predisposes to type-2 diabetes, dyslipidemia, hypertension, cardiovascular diseases (CVDs), non-alcoholic fatty liver disease (NAFLD), sleep apnea, infertility and certain types of cancers (Hurt et al, 2010). The excess calories consumed than expended gets accumulated as fats (triglycerides) in adipocytes and leads to growth and expansion of white adipose tissue (WAT) by the process of hypertrophy and hyperplasia (Meln et al, 2019). Due to excess accumulation of fats in hepatic tissue in conditions like hepatic steatosis, nonalcoholic steatohepatitis (NASH) and NAFLD the metabolic functions of liver are derailed (Nassir et al, 2015). Various therapeutic approaches such as lifestyle modification, pharmacotherapy, and bariatric surgery are advocated to combat obesity ailments (Apovian et al, 2015). Considering the growing public inclination toward natural product-based therapeutics, the present work was carried out with Bauhuniastatin-1 isolated from Bauhinia purpurea
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