Up-regulation of PPARγ, heat shock protein-27 and-72 by naringin attenuates insulin resistance, β-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes

Department of Pharmacology, Cardiovascular and Diabetes Research Laboratory, All India Institute of Medical Sciences, New Delhi, India.
The British journal of nutrition (Impact Factor: 3.45). 06/2011; 106(11):1713-23. DOI: 10.1017/S000711451100225X
Source: PubMed


Naringin, a bioflavonoid isolated from grapefruit, is well known to possess lipid-lowering and insulin-like properties. Therefore, we assessed whether naringin treatment ameliorates insulin resistance (IR), β-cell dysfunction, hepatic steatosis and kidney damage in high-fat diet (HFD)-streptozotocin (STZ)-induced type 2 diabetic rats. Wistar albino male rats were fed a HFD (55 % energy from fat and 2 % cholesterol) to develop IR and on the 10th day injected with a low dose of streptozotocin (40 mg/kg, intraperitoneal (ip)) to induce type 2 diabetes. After confirmation of hyperglycaemia (>13·89 mmol/l) on the 14th day, different doses of naringin (25, 50 and 100 mg/kg per d) and rosiglitazone (5 mg/kg per d) were administered orally for the next 28 d while being maintained on the HFD. Naringin significantly decreased IR, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, TNF-α, IL-6, C-reactive protein and concomitantly increased adiponectin and β-cell function in a dose-dependent manner. Increased thiobarbituric acid-reactive substances and decreased antioxidant enzyme activities in the serum and tissues of diabetic rats were also normalised. Moreover, naringin robustly increased PPARγ expression in liver and kidney; phosphorylated tyrosine insulin receptor substrate 1 in liver; and stress proteins heat shock protein (HSP)-27 and HSP-72 in pancreas, liver and kidney. In contrast, NF-κB expression in these tissues along with sterol regulatory element binding protein-1c and liver X receptor- expressions in liver were significantly diminished. In addition, microscopic observations validated that naringin effectively rescues β-cells, hepatocytes and kidney from HFD-STZ-mediated oxidative damage and pathological alterations. Thus, this seminal study provides cogent evidence that naringin ameliorates IR, dyslipidaemia, β-cell dysfunction, hepatic steatosis and kidney damage in type 2 diabetic rats by partly regulating oxidative stress, inflammation and dysregulated adipocytokines production through up-regulation of PPARγ, HSP-27 and HSP-72.

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Available from: Narender Kumar, Mar 14, 2014
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    • "e of ethanol - related behaviors , lead to an important conclusion , namely , that the changes in the voluntary ethanol intake and CPP scores of mice induced by naringin were dependent on PPAR - g activation . This is consistent with previous reports which showed that GW9662 significantly reverse the activities of the PPAR - g agonist , naringin ( Sharma et al . , 2011 ) ."
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    ABSTRACT: Recently, PPAR-γ activation has emerged as a potential treatment for alcoholism. However, the adverse effects of synthetic PPAR-γ activators, despite being effective drugs, prompted the need for novel PPAR-γ agonists that retain efficacy and potency with a lower potential of side effects. Hence, naringin, a bioflavonoid isolated from citrus fruits and recently identified as a natural ligand of PPAR-γ, has begun to be evaluated for treatment of alcoholism. It is well known to possess several therapeutic benefits in addition to its anti-anxiety and antidepressant properties. In the present study, we assessed whether naringin treatment possesses anti-ethanol reward properties in C57BL/6 mice. We used the two-bottle choice drinking paradigm and ethanol-induced conditioned place preference (CPP) to examine the effect of naringin treatment on ethanol drinking. Results have shown that, compared with vehicle, naringin (10–100 mg/kg) significantly and dose-dependently decreased voluntary ethanol intake and preference in a two-bottle choice drinking paradigm [3–15% (v/v) escalating over 2 weeks], with no significant effect observed on saccharin [0.02–0.08% (w/v)] or on quinine [15–60 μM (w/v)] intake. In addition, there was no significant difference in blood ethanol concentration (BEC) between groups following naringin administration of 3 g of ethanol/kg body weight. Interestingly, when mice were treated with vehicle or naringin (30 mg/kg) before injection of ethanol (1.5 g/kg) during conditioning days, naringin inhibited the acquisition of ethanol-CPP. More importantly, these effects were significantly attenuated when mice were pre-injected with the peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist, GW9662. Taken together, the present findings are the first to implicate naringin and PPAR-γ receptors in the behavioral and reward-related effects of ethanol and raise the question of whether specific drugs that target PPAR-γ receptors could potentially reduce excessive ethanol consumption and preference.
    Alcohol 09/2014; 48(7). DOI:10.1016/j.alcohol.2014.06.008 · 2.01 Impact Factor
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    • "and 81.51–98.1 mg/100 g fresh weight, respectively) (Yoo et al., 2004). Hesperidin and naringin attenuated hyperlipidaemia and hepatic steatosis, partly by regulating fatty acid and cholesterol metabolism through enhancing hepatic and adipocyte PPARγ expression in type-2 diabetic animals (Jung, Lee, Park, Kang, & Choi, 2006; Sharma et al., 2011). In this study, administration of yuzu peel increased the mRNA expression of markers of lipid oxidation (pparab and acadm in liver, pparg in adipose tissue, and acox1 in both) and mature adipocytes (adipoqb in adipose tissue) in DIO zebrafish without affecting markers of lipogenesis (fasn and acacb in adipose tissue and liver) (Figs 3 and 4). "
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    ABSTRACT: Effects of yuzu peel (Citrus junos Siebold ex Tanaka), yuzu pomace after hexane extraction, and auraptene on metabolic disorders in zebrafish with diet-induced obesity (DIO) were evaluated. All materials tested exhibited anti-obesity effects. Yuzu peel significantly suppressed the rise in plasma triacylglycerol (TG) and liver lipid accumulation. The hepatic mRNA expression of pparab (peroxisome proliferator-activated receptor, alpha b) and its target genes were significantly upregulated by yuzu peel, which suggests enhanced fatty acid β-oxidation in liver. In visceral adipose tissue, yuzu peel significantly increased the mRNA expression of pparg (peroxisome proliferator-activated receptor, gamma) and adipoqb (adiponectin, C1Q and collagen domain containing, b), which play roles in adipose differentiation and maintenance. Our findings suggest that yuzu peel exerts anti-obesity effects by activating hepatic PPARα and adipocyte PPARγ pathways. Additionally, the anti-obesity effects of yuzu pomace suggest a novel application to achieve complete use of yuzu instead of disposal as industrial waste.
    Journal of Functional Foods 09/2014; 10:499-510. DOI:10.1016/j.jff.2014.08.002 · 3.57 Impact Factor
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    • "In conclusion, our present work demonstrates that naringin may serve as a promising cardioprotective agent, which could effectively protect the myocardium against IR-induced myocardial damage and could be used as add on therapy in patients for the secondary prevention of post myocardial infarction or for the primary prevention in patients who are having multiple risk factors like family history of early coronary artery disease, hypertension, hypercholesterolemia and diabetes [10,22,34]. Our results indicate that augmentation of endogenous antioxidant activity, upregulation of p-Akt/p-eNOS/NO signaling and suppression of IKK-β/NF-κB along with modulation of MAPKs by naringin synergistically contribute to the alleviation of irreversible IR injury and promote cardiomyocyte survival. "
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    ABSTRACT: Naringin has antioxidant properties that could improve redox-sensitive myocardial ischemia reperfusion (IR) injury. This study was designed to investigate whether naringin restores the myocardial damage and dysfunction in vivo after IR and the mechanisms underlying its cardioprotective effects. Naringin (20-80 mg/kg/day, p.o.) or saline were administered to rats for 14 days and the myocardial IR injury was induced on 15(th) day by occluding the left anterior descending coronary artery for 45 min and subsequent reperfusion for 60 min. Post-IR rats exhibited pronounced cardiac dysfunction as evidenced by significantly decreased mean arterial pressure, heart rate, +LVdP/dt max (inotropic state), -LVdP/dt max (lusitropic state) and increased left ventricular end diastolic pressure as compared to sham group, which was improved by naringin. Further, on histopathological and ultrastructural assessments myocardium and myocytes appeared more normal in structure and the infarct size was reduced significantly in naringin 40 and 80 mg/kg/day group. This amelioration of post-IR-associated cardiac injury by naringin was accompanied by increased nitric oxide (NO) bioavailability, decreased NO inactivation to nitrotyrosine, amplified protein expressions of Hsp27, Hsp70, β-catenin and increased p-eNOS/eNOS, p-Akt/Akt, and p-ERK/ERK ratio. In addition, IR-induced TNF-α/IKK-β/NF-κB upregulation and JNK phosphorylation were significantly attenuated by naringin. Moreover, western blotting and immunohistochemistry analysis of apoptotic signaling pathway further established naringin cardioprotective potential as it upregulated Bcl-2 expression and downregulated Bax and Caspase-3 expression with reduced TUNEL positivity. Naringin also normalized the cardiac injury markers (lactate dehydrogenase and creatine kinase-MB), endogenous antioxidant activities (superoxide dismutase, reduced glutathione and glutathione peroxidase) and lipid peroxidation levels. Thus, naringin restored IR injury by preserving myocardial structural integrity and regulating Hsp27, Hsp70, p-eNOS/p-Akt/p-ERK signaling and inflammatory response.
    PLoS ONE 12/2013; 8(12):e82577. DOI:10.1371/journal.pone.0082577 · 3.23 Impact Factor
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