β-Sitosterol Circumvents Obesity Induced Inflammation and Insulin Resistance by down-Regulating IKKβ/NF-κB and JNK Signaling Pathway in Adipocytes of Type 2 Diabetic Rats.

Selvaraj Jayaraman,Chella Perumal Palanisamy,Bo Cui,Senthil Kumar Ganesan,Vishnu Priya Veeraraghavan,Kirubhanand Chandrasekar,Ponnulakshmi Rajagopal,Nalini Devarajan,Vijayalakshmi Periyasamy,Shyamaladevi Babu

doi:10.3390/molecules26072101

Abstract

β-sitosterol (SIT), the most abundant bioactive component of vegetable oil and other plants, is a highly potent antidiabetic drug. Our previous studies show that SIT controls hyperglycemia and insulin resistance by activating insulin receptor and glucose transporter 4 (GLUT-4) in the adipocytes of obesity induced type 2 diabetic rats. The current research was undertaken to investigate if SIT could also exert its antidiabetic effects by circumventing adipocyte induced inflammation, a key driving factor for insulin resistance in obese individuals. Effective dose of SIT (20 mg/kg b.wt) was administered orally for 30 days to high fat diet and sucrose induced type-2 diabetic rats. Metformin, the conventionally used antidiabetic drug was used as a positive control. Interestingly, SIT treatment restores the elevated serum levels of proinflammatory cytokines including leptin, resistin, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to normalcy and increases anti-inflammatory adipocytokines including adiponectin in type 2 diabetic rats. Furthermore, SIT decreases sterol regulatory element binding protein-1c (SREBP-1c) and enhances Peroxisome Proliferator–activated receptor-γ (PPAR-γ) gene expression in adipocytes of diabetic rats. The gene and protein expression of c-Jun-N-terminal kinase-1 (JNK1), inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) and nuclear factor kappa B (NF-κB) were also significantly attenuated in SIT treated groups. More importantly, SIT acts very effectively as metformin to circumvent inflammation and insulin resistance in diabetic rats. Our results clearly show that SIT inhibits obesity induced insulin resistance by ameliorating the inflammatory events in the adipose tissue through the downregulation of IKKβ/NF-κB and c-Jun-N-terminal kinase (JNK) signaling pathway.

Highlights

Obesity, a grave pathological condition characterized by excess fat accumulation in visceral adipose tissue forms the basis for the pathogenesis of insulin resistance and type 2 diabetes mellitus [1]
SIT treatment tremendously controlled the body weight gain in the high fat diet (HFD) and sucrose fed rats as effectively as metformin, which in turn is indicative of its potent anti-obesity properties (Table 1)
SIT Declines the Gene and Protein Expression of Jun N-Terminal kinase (JNK), IKKβ and NF-κB in Adipose Tissue Jun-N-terminal kinase-1 (JNK1), IKKβ and NF-κB are crucially involved in the pathogenesis of inflammation and insulin resistance and we investigated their gene and protein expression in the adipocytes of experimental rats by real time PCR and Western blotting respectively

Summary

Introduction

A grave pathological condition characterized by excess fat accumulation in visceral adipose tissue forms the basis for the pathogenesis of insulin resistance and type 2 diabetes mellitus [1]. The adipose tissue of obese people exhibit excess fat accumulation and secrete more levels of proinflammatory adipokines including leptin and resistin [5,6] These molecules activate IKKβ/NF-κB and c-Jun N-Terminal kinase (JNK) pathways in the adipose tissue and augment the synthesis of proinflammatory cytokines including, TNF-α, IL-6 and IL-1β via positive feedback loop [7,8]. Together, these proinflammatory adipokines and cytokines infiltrate macrophages, T-lymphocytes and dendritic cells into adipocytes, which in turn lead to dysfunctional lipid metabolism. Disruptions in the normal function of adipose tissue lead to defective glucose homeostasis in liver and skeletal muscles, which in turn result in systemic insulin resistance and the onset of type 2 diabetes

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Conclusion