Abstract

Excessive lipid accumulation in white adipose tissue (WAT) results in adipocyte hypertrophy and chronic low-grade inflammation, which is the major cause of obesity-associated insulin resistance and consequent metabolic disease. The development of beige adipocytes in WAT (browning of WAT) increases energy expenditure and has been considered as a novel strategy to counteract obesity. Thymoquinone (TQ) is the main bioactive quinone derived from the plant Nigella Sativa and has antioxidative and anti-inflammatory capacities. Fish oil omega 3 (ω3) enhances both insulin sensitivity and glucose homeostasis in obesity, but the involved mechanisms remain unclear. The aim of this study is to explore the effects of TQ and ω3 PUFAs (polyunsaturated fatty acids) on obesity-associated inflammation, markers of insulin resistance, and the metabolic effects of adipose tissue browning. 3T3-L1 cells were cultured to investigate the effects of TQ and ω3 on the browning of WAT. C57BL/6J mice were fed a high-fat diet (HFD), supplemented with 0.75% TQ, and 2% ω3 in combination for eight weeks. In 3T3-L1 cells, TQ and ω3 reduced lipid droplet size and increased hallmarks of beige adipocytes such as uncoupling protein-1 (UCP1), PR domain containing 16 (PRDM16), fibroblast growth factor 21 (FGF21), Sirtuin 1 (Sirt1), Mitofusion 2 (Mfn2), and heme oxygenase 1 (HO-1) protein expression, as well as increased the phosphorylation of Protein Kinase B (AKT) and insulin receptors. In the adipose tissue of HFD mice, TQ and ω3 treatment attenuated levels of inflammatory adipokines, Nephroblastoma Overexpressed (NOV/CCN3) and Twist related protein 2 (TWIST2), and diminished adipocyte hypoxia by decreasing HIF1α expression and hallmarks of beige adipocytes such as UCP1, PRDM16, FGF21, and mitochondrial biogenesis markers Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), Sirt1, and Mfn2. Increased 5′ adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation and HO-1 expression were observed in adipose with TQ and ω3 treatment, which led to increased pAKT and pIRS1 Ser307 expression. In addition to the adipose, TQ and ω3 also increased inflammation and markers of insulin sensitivity in the liver, as demonstrated by increased phosphorylated insulin receptor (pIR tyr972), insulin receptor beta (IRβ), UCP1, and pIRS1 Ser307 and reduced NOV/CCN3 expression. Our data demonstrate the enhanced browning of WAT from TQ treatment in combination with ω3, which may play an important role in decreasing obesity-associated insulin resistance and in reducing the chronic inflammatory state of obesity.

Highlights

  • Overweight individuals and obesity are growing worldwide public health concerns and pose a significant healthcare burden that warrants further investigation [1]

  • We showed that the combination treatment of TQ and ω3 reduced lipid droplet size and increased mitochondrial biogenesis, mitochondrial fusion genes, white adipose tissue (WAT) browning, and insulin receptor phosphorylation, which were associated with antioxidant enzyme heme oxygenase 1 (HO-1) induction in vitro (3T3L1 adipocytes) as well as in vivo (C57/BL6 mice)

  • These results suggest that the reduction of inflammatory responses, enhanced conversion of large unhealthy white to small healthy beige adipocytes, and the restoration of mitochondrial function appear to contribute to the improvement of obesity and related insulin resistance

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Summary

Introduction

Overweight individuals and obesity are growing worldwide public health concerns and pose a significant healthcare burden that warrants further investigation [1]. Increased adiposity is accompanied by the pathological impact of adipocyte hypoxia, leading to the activation of hypoxia-inducible factor 1α (HIF1α) and secretion of proinflammatory adipokines/cytokines such as leptin, interleukin (IL)-6, tumor necrosis factor (TNF) α, and nephroblastoma overexpressed (NOV/CCN3) [3,4,5]. These adipokines/cytokines play a pivotal role in the development of obesity-associated metabolic dysfunction such as insulin resistance, type 2 diabetes, hypertension, cardiovascular diseases, and certain types of cancer [6,7]. In humans, the expression pattern of browning genes is greater in visceral white adipose tissue (vWAT) than in subcutaneous white adipose tissue (sWAT,) further addressing the importance of vWAT browning to combat obesity in humans [10]

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