Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels.

Jinfeng Liu,Lili Song,Xiao Dong,Mingjun Cao,Qingjie Pan,Andrew Bulmer,Yong Zhang,David B Adams,Hongjun Wang,Huansheng Dong

doi:10.1038/srep09886

Abstract

Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice.

Highlights

Obesity has reached epidemic proportions globally, and at least 2.8 million people die each year as a result of being overweight or obese (WHO)
Bilirubin treatment resulted in improved glucose uptake and insulin utilization as evidenced by reduced blood glucose levels as well as reduced areas under the curve (GTT, Fig. 1h,j) or reverse areas above the curve (ITT, Fig. 1i,k), compared to GTT (Fig. 1d,e) and insulin tolerance test (ITT) (Fig. 1f,g) results before starting treatment
These data confirmed that bilirubin treatment reduced obesity and blood glucose levels and improved glucose tolerance and insulin sensitivity in diet induced obese (DIO) mice

Summary

Introduction

Obesity has reached epidemic proportions globally, and at least 2.8 million people die each year as a result of being overweight or obese (WHO). Adipose tissue plays a critical role in glucose homeostasis and lipid metabolism[3,4] via production of various proteins known as adipokines or adipocytokines including tumor necrosis factor-α (TNF-α), interleukin-6, monocyte chemoattractant protein 1, leptin, and adiponectin[5,6,7]. Bilirubin mimics the effect of HO-1 induction and improves insulin sensitivity in obese mouse models[28]. We have shown that systemic administration of bilirubin increases insulin sensitivity via suppressing ER stress and inflammation in DIO mice[35]. We have extended these observations and have investigated whether bilirubin regulates lipid metabolism as seen in patients with Gilbert’s disease[34] and whether bilirubin regulates serum adipokine levels in DIO mice. We assessed longer-term effects of bilirubin treatment on lipid metabolism and adipokine levels 7 weeks after completion of bilirubin treatment

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Conclusion