2-Bromo-4'-methoxychalcone and 2-Iodo-4'-methoxychalcone Prevent Progression of Hyperglycemia and Obesity via 5'-Adenosine-Monophosphate-Activated Protein Kinase in Diet-Induced Obese Mice.

Chi-Ting Hsieh,Yi-Hong Tsai,Tusty-Jiuan Hsieh,Yang-Chang Wu,Fang-Rong Chang

doi:10.3390/ijms19092763

Abstract

Obesity and diabetes are global health-threatening issues. Interestingly, the mechanism of these pathologies is quite different among individuals. The discovery and development of new categories of medicines from diverse sources are urgently needed for preventing and treating diabetes and other metabolic disorders. Previously, we reported that chalcones are important for preventing biological disorders, such as diabetes. In this study, we demonstrate that the synthetic halogen-containing chalcone derivatives 2-bromo-4′-methoxychalcone (compound 5) and 2-iodo-4′-methoxychalcone (compound 6) can promote glucose consumption and inhibit cellular lipid accumulation via 5′-adenosine-monophosphate-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase 1 (ACC) phosphorylation in 3T3-L1 adipocytes and C2C12 skeletal myotubes. In addition, the two compounds significantly prevented body weight gain and impaired glucose tolerance, hyperinsulinemia, and insulin resistance, which collectively help to delay the progression of hyperglycemia in high-fat-diet-induced obese C57BL/6 mice. These findings indicate that 2-bromo-4′-methoxychalcone and 2-iodo-4′-methoxychalcone could act as AMPK activators, and may serve as lead compounds for a new class of medicines that target obesity and diabetes.

Highlights

Obesity and metabolic syndrome are growing health issues and life-threatening situations worldwide [1,2]
We found that chalcones with chloro, bromo, and iodo substitutions at position 2 on the A-ring exhibited excellent activities in promoting glucose consumption in 3T3-L1 adipocytes [6]
Our results suggest that halogen chalcones may serve as novel lead compounds for developing

Summary

Introduction

Obesity and metabolic syndrome are growing health issues and life-threatening situations worldwide [1,2]. The consequence of obesity can result in many diseases, including impaired glucose tolerance and type 2 diabetes mellitus (T2DM) [1]. The major categories of medicines used to treat T2DM generally have adverse effects or problems with tolerability, especially for patients with liver and renal function disorders [3]. Different plant-derived forms of chalcone have been isolated that contain several substitutive patterns, including hydroxy, methyl, and methoxy substituents on both of the aromatic rings [6,7,8,9,10,11]. Halogen-containing chalcone derivatives are rare in the plant kingdom [5]. Using a simple synthetic method, we have been able to produce different halogen-containing chalcone derivatives [6,12]

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