The Demethoxy Derivatives of Curcumin Exhibit Greater Differentiation Suppression in 3T3-L1 Adipocytes Than Curcumin: A Mechanistic Study of Adipogenesis and Molecular Docking.

Ahmed Alalaiwe,Ching-Yun Hsu,Chun-Hui Chiu,Hsien-Ju Lee,Jia-You Fang

doi:10.3390/biom11071025

Abstract

Curcumin is a known anti-adipogenic agent for alleviating obesity and related disorders. Comprehensive comparisons of the anti-adipogenic activity of curcumin with other curcuminoids is minimal. This study compared adipogenesis inhibition with curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC), and their underlying mechanisms. We differentiated 3T3-L1 cells in the presence of curcuminoids, to determine lipid accumulation and triglyceride (TG) production. The expression of adipogenic transcription factors and lipogenic proteins was analyzed by Western blot. A significant reduction in Oil red O (ORO) staining was observed in the cells treated with curcuminoids at 20 μM. Inhibition was increased in the order of curcumin < DMC < BDMC. A similar trend was observed in the detection of intracellular TG. Curcuminoids suppressed differentiation by downregulating the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), leading to the downregulation of the lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). AMP-activated protein kinase α (AMPKα) phosphorylation was also activated by BDMC. Curcuminoids reduced the release of proinflammatory cytokines and leptin in 3T3-L1 cells in a dose-dependent manner, with BDMC showing the greatest potency. BDMC at 20 μM significantly decreased leptin by 72% compared with differentiated controls. Molecular docking computation indicated that curcuminoids, despite having structural similarity, had different interaction positions to PPARγ, C/EBPα, and ACC. The docking profiles suggested a possible interaction of curcuminoids with C/EBPα and ACC, to directly inhibit their expression.

Highlights

Obesity influences one-third of adults globally, and represents a primary health problem [1]
We found that adipocyte viability was not significantly affected by curcuminoids at concentrations ≤ 20 μM, demonstrating that these compounds suppressed adipogenesis through means other than apoptosis induced by membrane lysis
We currently demonstrated that BDMC inhibited 3T3-L1 differentiation, mainly through the downregulation of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), leading to a subsequent downregulation of their target proteins acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (Figure 8)

Summary

Introduction

Obesity influences one-third of adults globally, and represents a primary health problem [1]. Obesity can shorten the life span and disrupt the function of many organs [2]. This increases the risk of chronic obesity-related co-morbidities, including diabetes, hypertension, dyslipidemia, dyspnoea, fatty liver, cancer, and poor mental health [3]. Biomolecules 2021, 11, 1025 and hypertrophy of adipocytes are important characteristics of obesity. In addition to storing fat, adipocytes are considered to influence endocrine cells, which secrete numerous bioactive peptides called adipokines, and has a profound impact on the metabolic homeostasis of other tissues [4]. Amphetamine, rimonabant, and sibutramine have been shown to increase the risk of myocardial infarction and psychiatric disorder [5]

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