Elsevier

Nutrition

Volume 50, June 2018, Pages 82-90
Nutrition

Basic nutritional investigation
Magnolol promotes thermogenesis and attenuates oxidative stress in 3T3-L1 adipocytes

https://doi.org/10.1016/j.nut.2018.01.017Get rights and content

Highlights

  • Magnolol exhibits multiple modulatory functions in adipocytes.

  • Magnolol prevents 3 T3-L1 adipocytes from oxidative stress.

  • Magnolol promotes browning possibly via activation of PPARγ-, pAMPK-, and PKA-mediated pathways.

Abstract

Objective

The aim of this study was to explore the browning and antioxidative effects of magnolol in 3T3-L1 adipocytes, as recruitment of beige-like adipocytes (browning) by natural compounds is being considered as a promising strategy to fight against obesity.

Methods

Magnolol-induced browning effect was evaluated by determining the expression levels of specific marker genes and proteins using real-time polymerase chain reaction and immunoblotting, respectively. Induction of thermogenesis and suppression of oxidative stress in 3T3-L1 adipocytes were further validated by immunofluorescence.

Results

Magnolol significantly enhanced expression of a core set of brown fat–specific marker genes (Ucp1, Cd137, Prdm16, Cidea, and Tbx1) and proteins (UCP1, PRDM16, and PGC-1α). Increased expression of UCP1 and other brown fat–specific markers contributed to the browning of 3T3-L1 adipocytes possibly via activation of the AMPK, PPARγ, and protein kinase A (PKA) pathways. In addition, magnolol up-regulated key fatty acid oxidation and lipolytic markers (CPT1, ACSL1, SIRT1, and PLIN) and down-regulated lipogenic markers (FAS and SREBP1). Magnolol also reduced the production and release of reactive oxygen species.

Conclusion

The current data suggest possible roles for magnolol in browning of white adipocytes, augmentation of lipolysis, and thermogenesis, as well as repression of oxidative stress and lipogenesis. Thus, magnolol may be explored as a potentially promising therapeutic agent for the prevention of obesity and other metabolic disorders.

Introduction

Obesity incidence is increasing worldwide at an alarming pace and has become a major threat to public health [1]. Indeed, obesity facilitates the development of hypertension, diabetes, stroke, osteoarthritis, and cancer [2], [3]. It is well accepted that obesity results from an imbalance between energy expenditure and energy consumption, which causes excess energy storage in the form of lipids in white adipose tissue (WAT). Methods that either increase energy expenditure or reduce energy consumption are potential antiobesity strategies [4]. WAT enlargement is associated with elevation of body weight, whereas brown adipose tissue (BAT) prevents storage of excess energy by dissipation in the form of heat. Hence, BAT plays a fundamental role in the protection against cold and obesity [5], [6].

Earlier reports have proposed that WAT and BAT in mammals have opposite functions because of their structural differences, as WAT has a unilocular structure and BAT has a multilocular structure [7], [8]. Of importance, brown fat–like cells (“beige” fat) have been reported to have potential to combat obesity and other obesity-related complications [9]. White and brown adipocytes originate from different lineage precursor cells having the property of interconversion [10]. In response to various external stimuli mediated by different factors, multilocular structure cells expressing UCP1 in white fat depots become characterized as beige or brown in white adipocytes [11]. Cold exposure and activation of β3-adrenergic receptor by various external stimuli are fundamental factors responsible for the appearance of beige adipocytes in WAT via remodeling of progenitor WAT fat cells [12], [13].

Recent advances in the obesity treatment have indicated that WAT depots countered with certain external factors could lead to brown fat–like phenotype. Different pharmacologic and dietary compounds have been proposed as remedies for increasing energy expenditure and preventing lipid accumulation in mammals [14], [15]. In response to pharmacologic treatment such as capsaicin, beriberine, irisin, or PPARγ agonist, a brown fat–like gene expression program is induced in certain adipocytes of WAT [16], [17].

Magnolol is an active component isolated from Magnolia officinalis (magnolia bark) and is distributed in many Asian countries. It is a traditional medicine widely used as a remedy to facilitate bowel movement and ameliorate cough, pain, anxiety, and cardiovascular diseases [18], [19], [20]. Magnolol was found to act as an antiinflammatory molecule to inhibit progression of diabetes and body fat accumulation in an obese mice model [21], [22]. Magnolol has also been reported to have various biological effects, including antioxidant activity, smooth muscle relaxant activity, and an antithrombotic effect [23], [24]. Moreover, magnolol administration was reported to significantly reduce weight gain caused by white adipocytes as well as adipocyte size and protect against insulin resistance induced in obese mice [22]. Therefore, the present study was undertaken to elucidate the effects of magnolol on induction of the brown fat–like phenotype in 3T3-L1 adipocytes as well as its possible molecular mechanism for the regulation of thermogenesis.

Section snippets

Chemicals

Magnolol (99% purity; Fig. 1A) was purchased from Cayman Chemical and Arbor Assays (Ann Arbor, MI, USA). GW9622 and dorsomorphin were purchased from Tocris Bioscience (Bristol, UK) and Sigma Chemical Co. (St. Louis, MO, USA), respectively. All other chemicals used in this study were of analytical grade.

Cell culture and differentiation

3T3-L1 and HIB1 B preadipocytes were cultured in complete media, which consists of high-glucose Dulbecco's Modified Eagle's Medium (DMEM, Thermo, Waltam, MA, USA), 10% fetal bovine serum (FBS,

Magnolol stimulates conversion of 3T3-L1 adipocytes into beige adipocytes

To determine the role of magnolol in the conversion of 3T3-L1 adipocytes into beige adipocytes, cells were treated with different concentrations of magnolol (1–20 µM), after which the cytotoxicity of magnolol was evaluated by MTT assay. Magnolol had no significant cytotoxicity at a concentration of 20 µM (Fig. 1B). Magnolol significantly up-regulated brown fat markers (PGC-1α, UCP1, and PRDM16) in 3T3-L1 adipocytes in a dose-dependent manner (Fig. 1C). Next, 3T3-L1 adipocytes were treated with

Discussion

An energy expenditure strategy focused on the transdifferentiation of WAT into beige adipocytes is a promising approach to control and manage obesity as well as other metabolic disorders [4]. Raising the thermogenic ability of BAT or beiging features in WAT could be an effective therapeutic approach to overcome obesity and its complications [27], [28]. The present study provides evidence that magnolol treatment has potential to induce the brown fat–like phenotype and suppress oxidative stress

Conclusion

Our findings indicate that magnolol exhibits multiple functions, including induction of browning and suppression of oxidative stress in adipocytes, promotion of lipid metabolism, as well as activation of brown adipocytes, thereby exhibiting the therapeutic role of magnolol against obesity. However, further in vivo experiments are necessary to solidify its role in obesity.

Acknowledgment

This work was supported by the Mid-career Researcher Program (2016 R1 A2 B4006526) and SRC Program (Center for Food & Nutritional Genomics, Grant number 2015 R1 A5 A6001906) through an NRF grant funded by the Ministry of Science, ICT and Future Planning, Korea.

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    The authors have no conflicts of interest to declare.

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