Stimulation of brown adipose tissue by polyphenols in extra virgin olive oil

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Stimulation of brown adipose tissue by polyphenols in extra virgin olive oil

L. Melguizo Rodríguez , R. Illescas-Montes , V. J. Costela-Ruiz & O. García- Martínez

To cite this article: L. Melguizo Rodríguez , R. Illescas-Montes , V. J. Costela-Ruiz & O. García- Martínez (2020): Stimulation of brown adipose tissue by polyphenols in extra virgin olive oil, Critical

Reviews in Food Science and Nutrition, DOI: 10.1080/10408398.2020.1799930

To link to this article: https://doi.org/10.1080/10408398.2020.1799930

Published online: 29 Jul 2020.

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View related articles View Crossmark data REVIEW Stimulation of brown adipose tissue by polyphenols in extra virgin olive oil

L. Melguizo Rodr
ıgueza,b , R. Illescas-Montesb,c , V. J. Costela-Ruizb,c

, and O. Garc
ıa-Mart
ınezb,c aDepartment of Nursing, Faculty of Health Sciences (Ceuta), Biomedical Group (BIO277), University of Granada, Ceuta, Spain; bInstituto

Investigaci
on Biosanitaria, ibs.Granada, Granada, Spain; cDepartment of Nursing, Faculty of Health Sciences, Biomedical Group (BIO277),

University of Granada, Granada, Spain ABSTRACT Obesity is one of the main public health problems of the 21st century resulting from an imbalance between calorie intake and energy expenditure. Currently, the search for new treatments against this pathology has become a priority. One of the therapeutic strategies against obesity could be the activation of brown adipose tissue through different molecules such as the phenolic com- pounds of extra virgin olive oil (EVOO). The objective of this review was to provide an update of scientific knowledge on the relationship between EVOO phenolic compounds and brown adi- pose tissue.

According to this review, it has been demonstrated that extra virgin olive oil phenolic compounds can have beneficial effects on obesity by activating brown adipose tissue and enhance thermo- genesis through different signaling pathways mediated by molecules such as AMP-activated pro- tein kinase (AMPK), peroxisome proliferator-activated receptor c coactivator-1a (PGC1a) or sirtuin

1 (Sirt1).

KEYWORDS brown adipose tissue; extra virgin olive oil; phenolic compounds; obesity

Introduction Obesity is a chronic disease resulting from an imbalance between calorie intake and energy expenditure (Engin 2017).

It is one of the main public health problems of the 21st cen- tury, affecting up to 35% of men and 40% of women in the

USA (Flegal et al. 2016). It has been related to an increased risk of type 2 diabetes mellitus (Dandona, Aljada, and

Bandyopadhyay 2004), metabolic syndrome (Grundy 2004), and atherosclerosis (Ritchie and Connell 2007), among other diseases. The search for measures to combat this epidemic has become a top priority. Interest has recently grown in the potential of brown adipose tissue (BAT) to prevent obesity and adverse metabolic events (Wang et al. 2015b; Mulya and Kirwan 2016; Rui 2017).

BAT, one of the main constituents of adipose tissue alongside white adipose tissue, is present in the interscapu- lar, subscapular, axillary, perirenal, and periaortic regions of mammals, especially rodents (Zhang and Bi 2015). In humans, it is largely localized in cervical, supraclavicular, axillary, subscapular, pectoral, paravertebral, mediastinal, and perirenal regions (Harms and Seale 2013; Aldiss et al.

2017). BAT is formed by brown adipocytes, smaller than white adipocytes, with polygonal shape, multilocular lipid droplets, multiple mitochondria, and a central nucleus. It is a highly vascularized tissue innervated by the sympathetic nervous system (Betz and Enerb€ack 2015; Bargut, Aguila, and Mandarim-de-Lacerda 2016). It is related to heat pro- duction and body temperature maintenance, i.e., adaptive thermogenesis (Cannon and Nedergaard 2004). However, this function is not exclusive to BAT, given that white adi- pocytes, especially those located in subcutaneous fat depots, can differentiate to beige adipocytes after exposure to vari- ous stimuli (Sharp et al. 2012). These include prolonged exposure to cold (Loncar, Afzelius, and Cannon 1988), b-adrenergic receptor stimulation (Cousin et al. 1992), or endocrine factors such as thyroid hormone (Solmonson and

Mills 2016), fibroblast growth factor 21 (FGF21) (Fisher et al. 2012), or morphogenetic proteins (Whittle et al. 2012;

Okla et al. 2015). This process has been designated adipose tissue browning (Wu,

Cohen, and Spiegelman 2013; Montanari, Pos
ci
c, and Colitti 2017).

Adaptive thermogenesis starts with the sympathetic ner- vous system-stimulated release of noradrenaline, which then interacts with b-adrenergic receptors (especially adrenergic receptor beta 3 [AR-beta3]) (Jimenez et al. 2002). The adrenergic receptor couples with a G protein of the Gs sub- type, stimulating adenylyl cyclase (Granneman 1988) and consequently increasing cAMP (Zhao,

Cannon, and Nedergaard 1997; Hoffmann et al. 2015). This molecule in turn acts by activating protein kinase A (PKA) (Fredriksson et al. 2001; Cao et al. 2001; Hoffmann et al. 2015), which induces the phosphorylation of nuclear-related proteins and cytosolic proteins. This PKA stimulation is responsible for inducing lipolysis via two different pathways: activation of both hormone-sensitive lipase (HSL) and adipose triglycer- ide lipase (ATGL); and perilipin phosphorylation (Holm et al. 1987; Chaudhry and Granneman 1999). This process mobilizes reserves of triglycerides, which degrade in the

CONTACT Victor Javier Costela-Ruiz vircoss@ugr.es Faculty of Health Sciences, University of Granada, Granada 18016, Spain.

2020 Taylor & Francis Group, LLC CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION https://doi.org/10.1080/10408398.2020.1799930 form of glycerol and fatty acids (Figure 1). The general acti- vation/carnitine shuttle system transfers these fatty acids into the mitochondria, where they serve as substrate for b-oxidation and act on uncoupling protein one (UCP1), considered a specific BAT marker. This protein is located in the inner mitochondrial membrane and allows protons to filter into the mitochondrial matrix and dissipate the energy generated in the form of heat (Nicholls and Locke 1984;

Matthias et al. 2000; Rial and Gonz
alez-Barroso 2001;

Cannon and Nedergaard 2004). The mechanisms of inter- action between fatty acids and UCP1 have not been eluci- dated, although there are three possible pathways: allosteric interaction, cofactor theory, and shuttling theory (Rial,

Poustie, and Nicholls 1983; Winkler and Klingenberg 1994;

Garlid et al. 2000; Jab˚urek et al. 2001).

The downstream activation of p38 mitogen-activated pro- tein kinase (MAPK) is one of the pathways stimulated by cAMP/PKA signaling.

AMP-activated protein kinase (AMPK) is activated directly by AMP/ADP or through the phosphorylation of threonine residue 172 by upstream kin- ases, liver kinase B1 (LKB1), or Ca2þ/calmodium-dependent protein kinases. AMPK phosphorylates and inhibits acetyl- CoA carboxylase and promotes fatty acid oxidation, reduc- ing adipose tissue accumulation (J€ager et al. 2007; O’Neill,

Holloway, and Steinberg 2013; Fullerton et al. 2013).

Over the past few years, some new factors have been pro- posed as possible BAT activators, including physical activity (Ruiz et al. 2015a, 2015b; Acosta et al. 2019) and certain nutritional factors, e.g., capsaicin (Baskaran et al. 2016), car- otenoids (Murholm et al. 2013; Bonet et al. 2015), long chain (poly)unsaturated fatty acids (Fleckenstein-Elsen et al.

2016; Shen and McIntosh 2016), and polyphenols (Wang et al. 2015a; Mu et al. 2015; Lone et al. 2016; Choi et al.

2017). Recent studies have demonstrated the potential of olive oil and its phenolic compounds as thermogenesis inducers, either by increasing UCP1, UCP2, and UCP3 lev- els or by acting locally on BAT and skeletal muscle through the positive regulation of

UCP mRNA expression (Rodr
ıguez et al. 2002; Oi-Kano et al. 2007; Castro-Barquero et al. 2018).

Due to the high interest that the impact of phenolic com- pounds on health is generating in the scientific community, further study of the mechanism of action of EVOO phenolic compounds on the activation of brown adipose tissue is a new and important field of research based on the possible therapeutic potential of this tissue against obesity and related medical problems.

The objective of this review was to provide an update of scientific knowledge on the relationship between olive oil phenolic compounds and BAT.

Brown adipose tissue and olive oil phenolic compounds

Extra virgin olive oil (EVOO) contains five main phenolic compounds groups: flavonoids, lignans, phenolic acids, phenolic alcohols, and secoiridoids. Their presence can vary in quantity (150–700 mg/L) and quality according to the olive variety, degree of maturation, soil composition, cli- mate, harvesting technique, processing, and storage (Uceda et al. 1999; Mart
ınez Nieto, Hodaifa, and Lozano Pe~na 2010;

Inglese et al. 2011).

It has been demonstrated that EVOO polyphenols can have beneficial effects on health and act against cardiovascu- lar and neurodegenerative diseases, cancer, and osteoporosis, among other conditions (Berrougui, Ikhlef, and Khalil 2015;

Casamenti and Stefani 2017; Melguizo-Rodr
ıguez et al.

2018a, 2018b; Melguizo-Rodr
ıguez et al. 2019).

Secoiridoids Oleuropein Oleuropein is a secondary metabolite of olive oil and belongs to the secoiridoid group (Alagna et al. 2016), which is responsible for endowing the oil with organoleptic proper- ties such as acidity and bitterness (Servili and Montedoro

2002). Various studies have demonstrated the capacity of this phenolic compound to act on BAT. Thus, Oi-Kano et al. (2007) suggested that the oleuropein fraction, which includes oleuropein, and its absorbed form (oleuropein agly- cone), can increase the secretion of adrenalin and noradre- nalin, which are directly involved in BAT activation. An in vivo study (Oi-Kano et al. 2008) examined the effect of oleuropein on thermogenesis and the secretion of adrenalin and noradrenalin in rats fed with a high-fat diet supple- mented with this phenolic compound. The researchers found that UCP1 concentrations and adrenalin and noradre- nalin levels in urine and plasma were significantly higher in the animals fed with the oleuropein-supplemented diet than in controls. In 2017, the same authors studied the mecha- nisms of action of this molecule and of oleuropein aglycone on BAT, indicating that BAT can act on transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), related to weight maintenance, hormone secretion, thermo- genesis and neuronal function, increasing the expression of

UCP1 and reducing visceral fat (Oi-Kano et al. 2017).

Figure 1. Adaptive thermogenesis process.

2 L. MELGUIZO RODRÍGUEZ ET AL.

Flavonoids Luteolin Luteolin is a phenolic compound of the flavonoid group and is present in a wide variety of foods, including olive oil, pep- per, celery, and rosemary (L
opez-L
azaro 2009). Luteolin has important functions in the organism, acting as a potent anti- oxidant and anti-inflammatory, and it has been found to exert a protective effect against neurological disease and can- cer (Theoharides et al. 2015; Nabavi et al. 2015; Tuorkey

2016). This phenolic compound has been reported to pre- vent obesity development and inhibit adipocyte differenti- ation and lipid accumulation (Xu et al. 2014). Some authors have proposed that the mechanism of action underlying this protective effect against obesity may be related to adipose tissue browning, because luteolin can stimulate BAT and enhance thermogenesis via the AMPK/peroxisome prolifer- ator-activated receptor c coactivator-1a (PGC1a) signaling pathway (Xiao et al. 2014; Zhang et al. 2016), which plays a key role in metabolism regulation.

Rutin The flavonoid rutin or rutoside is characteristic of citruses, but a large amount is also present in olive oil (Oliveras- L
opez et al. 2007). In a model of obese mice, Yuan et al. (2017) demonstrated that rutin induces BAT and beige adi- pose tissue by activating the sirtuin 1 (Sirt1)/PGC1a/mito- chondrial transcription factor (Tfam) pathway and by increasing mitochondrial and UCP1 activation. Another mouse study described the potential of rutin to improve polycystic ovary syndrome by BAT activation, reducing insulin sensitivity, hyperandrogenism, acyclicity, and infertil- ity, among other symptoms of this disease (Hu et al. 2017).

Quercetin Quercetin is the most abundant flavonoid in the human diet and the most widespread in fruit and vegetables (Anand

David, Arulmoli, and Parasuraman 2016). It is exceptional for its anti-inflammatory, antihypertensive, and vasodilator effects and for its antihypercholesterolemic, antiatheroscler- otic, and anti-obesity properties (Boots, Haenen, and Bast

2008; Sultana and Anwar 2008; Salvamani et al. 2014). With regard to its anti-obesogenic effects, UCP1 expression and thermogenesis were increased in mice receiving a quercetin- enriched diet, and these effects appeared to be related to the

AMPK/Sirt1 signaling pathway (Dong et al. 2014). Lee,

Parks, and Kang (2017). observed white adipose tissue trans- differentiation after administering this phenolic compound in in vivo and in vitro studies, and they demonstrated the thermogenic potential of this molecule, finding that the highest dose administered (100 lM) enhanced the gene expression of markers closely related to this process, includ- ing Prdm 16, PGC1a, Ucp1, Fgf21, and Cidea. These results and the in vivo findings of Kuipers et al. (2018) in C57Bl/6 J mice suggest that quercetin may act by browning white adi- pose tissue.

According to Choi, Kim, and Yu (2018) the mechanism of action underlying the effect of this phenolic compound on

BAT may be related to sympathetic nervous system stimula- tion, revealed by an increase in norepinephrine levels and the upregulation of b-adrenergic receptor mRNA. After feeding

C57BL/6 mice a fat-rich diet supplemented with 0.05% quer- cetin, these authors observed stimulation of AMPK and the increased expression of genetic markers such as mitochon- drial transcription factor A (TFAM), nuclear respiratory fac- tor-1 (NRF-1), PR domain containing 16 (PRDM16), Cell death activator CIDE-A (Cidea), transmembrane protein 26 (TMEM26), and UCP1. UCP1 was also increased in in vitro studies in 3T3-L1 adipocytes of murine origin.

Cyanidin 3 glucoside The anthocyanin cyanidin 3 glucoside is widely distributed in nature and abundantly present in Turkish olive oil (Aslı

Yorulmaz et al. 2012). Its action on systemic energy homeo- stasis was demonstrated by You et al. (2017), who found that 16 weeks of treatment with guanine nucleotide-exchan- ger protein (C3G) at a dose of 1 mg/mL stimulated BAT in

C57BLKS/J-Leprdb/Leprdb (db/db) mice, inducing the for- mation of beige adipocytes. This treatment enhanced the gene expression of thermogenesis-related markers (e.g.,

UCP1) and activated and stimulated the mitochondrial func- tion of BAT, a metabolically active tissue characterized by an abundance of mitochondria.

Phenolic acids Chlorogenic acid Chlorogenic acid is a phenolic compound present at low concentrations in olives and olive oil (Venditti et al. 2015).

This simple phenol can also be found in other foods, includ- ing green coffee beans (Farah et al. 2008). This molecule has been found to act synergistically with leucine and its metab- olite b-hydroxy-b-methylbutyrate as a natural thermogenic agent capable of stimulating AMPK and Sirt1, favoring fatty acid oxidation (Bruckbauer and Zemel 2014).

Vanillic acid Olive oil is also an important source of vanillic acid, which acts as a potent aromatizing agent (Juturu 2014). This poly- phenol has beneficial health effects and has demonstrated cardioprotective (Radmanesh et al. 2017), chemopreventive (Vinoth and Kowsalya 2018), and anti-obesogenic (Jung et al. 2018) properties. Han et al. (2018) reported that its protective effect against obesity may be mediated by its action on BAT; in their study of C57BL/6J mice fed with a high-fat and high-fructose diet supplemented with vanillic acid, they found that this polyphenol can stimulate thermo- genesis, BAT mitochondrial activity, and inguinal white adi- pose tissue browning. Jung et al. (2018) postulated that the action mechanism underlying this upregulation of thermo- genesis may be related to activation of the AMPK signaling

CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 3 pathway. They administered vanillic acid at doses of 10, 100, and 1000 mg/kg/d to obese mice and observed increases in mitochondrial activity, UCP1, and PGC1a. PGC1a stimu- lates the secretion of aminoisobutyric acid, which also par- ticipates in adipose tissue browning (Roberts et al. 2014).

Gallic acid Gallic acid is an organic acid found in free form in plant galls and can be obtained by the hydrolysis of tannins.

Besides its antioxidant function, gallic acid possesses anti- carcinogenic, anti-mutagenic, anti-allergic, and anti-inflam- matory properties (Cheorun Jo et al. 2006; Kahkeshani et al.

2019). In vivo studies have indicated a protective effect of gallic acid against obesity and dyslipidemia (Latha and Daisy

2011; Oi et al. 2012; Setayesh et al. 2019), although the underlying mechanisms of action have not been fully eluci- dated. In vitro studies of the HepG2 cell line and in vivo mouse experiments found that gallic acid can act on the

AMPK/Sirt1/PGC1a pathway and modify the expression of

BAT genetic markers responsible for thermogenesis,

Table 1. Mechanism of action of EVOO phenolic compounds.

EVOO phenolic compounds groupS Phenolic compounds MECHANISM OF ACTION

References Flavonoids Luteolin Luteolin can stimulate BAT and enhance thermogenesis via the AMPK/peroxisome proliferator-activated receptor c coactivator-1a (PGC1a) signaling pathway

Xiao et al. 2014 Zhang et al. 2016 Rutin Rutin induces BAT and beige adipose tissue by activating the sirtuin 1 (Sirt1)/PGC1a/ mitochondrial transcription factor (Tfam) pathway and by increasing mitochondrial and

UCP1 activation Yuan et al. 2017 Quercetin 1. Quercetin increase UCP1 expression and thermogenesis through AMPK/Sirt1 signaling pathway. High doses of quercetin (100 lM) enhance the expression of Prdm 16, PGC1a, Ucp1,

Fgf21, and Cidea genes, closely related to thermogenesis.

2. Quercetin may stimulate sympathetic nervous system with an increase in norepinephrine levels and the upregulation of b-adrenergic receptor mRNA. This polyphenol stimulates AMPK and increase expression of genetic markers such as mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF-1), PR domain containing 16 (PRDM16), Cell death activator

CIDE-A (Cidea), transmembrane protein 26 (TMEM26), and UCP1

1. Dong et al. 2014 Lee, Parks, and Kang 2017 2. Choi, Kim, and Yu 2018

Cyanidin-3-glucoside This polyphenol induces the formation of beige adipocytes, enhancing the gene expression of thermogenesis-related markers (e.g., UCP1) and activating and stimulating the mitochondrial function of BAT

You et al. 2017 Phenolic acids Chlorogenic acid This molecule act synergistically with leucine and its metabolite b-hydroxy-b-methylbutyrate as a natural thermogenic agent capable of stimulating

AMPK and Sirt1, favoring fatty acid oxidation Bruckbauer and Zemel 2014

Vanillic acid 1. This polyphenol can stimulate thermogenesis, BAT mitochondrial activity, and inguinal white adipose tissue browning.

2. The upregulation of thermogenesis induced by vanillic acid may be related to activation of the

AMPK signaling pathway with an increase in mitochondrial activity, UCP1, and PGC1a (which stimulates the secretion of aminoisobutyric acid, a specific molecule related to adipose tissue browning)

1. Jung et al. 2018 2. Roberts et al. 2014 Gallic acid

Gallic acid can act on the AMPK/ Sirt1 / PGC1a pathway and modify the expression of BAT genetic markers responsible for thermogenesis

Doan et al. 2015 Phenolic ALCOHOLS Hydroxytyrosol 1. This compound inhibits the oxidation of low- density lipoproteins (LDLs)

2. Hydroxytyrosol promotes BAT stimulation by increasing UCP1 and AMPK in subcutaneous white adipose tissue

1. Covas et al. 2006 Soler Cantero 2009 2. Wang et al. 2019

Secoiridoids Oleuropein/ Oleuropein aglycone Oleuropein increase of the secretion of adrenalin, noradrenalin and UCP1 concentration which stimulate BAT. BAT can act on transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), related to weight maintenance, hormone secretion, thermogenesis and neuronal function and reducing visceral fat

Oi-Kano et al. 2008 Oi-Kano et al. 2017 4 L. MELGUIZO RODRÍGUEZ ET AL. supporting their usefulness against metabolic diseases (Doan et al. 2015).

Phenolic alcohols Hydroxytyrosol Hydroxytyrosol is the main phenolic alcohol in EVOO (Bonoli et al. 2004), although its concentration is generally low in fresh oils and increases during storage (Montedoro et al. 1992). Various studies have confirmed that this com- pound inhibits the oxidation of low-density lipoproteins (LDLs) (Covas et al. 2006; Soler Cantero 2009). However,

Oi-Kano et al. (2007) reported that hydroxytyrosol has no effect on BAT, observing no difference between rats receiv- ing a femoral dose of 10 or 30 mmol/L and those injected with vehicle alone. In contrast, a study by Wang et al. (2019) of mice exposed to fine particular matter (2.5 lM) showed that hydroxytyrosol promoted BAT stimulation by increasing UCP1 and AMPK in subcutaneous white adi- pose tissue.

Conclusion The phenolic compounds in olive oil may be useful in the management of obesity through their stimulating effect on

BAT and their anti-obesogenic potential (Table 1).

However, most published evidence is based on animal models, and further research is needed on the effects of

EVOO phenolic compounds in animals and humans, exploring in greater depth their mechanism of action on

BAT and their potential preventive role against metabolic diseases such as obesity.

Acknowledgements This study was supported by the research group BIO277 (Junta de

Andaluc
ıa) and Department of Nursing (University of Granada). The work outlined in this article has been partially funded by the Spanish

Ministry of Education under FPU fellowship reference FPU16-04141.

Disclosure statement The authors declare that they have no conflict of interest and/or com- peting financial interest.

Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

ORCID L. Melguizo Rodr
ıguez http://orcid.org/0000-0002-9176-6997

R. Illescas-Montes http://orcid.org/0000-0001-9795-8159

V. J. Costela-Ruiz http://orcid.org/0000-0001-7285-6615

O. Garc
ıa-Mart
ınez http://orcid.org/0000-0003-1912-4639

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