Dietary polyphenols turn fat “brown”: A narrative review of the possible mechanisms

Highlights

• Dietary phenolics promote white-to-brown fat conversion.

• Multiple signaling pathways, receptors, and transcription factors are involved.

• Polyphenol-induced browning of WAT may also occur in humans.

Abstract

Background

Inducible brown adipocytes called beige adipocytes are found in white adipose tissue (WAT) depots. They express functional UCP1 and have thermogenic fat-burning capacities as also found in classical brown adipocytes in response to various stimuli. Beige adipocytes may also secrete certain factors that affect WAT function and systemic metabolism. Therefore, a white-to-brown fat conversion could be a novel therapeutic avenue for tackling obesity and metabolic disorders.

Scope and approach

In this review, we examine the evidence supporting the concept that the anti-obesity action attributed to polyphenols might be contributed by their stimulation of WAT browning, and discuss the possible underlying mechanisms involved in this action.

Key findings and conclusions

Current evidence, mostly derived from animal models, strongly supports that dietary polyphenols may play roles in the browning of WAT. Studies also show multiple signaling pathways, receptors, and transcription factors have been associated with the browning effects of dietary polyphenols. In conclusion, polyphenol compounds and their principal metabolites may contribute to counteracting human obesity via promoting WAT browning.

Introduction

Obesity, which is accompanied by low-grade inflammation, insulin resistance, type 2 diabetes, hyperglycemia, hyperlipidemia, atherosclerosis, metabolic syndromes and decrease in life expectancy, has grown into a worldwide epidemic affecting large numbers of people (Engin, 2017). Current understanding indicates that the disruption of energy homeostasis leads to obesity (J. Gao, Ghibaudi, van Heek, & Hwa, 2002; Hall et al., 2011). Adipose tissues with different color, morphology, metabolic function, biochemical characteristics and gene expression patterns exist in mammals (including humans and mice), and have been mainly divided into two types of fat, namely white adipose tissue (WAT) and brown adipose tissue (BAT) (Lidell et al., 2013; Rosell et al., 2014). An excess of energy is primarily stored in subcutaneous and visceral WAT. In the last decade, functional BAT, which contains a large number of mitochondria and expresses the BAT-specific gene uncoupling protein-1 (UCP1) to produce heat, was found in healthy adults. Moreover, after the classical BAT was identified in human adults (originating from myf5+ precursors), there is sufficient evidence to suggest the presence of brown-like (beige) adipocytes (originating from myf5-precursors) in subcutaneous WAT depots, especially upon cold exposure or β-adrenergic stimulation (Table 1) (Cedikova et al., 2016; Park, Kim, & Bae, 2014). Although classical BAT and beige adipose tissue (BeAT) share many similarities, they still exhibit differences in their morphology and functions (Kissig, Shapira, & Seale, 2016), as illustrated in Fig. 1. However, current evidence suggests that a number of the transcriptional regulators and coregulators that determine the differentiation of classic brown adipocytes are also key factors in the conversion of white adipocytes into beige adipocytes (beige adipogenesis) (Harms & Seale, 2013; Kiskinis et al., 2014; Wang & Seale, 2016; Wu, Jun, & McDermott, 2015). For example, key regulators of brown adipocyte differentiation including CCAAT-enhancer-binding protein β (C/EBPβ), PR domain-containing 16 (PRDM16), peroxisome proliferator-activated receptor γ (PPARγ), and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1α), were also identified as main targets for WAT transdifferentiation (Kajimura et al., 2009; Seale et al., 2007; Villanueva et al., 2013). PPARγ agonists or ectopic expression of PGC1α promotes adipose browning; while the ablation of PRDM16 or PGC1α in white adipocytes inhibits formation and function of beige adipocytes (Ohno, Shinoda, Spiegelman, & Kajimura, 2012; Tiraby et al., 2003; Seale et al., 2011; Kleiner et al., 2012). Meanwhile, PRDM16 can also repress white adipocyte specific genes through its association with C-terminal binding proteins (Kajimura et al., 2008). Moreover, hormones and cytokines such as noradrenaline (NA), bone morphogenetic protein 7 (BMP7) and fibroblast growth factor 21 (FGF21) also play key roles in inducing white-to-brown conversion (Hu & Christian, 2017; Y. H. Lee, Jung, & Choi, 2014; Wu et al., 2015) (Fig. 1). Since the discovery of inducible beige adipocytes, modulation of adipose tissue browning to increase energy consumption, especially via dietary intervention, has become an attractive idea due to its promising application in obesity and metabolic diseases prevention and treatment (S. Wang et al., 2014). Indeed, beige adipocytes are functionally very similar to classical brown adipocytes upon various stimuli (such as cold exposure) and can contribute to energy expenditure through heat production, therefore, they are also categorized as thermogenic adipocytes (Scheja & Heeren, 2016). The contribution of beige adipocytes to whole body energy balance is yet to be fully determined. However, mice with specific inactivation of beige adipocytes through ablation of PRDM16 (with minimal effects on classical BAT) become more obese and severely insulin resistant on a high fat diet (Cohen et al., 2014) clearly indicating an important role of these cells in whole-body energy homeostasis.

Polyphenols are a class of secondary metabolite compounds widely present in plants (Z. Wang et al., 2019). Currently, there are over 8000 identified polyphenols found in foods such as fruits, vegetables, tea, wine, chocolate, nuts, seeds, and even spices and seasonings (X. Z. Han, Shen, & Lou, 2007). Polyphenols can be divided into four categories: flavonoids; phenolic acids; stilbenes and lignans (Fig. 2). Aside from their well-known anti-oxidative functions, recent studies have suggested further mechanisms whereby polyphenols exert their beneficial health effects. Recent evidence challenges the concept that the health benefits of polyphenols are mainly attributed to their scavenging of free radicals, which may be an oversimplified view. Indeed, cells responding to polyphenol treatment can elicit changes in a number of receptors or enzymes involved in signal transduction (Scalbert, Johnson, & Saltmarsh, 2005). In addition, polyphenols can also potentially bind directly to membrane components such as lipids, proteins and receptors (eg. EGCG was identified as the agonist of laminin receptor (67LR) with high affinity (in nanomolar K_d value) (Tachibana, Koga, Fujimura, & Yamada, 2004)). Furthermore, polyphenols may also undergo extensive biotransformation including phase I and phase II metabolism reactions in enterocytes and liver and be fermented by gut microbiota in vivo, to form a range of metabolites (Luca et al., 2019). Studies have also revealed that plant polyphenols may help the body to produce and utilize short-chain fatty acids (SCFAs) in the gut (Parkar, Trower, & Stevenson, 2013), which is associated with a range of potential health benefits and act as the natural ligands for GPR41/43 (Hu, Lin, Zheng, & Cheung, 2018; Li et al., 2018). Along with the advancing research on the biological effects of polyphenols and their metabolites, increasing evidence has highlighted the capacity of dietary polyphenols to promote adipose tissue browning and thereafter improve metabolic homeostasis and decrease body weight (Table 2). In the current review, we critically evaluate the previous studies reporting the possible mechanisms of dietary polyphenols promoting WAT browning.