Obesity has reached epidemic proportions globally, with over 650 million adults worldwide being obese as of 2016 (Singh et al., 2020). Obesity significantly increases the risk of other chronic diseases like type 2 diabetes, heart disease, stroke, and certain cancers (CDC, 2022). Besides the toll on health, obesity also incurs a huge economic burden exceeding $150 billion per year in the United States alone (Cawley & Meyerhoefer, 2012). As the prevalence of obesity continues to rise, there is an urgent need to develop safe, effective and practical strategies for weight management.
Polyphenols—a diverse class of over 8000 compounds found in plant foods—have recently emerged as promising agents that may help prevent and treat obesity. Polyphenols are secondary metabolites produced by plants that play roles in defense, pigmentation, reproduction, and more (Singh et al., 2020). Common polyphenol subclasses include flavonoids, phenolic acids, stilbenes, lignans and tannins. Polyphenol-rich foods include fruits, vegetables, nuts, seeds, coffee, tea and wine (Rodriguez-Mateos et al., 2014). Epidemiological studies frequently associate diets rich in polyphenols with lower adiposity and obesity risk (Santana-Ferrer et al., 2019). However, the mechanisms of action are still being elucidated through cell culture and animal studies.
Two recent studies—Singh et al. (2020) and Li et al. (2019)—provide updated evidence regarding the anti-obesity effects of polyphenols and their mechanistic targets. This in-depth analysis will review these two studies, discuss their key findings and limitations, and interpret the significance of these works in advancing our understanding of polyphenols for obesity management.
Overview of Studies
Singh et al. (2020) provided a broad review of natural polyphenols shown to have anti-obesity activity in previous in vitro, animal and human studies. After covering the types and sources of common polyphenols, the authors summarized proposed mechanisms of anti-obesity action. These mechanisms include inhibiting digestive enzymes like lipase, increasing satiety, boosting metabolism and fat burning, blocking fat cell growth and differentiation, altering lipid metabolism, and modulating the gut microbiota. For each mechanism, the authors compiled evidence from studies on specific polyphenols like quercetin, curcumin, resveratrol and green tea catechins that display that particular activity. Finally, the authors critically evaluated the strengths and limitations of the evidence and concluded that polyphenols are promising anti-obesity agents but require more rigorous clinical validation.
Whereas Singh et al. broadly reviewed anti-obesity mechanisms of polyphenols, Li et al. (2019) focused their original study on defining the mechanistic role of tea polyphenols in obesity. Using a mouse model, Li et al. compared mice fed a normal diet, high-fat diet, or high-fat diet with 0.4% added tea polyphenols. The tea polyphenols reduced weight gain, fat mass, cholesterol and insulin resistance compared to the plain high-fat diet. The researchers found altered expression of regulatory small RNAs like miRNAs and piRNAs in fat tissue of mice fed tea polyphenols. Bioinformatic analysis suggested these small RNAs are involved in regulating lipid metabolism and cell differentiation. Therefore, Li et al. concluded that small RNA modulation mediates the anti-obesity effects of tea polyphenols.
Both studies overall agree that polyphenols likely act through diverse, complementary mechanisms to mitigate obesity, though Li et al. newly identified small RNA regulation as one such mechanism. The following sections will expand on the key findings and limitations of these two papers.
Detailed Analysis of Anti-Obesity Mechanisms
Singh et al. (2020) reviewed six major mechanisms that may underlie the anti-obesity potential of polyphenols based on previous studies in cell cultures, animal models and human clinical trials.
Inhibition of Digestive Enzymes
Polyphenols can inhibit enzymes involved in the digestion of carbohydrates and fats—namely pancreatic amylase, glucosidase and lipase (Singh et al., 2020). For example, polyphenols from muscadine grape, Nelumbo nucifera, Terminalia paniculata and other sources potently inhibited lipase and amylase activities in vitro (You et al., 2011; Liu et al., 2013; Ganjayi et al., 2017). By blocking these enzymes, polyphenols may reduce the digestion and absorption of dietary carbs and fats, decreasing calorie intake. However, human studies are still needed.
Appetite Suppression
Some polyphenols appear to suppress appetite by interacting with hunger and satiety pathways in the hypothalamus (Singh et al., 2020). For instance, polyphenol-rich extracts from Bushman’s hat, bitter orange, green tea and black soybean reduced food intake and body weight gain in rodents, possibly by regulating neurotransmitters and neuropeptides involved in appetite control (Moon et al., 2007; Kazemipoor et al., 2016; Badshah et al., 2013). Clinical studies with tea and herbal extracts showed reduced hunger and calorie intake in overweight humans, though more rigorous trials are warranted.
Increased Energy Expenditure
Polyphenols may promote fat burning by increasing the activity of mitochondria and uncoupling proteins (UCPs) that dissipate energy as heat (Singh et al., 2020). Resveratrol, curcumin, quercetin and catechins have been shown to upregulate UCPs and enzymes involved in fat oxidation and mitochondrial biogenesis in cell and animal studies (Mele et al., 2017). This thermogenic effect was associated with protection against fat accumulation and obesity in mice. However, human evidence is limited thus far.
Inhibition of Adipocyte Differentiation
Some polyphenols can suppress fat cell growth and differentiation (Singh et al., 2020). Compounds like curcumin, resveratrol and grapefruit polyphenols inhibited pre-adipocyte proliferation and differentiation into mature fat cells in cell cultures, which could restrict fat accumulation (Lai et al., 2013; Mohamed et al., 2014). Extracts containing anthocyanins and other polyphenols also inhibited adipogenesis and reduced fat mass in obese rodents, but direct effects in humans remain unclear.
Modulation of Lipid Metabolism
Polyphenols may influence lipid metabolism by activating enzymes like AMP-activated protein kinase (AMPK) and transcription factors like PPARs that regulate fatty acid synthesis and oxidation (Singh et al., 2020). Polyphenols from blueberries, Hibiscus plants and green tea altered expression of genes involved in lipid metabolism and reduced circulating and liver lipids in obese rodents (Herranz-Lopez et al., 2019; Jiao et al., 2018). However, the effects on lipid metabolism in humans need further examination.
Modulation of Gut Microbiota
The gut microbiota appears to play an important role in weight regulation, and polyphenols may modulate the gut microbial profile in ways that promote weight loss (Singh et al., 2020). For example, quercetin and tea polyphenols increased the ratio of Bacteroidetes to Firmicutes bacteria, which is associated with leanness, and reduced endotoxemia-induced inflammation in obese mice (Zhao et al., 2017; Cheng et al., 2017). Human studies regarding the prebiotic effects of polyphenols are still limited.
In their original study, Li et al. (2019) newly identified small regulatory RNA pathways as another anti-obesity mechanism of polyphenols. Using a mouse model of high-fat diet-induced obesity, the researchers showed that supplementing tea polyphenols in the diet altered the expression of small RNAs like miRNAs and piRNAs in adipose tissue. The differentially expressed small RNAs were computationally predicted to target genes involved in lipid metabolism, cell differentiation and related processes. Therefore, Li et al. proposed that tea polyphenols exert anti-obesity effects at least in part by modulating small RNA pathways in key metabolic tissues. This study provides novel, intriguing evidence that small RNAs mediate polyphenol effects on metabolism.
In summary, Singh et al. and Li et al. suggest polyphenols act through diverse but complementary mechanisms to influence weight gain and associated metabolic dysfunction. Singh et al. compiled previous evidence on six major mechanisms ranging from enzyme inhibition to microbiome modulation, while Li et al. newly identified involvement of regulatory small RNA pathways. The diverse targets likely underlie the efficacy and potency of polyphenols compared to single-target pharmaceuticals. However, exactly which mechanisms predominate in humans needs further examination through rigorous clinical trials.
Limitations and Future Research Directions
While Singh et al. (2020) and Li et al. (2019) significantly advance our mechanistic understanding of polyphenols in obesity treatment, both studies have limitations that should be considered.
Singh et al. included a lot of in vitro data, which does not always predict efficacy in humans due to differences in bioavailability, metabolism and physiological concentrations. Many animal studies were also discussed, but rodent models do not always translate well to human biology. Hence, carefully designed human trials are critical to truly validate the promising anti-obesity effects seen with polyphenols in cell and animal studies.
Li et al. relied entirely on a mouse model, so the relevance of the observed small RNA expression changes to human obesity is unclear. The study was also quite mechanistic rather than evaluating tangible impacts on adiposity. Future studies should examine if similar small RNA changes occur in humans in response to polyphenols and if this correlates with weight loss or altered metabolism.
In general, both reviews highlighted that lack of clinical data in humans is the major limitation preventing definitive conclusions about the anti-obesity efficacy of polyphenols. To fill this gap, future research should focus on randomized controlled trials testing various purified polyphenols or polyphenol-rich extracts at physiologically relevant doses. Study design factors like enrollment criteria, polyphenol dose and source, intervention duration, adherence monitoring, and endpoint measures will be critical. Endpoints should include not just weight but also metabolic parameters, body fat percentage, appetite ratings, etc. Larger, longer studies with rigorous design will provide more definitive evidence regarding the efficacy, safety, optimal doses and sources of anti-obesity polyphenols for human use. Multi-center trials and public-private partnerships will likely be needed to undertake such ambitious, expensive human studies.
Besides additional human trials, future research can continue delving into the mechanistic targets of polyphenols using techniques like transcriptomics, metabolomics, microarray analysis, microbiome sequencing and more. A better understanding of mechanisms—for instance, defining the predominant polyphenol metabolite-protein interactions or small RNA pathways—could facilitate the development of biomarkers to objectively monitor bioactivity and help optimize polyphenol formulations.
Significance and Conclusions
The studies by Singh et al. (2020) and Li et al. (2019) make significant contributions to the growing body of literature regarding polyphenols for obesity management. Here are some key implications from these works:
- They confirm that a multitude of complementary mechanisms likely underlie the anti-obesity effects of polyphenols, ranging from enzyme inhibition to microbial modulation to small RNA regulation. This contrasts with pharmaceuticals that typically act through a single target.
- They substantiate that certain well-studied polyphenols like tea catechins, resveratrol and anthocyanins show particular promise as anti-obesity agents based on repeated evidence of weight lowering effects in cell and animal studies.
- They emphasize that despite intriguing preclinical results, rigorous and large-scale human trials are critical to validate the efficacy and safety of anti-obesity polyphenols before they can be recommended clinically. Advanced study designs and multi-center collaborations will be needed given the costs of such ambitious trials.
- They provide frameworks upon which future research can build, be it performing additional mechanistic studies or undertaking new clinical trials using dose equivalents and intervention durations informed by preclinical evidence.
In conclusion, these two papers significantly advance our understanding of polyphenols in obesity prevention and treatment. The mechanistic insights may guide the development of bioactive food ingredients and functional foods enriched with anti-obesity polyphenols like tea catechins or anthocyanins. The summaries of previous findings can inform the appropriate design of future human trials to finally realize the translational potential of polyphenols for obesity management. While more work remains, these papers move us closer to harnessing the weight loss benefits of polyphenols from the lab into clinical and public health practice.
We have previously discussed the role of polyphenols and a ketogenic diet here.
References
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