Obesity is a significant contributor to increased morbidity and premature mortality due to increasing the risk of many chronic metabolic diseases such as type 2 diabetes, cardiovascular disease and certain types of cancer. Lifestyle modifications such as energy restriction and increased physical activity are highly effective first-line treatment strategies used in the management of obesity. However, adherence to these behavioral changes is poor, with an increased reliance on synthetic drugs, which unfortunately are plagued by adverse effects. The identification of new and safer anti-obesity agents is thus of significant interest. In recent years, plants and their phenolic constituents have attracted increased attention due to their health-promoting properties. Amongst these, Cyclopia, an endemic South African plant commonly consumed as a herbal tea (honeybush), has been shown to possess modulating properties against oxidative stress, hyperglycemia, and obesity. Likewise, several studies have reported that some of the major phenolic compounds present in Cyclopia spp. exhibit anti-obesity effects, particularly by targeting adipose tissue. These phenolic compounds belong to the xanthone, flavonoid and benzophenone classes. The aim of this review is to assess the potential of Cyclopia extracts as an anti-obesity nutraceutical as underpinned by in vitro and in vivo studies and the underlying cellular mechanisms and biological pathways regulated by their phenolic compounds.
The prevalence of obesity has steadily increased in recent decades, with current estimates reporting that approximately 8.9% of the world’s population (641 million individuals) are classified as obese with a body mass index (BMI) ≥ 30 kg/m2. Obesity is regarded as the largest modifiable risk factor for chronic diseases such as type 2 diabetes (T2D), cardiovascular diseases (CVD) and certain types of cancers. Although historically considered a disease of affluence, obesity rates are rapidly increasing in low-and middle-income countries, thus placing a major burden on already struggling and over-burdened health systems. While innate biological mechanisms may predispose to obesity, lifestyle factors, which include the consumption of unhealthy, energy-dense diets and limited physical activity, are arguably the main determinants of the current obesity pandemic, and the focus of first-line anti-obesity strategies, including calorie-restrictive diet and increased physical exercise. However, adherence to behavioral changes is poor, with an increased reliance on synthetic drugs, which are plagued by adverse effects. Thus, the identification of new and safer anti-obesity agents is of significant interest. In recent years, plants and their phenolic compounds have attracted increased attention due to their perceived health-promoting properties. Natural products are usually considered safer and more socially acceptable than conventional drugs, and in the case of food, consumed as part of the diet. Amongst these, extracts of Cyclopia, an endemic South African plant commonly consumed as a herbal tea (honeybush), has been shown to possess ameliorative properties against oxidative stress, inflammation, hyperglycemia, and obesity. Likewise, a number of studies have reported that major phenolic compounds present in Cyclopia spp. exhibit anti-obesity effects.
This review provides a comprehensive summary of all published in vitro and in vivo studies that have reported on the ameliorative properties of the major phenolic groups (xanthones, flavonoids, and benzophenones) and extracts of Cyclopia spp. against obesity. Three databases, PubMed, Scopus, and Web of Science, were searched for studies published between January 2000 and March 2019 and reporting on the anti-obesity effects of the major phenolic compounds and extracts of Cyclopia in adipocytes. Keywords included Cyclopia, xanthone, flavonoid, benzophenone, obesity, and adipose tissue, as well as the corresponding synonyms and associated terms for each word (Table S1).
Adipose tissue as a therapeutic target
Obesity is characterized by the excessive expansion of white adipose tissue, which occurs by either hyperplasia (increase in adipocyte number) or hypertrophy (increase in adipocyte size). Adipocyte hyperplasia is considered a mechanism for healthy storage of excess energy as triglycerides and releasing of energy as free fatty acids (FFA) during energy deprivation. Adipocyte hypertrophy is associated with hypoxia, fibrosis, oxidative stress, endoplasmic reticulum stress, insulin resistance and adipocyte dysfunction. In addition, adipocyte hypertrophy induces cell death and inflammation due to the infiltration of M1 pro-inflammatory macrophages into adipose tissue. Adipocyte dysfunction and inflammation are considered the primary mechanisms linking obesity to metabolic disease (Fig. 1). Dysfunctional adipocytes secrete high levels of FFA and pro-inflammatory cytokines into the circulation, inducing insulin resistance and inflammation in peripheral tissues such as the liver, muscle, pancreas, heart, and brain (Fig. 1). Similar to adipose tissue, increased levels of FFA and pro-inflammatory cytokines induce the recruitment of immune cells in these tissues and subsequently induce chronic inflammatory responses (Fig. 1) . High levels of FFA and pro-inflammatory cytokines, mainly tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), induce insulin resistance in peripheral tissues such as the muscle and liver by directly inhibiting the insulin receptor substrate 1 (IRS-1) signaling or through the activation of inflammatory kinases that inhibit insulin signaling pathways . Furthermore, increased concentrations of circulatory FFA result in ectopic fat deposition in peripheral tissues and increase the production of toxic lipid metabolites such as ceramides, which increases oxidative stress and metabolic dysfunction (Fig. 1).