Effect of a herbal extract powder (YY-312) from Imperata cylindrica Beauvois, Citrus unshiu Markovich, and Evodia officinalis Dode on body fat mass in overweight adults: a 12-week, randomized, double-blind, placebo-controlled, parallel-group clinical trial

Obesity is a condition involving excessive accumulation of body fat that may impair health. The global prevalence of obesity has risen dramatically, increasing more than 2-fold since 1980. In 2014, over 1.9 billion adults worldwide were overweight, of which more than 600 million were estimated to be obese [1]. Obesity contributes to the development of hypertension, dyslipidemia, type 2 diabetes mellitus, coronary artery disease, and stroke, as well as overall mortality [2]. Obesity also leads to an increase in socioeconomic burden. The total socioeconomic costs of overweight and obesity in Korean adults in 2005 were estimated to be approximately US$1.8 billion, equivalent to 3.7% of the national health care expenditure for that year [3]. Hammond et al. [4] suggested that the total annual economic costs associated with obesity in the United States are in excess of US$ 215 billion. Development and implementation of cost-effective interventions for obesity prevention and management are essential to reduce the huge economic burden of obesity [5].

Treatment of obese patients requires a multifaceted approach, including dietary therapy, regular physical activity, behavioral therapy, and/or pharmacotherapy [6]. Comprehensive lifestyle intervention is foundational to obesity management, and adjunctive pharmacotherapy may be considered for individuals who are unable to achieve or maintain weight loss with comprehensive lifestyle intervention and have a body mass index (BMI) ≥30 kg/m², or ≥27 kg/m² with comorbidity [7]. Although the addition of weight loss medications to a lifestyle modification intervention can help obese individuals achieve greater weight loss, their body weight can rebound if they stop taking the medications. Since the withdrawal of sibutramine in 2010 because of the risk of serious cardiovascular adverse events, concerns about the safety of anti-obesity medications have led to a steady decline in prescription and use of these medications [8]. Due to the high costs, serious complications, and limited duration of effectiveness of anti-obesity drugs, there has been growing interest in and use of relatively inexpensive, safe, and effective functional food products from natural sources that are capable of aiding weight loss [9, 10].

Plants are considered good natural sources of bioactive compounds with potential anti-obesity properties [11, 12]. These plant-derived anti-obesity compounds induce weight loss through various mechanisms, including regulating lipid metabolism, suppressing food intake, and stimulating energy expenditure [10, 11]. However, there is still a paucity of data on the efficacy and safety of herbal plant preparations in obesity treatment. In order to provide obese patients with accurate and reliable information about effective and safe natural anti-obesity agents, there is a need for high-quality studies on the efficacy and safety of natural herbal products that claim to exert a weight reducing effect [13, 14]. In Korea, it is possible for a health functional food with body fat reducing effects to be approved for use after review, by the Ministry of Food and Drug Safety, of results of a clinical trial on the efficacy and safety of the product [15].

YY-312 is a herbal extract powder from Imperata cylindrical Beauvois, Citrus unshiu Markovich, Evodia officinalis Dode [16]. These plants have been commonly used as medicinal herbs in Korea, and have been reported to have health promoting effects, including reduction of body fat. Evodiamine, a major alkaloidal compound extracted from Evodia officinalis Dode, was thought to elicit anti-obesity effects through uncoupling protein-1 (UCP1) thermogenesis, but it was also suggested to have the potential to prevent obesity by inhibiting adipocyte differentiation through stimulating the extracellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK) signaling pathway [17]. Citrus unshiu Markovich, the peel of immature citrus fruit in the Rutaceae family, is known to have plenty of flavonoids [18]. Citrus peel extracts have been reported to exert an anti-obesity effect through the promotion of β-oxidation and lipolysis in adipose tissue [19]. Imperata cylindrical Beauvois, the root of cogongrass in the Poaceae family, is known to have potent anti-oxidant activity due to its abundant polyphenols [20].

A previous study showed that YY-312 has an anti-obesity effect in high-fat diet (HFD)-induced obese mice and that it suppresses adipocyte differentiation in 3 T3-L1 cells [16]. However, it can be ascertained only through human clinical trials whether the individual ingredients in YY-312 have a synergistic effect in the human body, or whether their interactions augment toxicity. Hence, this randomized controlled trial was conducted to evaluate the efficacy and safety of YY-312 for body fat reduction in overweight Korean adults.

This clinical trial aimed to evaluate the body fat reducing effect and safety of YY-312, a herbal extract powder from Imperata cylindrica Beauvois, Citrus unshiu Markovich, and Evodia officinalis Dode, in overweight adults. The participants who took YY-312 for 12 weeks had significantly greater reductions in BFM, BF%, body weight, and WC than the participants who took the placebo. This is consistent with results from a previous study investigating the anti-obesity effects of YY-312 in HFD-induced obese mice. Mice that had been given YY-312 with a high fat diet for 10 weeks showed a 10.7% reduction in body weight and a 25.0% reduction in abdominal adipose tissue weight compared to control mice that had been fed only a high fat diet [16].

Herbal plants can have anti-obesity effects through a variety of mechanisms, including decreased lipid absorption, suppressed energy intake, stimulated energy expenditure, inhibited adipocyte differentiation, and enhanced lipolysis [10, 21]. There is little evidence that a natural compound with a single mechanism of action results in successful treatment of obesity. Thus, combinations of multiple natural compounds with different mechanisms of action — that may have synergistic effects — could be an effective approach to address obesity [21, 22]. Imperata cylindrica Beauvois, Citrus unshiu Markovich, and Evodia officinalis Dode (the active ingredients of YY-312) have all traditionally been used in Korea as medicinal herbs. There have been several recent reports regarding the health promoting effects of these individual herbs — including reduction in body fat. Therefore, combined administration of these herbs might produce a synergistic action in terms of anti-obesity effects in the human body.

Evodiamine is an alkaloid that is present in high concentrations in Evodia officinalis Dode, and it is noted to possess a broad spectrum of biological activities, including anti-obesity, anti-inflammatory, anti-microbial, and anti-cancer activity [23]. Kobayashi et al. [24] supposed that evodiamine elicits capsaicin-like anti-obesity effects through enhancement of lipolysis, activation of brown adipose tissue, and heat dissipation. However, Wang et al. [17] showed that evodiamine has potential to prevent diet-induced obesity even in UCP1-knockout mice, suggesting that it activates a UCP1-independent mechanism to prevent the development of diet-induced obesity. They reported that evodiamine, unlike capsaicin, increased ERK/MAPK phosphorylation and reduced the expression of peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer binding protein (C/EBP)β, and thereby inhibited adipocyte differentiation.

Citrus unshiu Markovich is rich in various flavonoids and carotenoids [18]. Hesperidin, a major flavonoid abundant in Citrus unshiu Markovich, has been reported to inhibit the lipase activity from porcine pancreas and to increase fecal lipid excretion from rats [25]. β-cryptoxanthin, a major carotenoid abundant in Citrus unshiu Markovich, has been reported to suppress 3 T3-L1 adipogenesis via the down-regulation of mRNA expression of PPARγ, through retinoic acid receptor activation [26]. It was also reported to suppress hypertrophy of abdominal adipocytes in an obese mouse model [27]. Kang et al. [19] showed that citrus peel extract increased β-oxidation by activating the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase in mature 3 T3-L1 adipocyte and enhanced lipolysis by stimulating the phosphorylation of cAMP-dependent protein kinase and hormone-sensitive lipase in mature 3 T3-L1 adipocyte.

Imperata cylindrica Beauvois is rich in coumarins, triterpenoids, saccharides, and organic acids, and is known to have hemostatic, diuretic, anti-inflammatory, anti-bacterial, and anti-tumor effects. Imperata cylindrica Beauvois has been reported to have potent anti-oxidant properties that may be attributed to its abundant polyphenols [20, 28]. Although there is a paucity of data on the potential anti-obesity effects of Imperata cylindrica Beauvois, polyphenols can contribute to a reduction in body fat by various mechanisms, including inhibited adipocyte differentiation, increased adipocyte apoptosis, and decreased fat absorption in the gut [29].

Kang et al. [16] reported that treatment with YY-312 suppressed adipocyte differentiation in 3 T3-L1 cells. They explained that this was because YY-312 suppressed expression of the key adipogenic transcription factors, including PPARɣ, C/EBPα, and fatty acid synthase, and increased the phosphorylation of AMPK in 3 T3-L1 cells. YY-312 is also expected to have anti-obesity activity through enhanced fatty acid oxidation by AMPK activation. In addition to inhibiting adipocyte differentiation and promoting lipolysis, Imperata cylindrica Beauvois, Citrus unshiu Markovich, and Evodia officinalis Dode - the active ingredients of YY-312 - are known to have other anti-obesity properties, such as stimulating energy expenditure and decreasing lipid absorption. Hence, further studies are required to elucidate whether YY-312, as an extract from these herbs, has these additional anti-obesity properties.

Although combined administration of multiple natural herbs with various anti-obesity effects may increase the body fat reducing effects, the interactions between the herbs may cause unexpected side effects [30]. Nevertheless, all safety parameters in this trial, including blood pressure, liver function tests, and renal function tests, were within normal ranges from baseline throughout the duration of the study. In addition, there were no serious adverse events over the study period. Thus, it is thought that YY-312 is a safe and well-tolerated anti-obesity agent.

This study has some limitations, including the small sample size of 60 participants and the short-term duration of 12 weeks. Because this study was performed only in overweight adults, we could not determine the possible influence of YY-312 in non-overweight adults. However, this study is of value in that this is the first randomized controlled trial to evaluate the efficacy and safety of the herbal extract YY-312 for body fat reduction in overweight Korean adults.

In conclusion, in this 12-week clinical trial in overweight adults, YY-312 resulted in significantly greater reductions in body fat compared to placebo, while being safe and well tolerated. In future studies, the long-term efficacy and safety of YY-312 should be examined in a larger number of participants.