The results from this study demonstrate that as an adjunct to an 8-week diet and weight loss program, administration of METABO significantly decreases body weight, body fat mass, waist and hip girth, while increasing lean mass compared to the placebo. Although a restricted diet can lead to weight loss, it is often accompanied by a loss of lean tissue[28–30], which can have deleterious metabolic consequences. Because of this, it is important to achieve weight loss with a high ratio of fat to lean mass loss that is essential for both short-term efficacy and long-term metabolic health and body weight maintenance[31, 32]. In this study, overweight subjects who received METABO achieved significantly greater improvements in their lean mass-to-fat mass ratio. Future studies should follow subjects during a washout period to determine if this effect helps maintain long-term weight control (i.e. minimize weight re-gain). Additionally, a future investigation should include a METABO only group with dietary control and no structured exercise program to explore the role of diet with METABO alone on body composition and metabolic outcomes.
Neither placebo nor METABO administration affected concentrations of blood lipids, including cholesterol, HDL, LDL, cholesterol/HDL ratio and TAG, although there was a strong trend (p < 0.07) for TAG concentrations to decrease more in the METABO group (-15.9%) compared to the placebo group (-2.6%). Future studies may attempt to explore this observation further with studies designed to look for differences in these important metabolic and biochemical markers as primary outcome measures.
Another important finding in our study relates to the observed differences in adipokine concentrations in the METABO group, although most of these did not achieve statistical significance. For example, we observed a trend for decreased serum resistin concentrations in subjects who received METABO compared to placebo at week 4, but not week 8. High serum resistin concentrations have been found in obese individuals and have been linked to insulin resistance, hence the trend for decreased resistin levels in METABO is an intriguing finding that requires further investigation in a future study. The current study may have been underpowered to detect significant differences in serum adiponectin, given that fat loss occurred in both groups as a result of caloric restriction and a consistent exercise program. In addition, trends for maintaining elevated serum leptin (from week 0 to week 4) were observed in subjects who received METABO compared to placebo. Leptin acts on receptors in the hypothalamus to regulate appetite, energy expenditure, sympathetic tone and neuroendocrine function, and circulating levels have been shown to decline in response to caloric restriction or negative energy balance. Leptin deficiency has been shown to promote hunger and food seeking behaviour, in addition to reduced metabolic rate in humans. Collectively, the trend for resistin and significant change in leptin may help to partly explain the effects of METABO on body composition.
The combination of ingredients with potentially complementary and interactive mechanisms of action may account for the favorable changes observed in many of the clinical endpoints in the METABO group. Razberi-K® contains Raspberry ketone (4-(4-hydroxyphenyl) butan-2-one), which is a naturally occurring phenolic compound in red raspberry (Rubus ideas) that has been shown to enhance norepinephrine-induced lipolysis in adipocytes, prevent high-fat diet-induced body weight gain in mice, and increase adiponectin gene expression and secretion in adipocytes in culture[12, 13]. Moreover, Wang et al. demonstrated anti-inflammatory benefits, improved antioxidant capacity, and enhanced leptin and insulin sensitivity in Sprague-Dawly rats using a high-fat diet induced nonalcoholic steatohepatitis (NASH) model. From the limited preclinical literature, it appears that raspberry ketones require norepinephrine for maximizing their hormone-sensitive lipolytic action. Capsimax® is a concentrated capsicum extract found in an encapsulated beadlet form to decrease gastric irritation. Capsaicinoids have been shown in animal studies to activate TRPV1 receptors in vagal afferents of the gut, leading to sympathomimetic action with reductions in abdominal/visceral fat. There have been a number of short-term human clinical studies utilizing between 2 mg/day and 10 mg/day of active capsaicinoids that have reproduced some of these preclinical animal efficacy and human clinical studies[37–39] including increases in norepinephrine secretion[15, 17]. Further, a systematic review of 90 clinical trials, 20 of which were selected for inclusion demonstrated that capsaicinoid consumption of greater than 2 mg/day resulted in increases in energy expenditure of approximately 50 kcal/day and concentrations of anorexigenic hormone glucagon-like peptide-1[37, 39]. Moreover, significant decreases in energy intake of up to 8%, reductions in preoccupation with food and desire for fatty foods have been reported that appears consistent with our food craving analyses in the METABO group (Table 5).
Advantra Z® is an ingredient extracted from the Citrus aurantium (traditional Chinese herb known as zhi-shi) and standardized for the bioactive alkaloid p-synephrine. Other alkaloids are present in the extract including: octopamine, hordenine, and n-methyltyramine. Taken together, the bioactive amines found in Advantra Z® have been shown to increase thermogenesis, and there is cell and tissue culture evidence to suggest lipolysis is accelerated via a β3 adrenergic receptor pathway. A recent systematic review of human clinical studies involving Citrus aurantium with its primary p-synephrine alkaloid alone or in combination with other ingredients revealed reliable increases in resting metabolic rate of between 2.41% and greater than 7.2%, energy expenditure of up to 13.4%, and weight loss of over 2.9 kg, with no serious adverse events affecting hemodynamic, electrocardiographic, hematologic or clinical chemistry biomarkers when administered over the course of 6-12 weeks.
Caffeine is regarded as one of the most commonly consumed methylxanthine alkaloids known to act as an adenosine receptor antagonist and phosphodiesterase inhibitor. As such, the presence of caffeine may have contributed to amplifying the beta-adrenergic and lipolytic effects of the METABO formulation. Despite being on a calorie-reduced diet, subjects in this study reported feeling improved energy and decrease in cravings for energy-dense, fatty foods. Previous studies have indicated that food cravings are significantly related to food intake with specific cravings correlating with types of food consumed and a high-fat diet is a strong risk factor for the development of obesity and metabolic syndrome, as a result of increased energy density and overall caloric intake. Caffeine, in isolation or in combination with other bioactive nutritional compounds, has also been shown in multiple human clinical trials to increase the perception of energy, blunt appetite, and improve measures of mood, alertness, attention, and concentration[14, 42, 43]. Caffeine may be a thermogenic potentiator in METABO, as it has been shown to increase energy expenditure by 4-5% and fat oxidation by 10-16%, in addition to enhancing endurance and high-intensity exercise performance[44, 45].
Although subject demographics were similar between groups, there was greater attrition of the placebo group relative to METABO. Most of the attrition was the result of poor compliance with the diet, supplement and/or exercise program. It has been reported that decreased levels of mental and physical energy and increased cravings for energy-dense foods can diminish dietary and exercise adherence during outpatient weight loss programs[46, 47]. A notable finding in this regard is that, compared to the placebo group, the METABO group experienced a significant increase in their energy levels and decreased cravings for energy-dense foods. Future studies may examine if METABO improves adherence to a comprehensive diet and exercise weight loss program. Gender differences were not explored in our study, but future investigations are currently underway in an attempt to answer this question.
The authors would like to clarify why the data presented in Table 3 does not appear to underfeed each subject by 500 kcals/day. The mean target caloric intake for the METABO group using the Mifflin-St. Jeor equation multiplied by an activity factor of 1.2 –(minus) 500 kcal equals 1955 kcal/day. The target intake for placebo using same method was 1907 kcal/day. We realize these targets are greater than the mean of each group’s reported baseline caloric intake based on three-day food records. However, three-day food records are notorious for recall bias and an underestimation of actual energy consumption. Thus, it is not surprising that both groups moved closer to their “target” kcal/day intake over the course of this 8 week study. The target caloric intakes being greater than the reported intakes from baseline (pre-intervention) three-day food records helps to explain why both groups may have actually increased their reported intakes by 4% and 9% for METABO and placebo, respectively. Therefore, it is plausible that subjects in both groups may have experienced even more dramatic body composition and/or metabolic benefits had the 500 kcal deficit been applied to their baseline, reported intakes as opposed to their estimated caloric requirements obtained via Mifflin-St. Jeor equation.
The obese and overweight state is characterized by chronic, low-grade systemic inflammation as a result of the expanded white adipose tissue compartment, particularly the visceral adipose depot. Adipose tissue from obese individuals is known to be an important endocrine organ capable of contributing to insulin resistance, persistent inflammation, and metabolic and vascular dysfunction via the perturbed adipokine secretion profile. The collective action of garlic extract standardized for organosulfur compounds, ginger extract standardized for gingerols and shogaols, biotin and chromium in METABO may contribute to antiadipogenic, anti-inflammatory actions in conjunction with metabolic health benefits[20, 21, 36, 37, 49–51]. The bioactive compounds in garlic, ginger, and raspberry in addition to biotin and chromium have been suggested to modulate high-leverage metabolic pathways with nutrigenomic signaling, including: NF-kB, PPAR-γ, PPAR-α, orexigens, and aforementioned adipocytokines. It is conceivable that although increased sympathomimetic drive, lipolysis and thermogenesis contributed to the positive outcomes in body composition, the interaction of reduced dietary energy intake with exercise and METABO lead to further improvements in the adipokine profile that facilitated improvements in serum triacylglycerol, selective fat loss, skeletal muscle retention and abdominal girth reduction. It would be helpful for future studies to explore the influence of METABO on the systemic adipokine profile to clarify if this is one potential mechanism.