Metabolic syndrome is a common cardio-metabolic disorder that is characterized by the simultaneous occurrence of cardiovascular risk factors including central obesity, dyslipidemia, hyperglycemia and hypertension [1
]. Central obesity is a major predisposing factor to the development of metabolic syndrome and is a key component of metabolic syndrome [2
]. The exact mechanism by which metabolic syndrome develops is not yet fully understood but it appears to be related to insulin resistance and excessive free fatty acid release from intra-abdominal adipocytes [5
]. It is also believed that a pro-inflammatory and pro-thrombotic state contribute to the pathogenesis of the syndrome [8
]. Metabolic syndrome poses a major health risk for the development of cardiovascular disease (CVD) and type II diabetes mellitus (T2DM), thus an effective therapeutic approach is in high demand for those who are at risk [9
]. The majority of individuals affected with metabolic syndrome are overweight or obese and therefore treatment is primarily focused on weight reduction [10
Lifestyle interventions such as dietary modification and physical activity remain the cornerstone of weight loss treatment. In theory, reducing energy intake and increasing energy expenditure will elicit weight loss [10
]. However, obesity is a multifactorial condition encompassing complex environmental and genetic influences leading to overconsumption and reduced physical activity making weight loss a challenging issue [13
]. As the prevalence of overweight and obesity continues to rise at an alarming rate, more effective weight-control therapies are required [14
]. The availability and popularity of natural weight loss supplements has increased drastically over recent years. Coleus forskohlii
auct. (Plectranthus barbatus
extract is among those natural products that shows promising therapeutic anti-obesity potential [15
auct. is a perennial plant of the Lamiaceae (mint) family and is native to Nepal, Thailand and India. Forskolin is the major active constituent of C. forskohlii
which is of clinical interest [16
]. Forskolin (7β-Acetoxy-8, 13-epoxy-1α, 6β, 9 α-trihydroxy-labd-14-ene-11-one) (Figure 1
) is a labdane diterpene that was first isolated from the plant in 1974. Forskolin is extracted from the tuberous roots of the plant and thus far, C. forskohlii
is the only species known to contain significant amounts of the bioactive component [17
]. It has been documented that forskolin increases the rate of lipolysis via cyclic adenosine monophosphate (cAMP) accumulation by mechanisms independent of hormonal stimulation both in vitro
] and in animal models [20
]. Furthermore, forskolin also directly activates hormone sensitive lipase by phosphorylation of protein kinase A resulting in further lipolysis and release of free fatty acids [19
Chemical structure of forskolin.
Chemical structure of forskolin.
Limited human studies have indicated that supplementation with C. forskohlii
extract elicits favorable changes to body composition. Godard, et al.
] found a significant reduction of body fat percentage in overweight and obese men after 12 weeks of supplementation with C. forskohlii
extract. Similar results have also been documented in preliminary open-label trials conducted on overweight and obese female volunteers [23
] and men and women within the healthy BMI range (24.92 ± 0.87) [24
]. In addition, Henderson, et al.
] reported significant reductions in dietary intake in overweight women but did not find any significant differences in subjective appetite sensations or body composition after 12-weeks of supplementation. The aim of the present study was to evaluate the effects of 12-weeks supplementation with C. forskohlii
extract on dietary intake and appetite, anthropometric measures, and metabolic parameters in overweight and obese individuals. To the best of our knowledge, this is the first study investigating the efficacy of C. forskohlii
extract on the appetite hormones, leptin and ghrelin, and insulin sensitivity in overweight and obese individuals.
In the present study, supplementation with C. forskohlii
extract in conjunction with a hypocaloric diet did not significantly affect weight loss or other anthropometric measures when compared to the placebo group. However, a significant time effect was observed in the reduction of waist and hip circumferences in both groups after the 12 week intervention (Table 2
). Therefore, it appears likely that the reductions in waist and hip circumference occurred due to the dietary advice to follow a hypocaloric diet. Previous human studies have documented inconsistent results regarding changes in anthropometry with C. forskohlii
supplementation. For instance, Henderson and colleagues [25
] reported no significant changes to body weight or anthropometry, whereas Godard, Johnson and Richmond [22
] recorded significant reductions in fat mass parallel to significant increases in bone mass (as determined by dual energy X ray absorptiometry (DXA) but not in total body weight in obese men after 12 weeks of supplementation with C. forskohlii
extract. It is also important to note that the changes in waist and hip circumference occurred independent of body weight. A possible explanation for this could be that participants experienced simultaneous gains in bone and muscle mass parallel to increased fat loss as in the study by Godard, Johnson and Richmond [22
]. However, the present study is limited as body composition was not measured. Methods such as DXA or 3D whole body laser scans would be useful in future studies to validate this hypothesis. Abdominal obesity is a key feature of metabolic syndrome as visceral fat is responsible for the secretion of various adipocytokines such as leptin, interleukin-6 and adiponectin. The secretion of these adipocytokines is altered in metabolic syndrome and contributes to the chronic inflammatory pathogenesis of the syndrome [37
]. Changes between 1.8 and 4.1 cm in waist circumference are reported to be clinically relevant in individuals with waist circumferences ranging from 60 to 135 cm [38
]. Since waist circumference is a useful indicator of visceral fat, the significant reduction in waist circumference in both experimental and placebo groups observed in our study is of potential clinical importance [1
]. Albeit the change in waist circumference was achieved over a 12-week period and it is unknown whether the change would be maintainable over a longer period of time, thus limiting its clinical relevance.
Underreporting of food intake is a common issue in clinical practice and obesity research [40
]. It was therefore deemed useful to use two different methods, that is, FFQ and self-reported food diaries to ascertain food intake throughout the study. The main findings from the present study was the significant reduction of total energy, total fat, saturated fat, carbohydrate and dietary cholesterol intakes in the experimental group based on the FFQ which suggests that dietary intake was significantly affected by C. forskohlii
extract supplementation(Table 5
). Conversely, the food diary analyses revealed a significant time effect for total energy, total fat, saturated fat and carbohydrate intakes which indicates that dietary changes were not significantly influenced by the C. forskohlii
intervention and were instead achieved as a result of the dietary advice to maintain a hypocaloric diet. The significant time effects observed from the food diary results support the explanation that the changes in waist and hip circumference were achieved by following hypocaloric diets. The food diary results of the present study are consistent with that of Henderson, et al.
] who also reported a significant time effect in dietary intake. The inconsistencies between the findings of the food diary records and FFQ are likely to be attributed to the differences in the methods of food intake reporting used (i.e
., the FFQ presents an extensive but not exhaustive list of food items consumed during a given period of time, whereas the food diary relies on dietary recall from the participants). We recognize that the present study is limited by inter-individual variability in food intake and the subjective nature of reporting and interpreting. Furthermore, the validity and reliability of the dietary intake results would have been strengthened by measuring a biomarker such as urinary minerals or nitrogen excretion [41
]. Although it is not clear how (or if) C. forskohlii
supplementation influences dietary fat intake, emerging studies have shown that low fat taste sensitivity is associated with overweight and obesity [42
]. Thus, we hypothesize that by reducing fat tissue (i.e
., reducing waist circumference) in overweight and obese subjects it could have led to improved fat taste sensitivity leading to a decreased intake of fatty foods as observed in our study.
Ghrelin is a brain-gut peptide that signals hunger and increases food intake in humans [44
]. Conversely, leptin is an adipocyte derived hormone that signals satiety in the hypothalamus. Circulating plasma leptin concentration is proportional to adiposity. In overweight and obesity, leptin function is thought to be deregulated whereby individuals are desensitized to the hormone and as a result still experience a heightened desire to eat despite plentiful energy stores [45
]. The present study is the first to assess fasting plasma ghrelin and leptin concentrations following supplementation with C. forskohlii
extract in humans. Previous animal studies have reported that supplementation with C. forskohlii
extract diminished appetite (determined by measured food intake) and reduced weight gain in rodent models of obesity [46
]. Despite the significant reductions observed in the experimental group for energy and macronutrient intakes, there were no significant changes in fasting plasma ghrelin or leptin concentrations in either group (Table 3
). These findings are consistent with the appetite and satiety results obtained from the VAS. These results are also in agreement with that of Henderson, et al.
] who also reported no significant results from a similar VAS method. Yet the present study is limited as only single blood samples were collected on each testing day, prior to the ingestion of the test breakfast meal. To conclusively demonstrate the effect of C. forskohlii
extract on appetite it would be useful to take several blood samples after the ingestion of a test meal to monitor postprandial changes in ghrelin and to also correlate this data with the responses from the VAS. Furthermore, the VAS is limited in the sense that it is not completed under normal living conditions and therefore participants may experience altered appetite sensations compared to what they would in a free living context [48
]. Given that the FFQ results showed that energy intake was significantly reduced in the experimental group in the present study, analysis of other peptides which regulate energy balance such as orexin, neuropeptide Y, glucagon-like-peptide-1, and peptide YY would be useful to further investigate the effects of C. forskohlii
supplementation on appetite in humans [49
Insulin is secreted from the pancreatic beta cells in response to rises in blood glucose concentration and promotes the cellular uptake of glucose. In the present study we found a significant decrease in fasting plasma insulin concentration and insulin resistance in the experimental group. This could be related to the significant decreases in saturated fat and carbohydrate intake in the experimental group (Table 5
). Diets rich in saturated fats have been shown to influence circulating insulin concentration and insulin sensitivity [10
]. Furthermore, the reduced plasma insulin concentration may be associated with a decreased abdominal fat mass as indicated by the decline in waist circumference in the experimental group. Insulin is primarily secreted when the body is in a fed state and has an overall anabolic effect on metabolism, thus causing the body to store energy [8
]. In the pathogenesis of diseases such as T2DM and metabolic syndrome, there is an increase in hepatic glucose production which results in hyperglycemia and an increased secretion of insulin leading to hyperinsulinemia. Hyperinsulinemia causes tissues to become desensitized to insulin and subsequently insulin resistance develops causing chronic hyperglycemia which can have deleterious effects on the circulatory and renal systems if left untreated [6
]. Thus, improving insulin sensitivity in individuals with, or at risk of developing metabolic syndrome, has an important clinical implication. In the present study, the significant change in insulin concentration and insulin resistance was independent of fasting glucose concentration (Table 3
). However, the results for fasting plasma glucose concentration obtained at both the baseline and at week 12 of the study indicate that both groups were within normal levels (<5.6 mmol/L) regardless of insulin concentration [11
]. This implies that insulin sensitivity could have improved after 12 weeks of supplementation in the experimental group as a lower level of insulin was required to maintain euglycemia. In comparison, Henderson and colleagues [25
], reported no significant changes in fasting insulin or glucose concentrations for both the placebo and experimental group after 12 weeks supplementation with C. forskohlii
Low HDL-C (<1.03 mmol/L for females and <1.29 mmol/L for males) is a core feature of the dyslipidaemia which occurs in the metabolic syndrome [2
]. At the baseline of the study, both the experimental and placebo groups presented with relatively low levels of plasma HDL-C (Table 3
). After the 12 week intervention, both groups showed a significant increase in plasma concentration of HDL-C (Table 3
). The increase in HDL-C concentration may be linked to the reduction of dietary carbohydrate intake. Previous studies have reported that carbohydrate intake shows an inverse relationship with circulating HDL-C [50
]. Furthermore, raised insulin and low HDL-C were found to be associated with an increased activity of hepatic lipase [53
]. It has been shown that fasting insulin concentration is correlated with the hepatic lipase to lipoprotein lipase ratio, which in turn is correlated with fasting very-low density lipoprotein cholesterol [53
]. The significant increase in HDL-C concentration is of potential clinical importance as HDL-C has cardio-protective and anti-inflammatory properties through its role in blocking LDL-C oxidization and thus protects against atherosclerosis and coronary heart disease [54
]. Previous studies have reported that sustained alterations in dietary cholesterol intake have been associated with modest changes to circulating levels of TC and LDL-C in individuals with dyslipidaemia. Despite the significant reduction in dietary cholesterol intake observed in the experimental group, there were no significant changes observed in the plasma concentrations of LDL-C, TC or TG (Table 3
). This might be due to the relatively short duration of intervention. Further studies of a longer duration and with a larger sample size would be useful to verify the effect of C. forskohlii
extract on blood lipids. Moreover, circulating lipid levels are more proportionate to the endogenous cholesterol synthesized in the liver rather than to dietary cholesterol. In metabolic syndrome, the liver synthesizes increased amounts of very-low density lipoprotein cholesterol and LDL-C and decreased amounts of HDL-C [56
]. Thus, data on hepatic enzyme activity related to cholesterol metabolism in animals supplemented with C. forskohlii
would also be helpful to elucidate the mechanism of C. forskohlii
on plasma cholesterol.
Generally C. forskohlii
extract supplementation is very well tolerated and is recognized as safe to use [57
]. However there were two reports of adverse events within the experimental group of the present study which were both related to the gastrointestinal system. This is the first controlled study to report side effects associated with the supplementation of C. forskohlii
extract. It is plausible that the occurrence of increased bowel motions and loose stools was due to an initial increase in gastric acid secretion [58
] following supplementation with C. forskohlii
extract as forskolin has previously been shown to increase acid formation [59
]. The reported gastrointestinal side effects were mild in nature and did not lead to discontinuation of the intervention. Furthermore, the symptoms subsided within four weeks of use.
Although the total number of participants satisfied the minimum number required by power analysis, the sample size was still relatively small and it is unlikely that it was a true representation of the general overweight and obese adult population, thus limiting the applicability of the results. For instance, 80% of the participants who completed the study were female. It would be useful for future studies to restrict participation to a more specific sample population and/or recruit a larger sample size. Future research directions may focus on measuring specific biomarkers to validate the reductions in energy intake and implementing DXA scans to evaluate changes in body composition. Longer term studies may also be warranted in the future to determine whether the favorable changes are maintainable for an extended period.