Curr Obes Rep (2016) 5:262–270

DOI 10.1007/s13679-016-0214-y

OBESITY TREATMENT (CM APOVIAN, SECTION EDITOR)

New Dietary Supplements for Obesity: What We Currently Know

Alejandro Ríos-Hoyo 1 & Gabriela Gutiérrez-Salmeán 1

Published online: 6 April 2016

# Springer Science+Business Media New York 2016

Abstract Obesity and its associated cardiometabolic alter- pharmacologic therapy, surgery, and the use of dietary supple-
ations currently are considered an epidemic; thus, their treat- ments. Dietary supplements represent an attractive adjuvant
ment is of major importance. The cornerstone for such treat- alternative to traditional therapy because most have a low-
ment involves therapeutic lifestyle changes; however, the vast toxicity profile and are accessible to the general population.
majority of cases fail and/or significant weight loss is main- It is therefore not surprising that these supplements account
tained only in the short term because of lack of compliance. for more than $37 billion in sales in the USA [1].
The popularity of dietary supplements for weight management Dietary supplements are legally defined as products
has increased, and a wide variety of these products are avail- intended to supplement the diet (i.e., add further nutritional
able over the counter. However, the existing scientific evi- value), as they contain one or more Bdietary ingredients^ (e.g.,
dence is insufficient to recommend their safe use. Hence, the vitamins, minerals, amino acids, herbs, metabolite, extract).
purpose of this article is to review the clinical effects, pro- Moreover, dietary supplements generally are taken orally;
posed mechanism of action, and safety profile of some of thus, they may be found as capsules, tablets, gelatin capsules,
the new dietary supplements, including white bean extract, liquids, or powders [2, 3].
Garcinia cambogia, bitter orange, Hoodia gordonii, forskolin, Considering the aforementioned definition, dietary supple-
green coffee, glucomannan, β-glucans, chitosan, guar gum, ments are not intended to either treat or prevent any disease; in
and raspberry ketones. fact, the clinical effects of most of these supplements have not
been evaluated in sufficient double-blinded, randomized clin-
Keywords Dietary supplements . Obesity . Weight loss ical trials. Although dietary ingredients may have demonstrat-
ed certain effects within preclinical and small clinical scenar-
ios, the vast majority lack evidence when considering Bthe
Introduction whole picture,^ including the purity grade of the supplement
ingested, the overall lifestyle (i.e., diet and exercise) and other
The current overweight and obesity pandemic and its associ- health-related conditions of the patient (e.g., nutritional status
ated issues regarding adherence to treatment (i.e., lifestyle or concomitant diseases), food–drug interactions, excessive
modification including a change in dietary patterns and exer- dosing, and potential side effects. Assessing the clinical effec-
cise) have led to different interventional approaches, including tiveness of dietary supplements is extremely difficult because
regulation of these products differs from that of conventional
This article is part of the Topical Collection on Obesity Treatment pharmaceuticals. This situation has made dietary supplements
widely available as over-the-counter (OTC) products, thus
* Gabriela Gutiérrez-Salmeán easily accessible to the general population. Because dietary
[email protected] supplements are not considered drugs, regulations based on
their clinical effectiveness are not as Bstrict^ as those of con-
1
Facultad de Ciencias de la Salud, Universidad Anáhuac México
ventional drugs; therefore, they can be marketed and sold
Norte, Av. Universidad Anáhuac #46. Lomas Anáhuac, regardless of scientifically demonstrated clinical evidence.
52786 Huixquilucan, Estado de México, México Furthermore, a recent study reported more than 23,000
Curr Obes Rep (2016) 5:262–270 263

emergency department visits due to adverse events related to C. aurantium extract. The most common adverse events in-
dietary supplements; interestingly, a quarter of these cases cluded chest pain, tachycardia, anxiety, dyspnea, and pain in
involved weight loss products [4•]. the lower left quadrant [15].
Because of the aforementioned situation, the objective this In summary, most studies have not found significant
study is to review the bioactive ingredients, their—at least weight loss effects from administration of C. aurantium;
theoretical—molecular mechanisms, and any evidence- therefore, its effectiveness remains doubtful. In addition, cer-
supported weight-loss effects of some of the commonly con- tain predisposed individuals—e.g., those with hypertension,
sumed dietary supplements. tachyarrhythmias, etc.—may present adverse events after
ingesting. Thus, currently, there is not enough evidence to
recommend the consumption of C. aurantium as an adjuvant
Bitter Orange in weight loss management.

Also known as Citrus aurantium, Seville orange, or sour

orange, bitter orange has been used in traditional Chinese Hoodia gordonii
as well as South American folk medicine for a variety of
conditions [5]. Its extracts have been used as supplements Hoodia gordonii is a medicinal plant from the Apocynaceae
to treat obesity and to enhance exercise performance. It family, native to South Africa, Botswana, and Namibia
contains multiple phytochemicals, including octopamine, [16], and has been studied as a weight loss adjuvant be-
as well as alkaloids, particularly synephrine. These alka- cause of its appetite suppression activity [17]. Several me-
loids may exert sympathomimetic effects [6, 7] that con- tabolites have been isolated from H. gordonii, particularly
tribute to an oxidative metabolism—for example, by pro- pregnane glycosides containing 6-deoxy and 2,6-dideoxy
moting lipolysis and stimulating β3- and α-adrenergic re- sugars. Although the active compound that causes its an-
ceptors, as well as by inhibiting cyclic adenosine orexigenic effect is unclear, the oxypregnane glycoside
monophosphate (cAMP) production [6, 8]. P57AS3 (also known as P57) is commonly accepted as
Various clinical trials studying the effect of bitter or- the responsible metabolite [18].
ange extracts on weight loss reported significant results; Studies on the effects of P57 in vivo revealed that intraven-
however, these studies evaluated a combination of differ- tricular injection of purified P57 in rats decreased food intake
ent products (C. aurantium extract, caffeine, and St. and significantly increased hypothalamic ATP production,
John’s wort); thus, the individual effect of bitter orange which may decrease appetite response [19]. An in vitro study
could not be evaluated [9, 10]. On the other hand, in a found that P57 initiated cholecystokinin secretion in human
small clinical trial evaluating the immediate effects of a enteroendocrine cells; cholecystokinin has been studied for its
single administration of synephrine, as well as of a com- effects on appetite suppression via the vagus nerve [20].
bination of synephrine and flavonoids (naringin and/or Nevertheless, it has been observed that oral administration of
hesperidin), an increase in basal metabolic rate (BMR) H. gordonii leads to an extensive gastric breakdown of P57;
was observed after these compounds were ingested, either thus, H. gordonii extract must be consumed in high doses to
individually or in combination. Therefore, these results achieve clinically significant effects [18].
are presented as possible evidence for the use of isolated To our knowledge, only one clinical trial evaluated the
synephrine in treating obesity; however, further studies effects of H. gordonii on weight loss: Blom et al. [21]
are needed to evaluate its long-term effects on BMR and conducted a double-blind, placebo-controlled, parallel
weight loss [11]. clinical trial lasting 15 days in 49 overweight women.
It is important to consider that synephrine is not the only They found that administration of an H. gordonii extract
bioactive compound in C. aurantium; bitter orange also con- had no effect on body weight, body fat, or energy intake.
tains flavonoids, particularly hesperidin, naringin, limonene, Moreover, they reported adverse events in the H. gordonii
and tangaretin [12], which have been studied and used to treat group, including disturbance of skin sensation, headache,
overweight and obesity. dizziness, nausea, increased systolic and diastolic blood
In terms of safety, the administration of up to 98 mg of pressure, increased pulse, electrocardiogram abnormalities
C. aurantium–derived synephrine for 60 days did not present (longer PR interval, higher ventricular heart rat, and a low-
any adverse effects [13, 14]. However, because of the sympa- er QT interval), and blood chemistry abnormalities (in-
thomimetic activity of synephrine, it has been proposed that its crease in total bilirubin and alkaline phosphatase, decrease
consumption might exert negative effects on the cardiovascu- in blood urea nitrogen) [21]. Given these results, it may be
lar system. Indeed, from April 2004 through October 2009, concluded that administration of H. gordonii is not effec-
the US Food and Drug Administration (FDA) received 22 tive for weight loss management and that it may lead to
adverse event reports related to products containing significant adverse events.
264 Curr Obes Rep (2016) 5:262–270

Irvingia gabonensis therapy. Given these results, though, green coffee extract should
be studied in larger clinical trials to assess its effect.
Also known as African wild mango or African bush mango,
Irvingia gabonensis is native to central and western Africa; its
seed contains high amounts of lipids, mostly saturated fatty Forskolin
acids [22]. I. gabonensis is also rich in polyphenols, particu-
larly flavonoids, although the specific flavonoids present in Forskolin is the active compound of Coleus forskohlii, a mem-
the seed have not been determined [23, 24]. An in vitro study, ber of the mint family. Because it is native to India, it has been
Oben et al. [25] used an adipocyte culture treated with an used since ancient times in Ayurveda medicine to treat heart
I. gabonensis extract. They observed an inhibition in the ex- diseases, abdominal colic, and respiratory disorders, among
pression of peroxisome proliferator-activated receptor gamma other conditions [36]. Forskolin is a potent stimulator of
(PPAR-γ) and leptin protein levels and up-regulation of cAMP, which activates the hormone-sensitive lipase, thus pro-
adiponectin expression. moting the release of fatty acids from adipose tissue [37].
Randomized double-blind clinical trials evaluated the Small clinical trials have evaluated the effect of forskolin
weight loss effects of the administration of an I. gabonensis on weight loss and found different effects based on gender. In
extract [26, 27]. These studies were included in a systematic one double-blind, placebo-controlled clinical trial including
review by Onakpoya et al. [28], who reported that 200 to 15 obese men, 500 mg/day of 10 % forskolin extract was
3150 mg/day of an I. gabonensis extract given for 4 and administered for 12 weeks. At the end of this period, the
10 weeks resulted in both statistically and clinically significant forskolin group showed a significant decrease in body fat,
reductions in body weight and waist circumference compared together with an increase in lean body mass, but no changes
with placebo. The most common adverse events included in BMR [38]. Meanwhile, in a randomized clinical trial, 19
headache, sleep difficulties, and flatulence; however, these moderately overweight women were assigned to receive either
events were not significantly different between the study placebo or 500 mg/day of 10 % forskolin extract for 12 weeks.
groups. At the end of this period, it was observed that forskolin ad-
Based on the available clinical trials, as well as the system- ministration tended to mitigate gains in body mass, but no
atic review, the use of I. gabonensis as a dietary supplement significant differences were seen in body fat or fat-free mass.
represents an attractive adjuvant in weight loss strategies. It No significant adverse events were reported in this study [39].
should be noted, however, that all the clinical trials were per- Because of the conflicting results observed in men versus
formed in Black Africans and in relatively small study sam- women, as well as the small number of participants in the
ples; therefore, more research is needed to evaluate the effect studies, conclusions cannot be drawn regarding the effect of
of I. gabonensis in a larger, more diverse population. forskolin on weight loss management. The results from these
clinical trials, however, lead to speculation that forskolin
might be helpful in the management of overweight, although
Green Coffee more evidence is needed.

Green coffee extract is derived from green unroasted coffee

beans and has been marketed in both decaffeinated and caf- Fucoxanthin
feinated forms. Within its bioactive substances, it contains
chlorogenic acid, a polyphenol from the subfamily of phenolic Fucoxanthin, a carotenoid widely distributed in nature, has been
acids [29, 30]. The mechanisms proposed for the effects of isolated from a variety of seaweeds and diatoms [40]. Multiple
green coffee extract on weight loss include a lipolytic effect on preclinical trials studied the possible mechanisms of fucoxan-
adipocytes as well as a decrease in pancreatic lipase activity thin in the treatment of obesity and its associated cardiometa-
[31• , 32, 33]; inhibition of fatty acid synthase, bolic alterations. Fucoxanthin reduces both plasmatic and he-
hydroxymethylglutaryl-CoA reductase, and acyl-CoA- patic triglyceride concentrations. It also decreases acetyl-CoA
cholesterol acyltransferase; an increase in β-oxidation; and carboxylase expression, thus decreasing malonyl-CoA forma-
promotion of PPAR-α expression in the liver [34]. tion, as well as the expression of fatty acid synthase, decreasing
A meta-analysis reported a statistically significant weight loss the synthesis of long-chain saturated fatty acids [41–44].
of almost 2.5 kg after supplementation with green coffee extract Studies have revealed that fucoxanthin downregulates the ex-
in doses ranging from 180 to 200 mg/day over a treatment pression of the low-density lipoprotein receptor in the liver
period of 4 to 12 weeks [35]. However, because of the moderate [41–43]. Moreover, fucoxanthin decreases the expression of
clinical magnitude and the significant heterogeneity of the re- PPAR-γ, CCAAT/enhancer-binding protein-α (C/EBPα), and
ported clinical trials, the current evidence is insufficient to rec- sterol regulatory element-binding protein 1c (SREBP-1c) dur-
ommend green coffee as an adjuvant within weight management ing the intermediate and late stages of adipocyte differentiation.
Curr Obes Rep (2016) 5:262–270 265

During the early stages of adipocyte differentiation, however, Glucomannan

fucoxanthin increases the expression of PPAR-γ, C/EBPα,
SREBP-1c, adipocyte-binding protein, lipoprotein lipase, and Glucomannan, a hydrocolloid polysaccharide of the mannan
glucose transporter 4 (GLUT4) [45]. Fucoxanthin also has been family, is present naturally and abundantly in diverse prod-
shown to stimulate the expression of uncoupling protein1 ucts, such as softwoods, roots, tubers, and many plant bulbs
(UCP-1) in white adipose tissue, thus increasing thermogenesis [54]. The most used type of glucomannan comes from the
and energy expenditure [46, 47]. tuber konjac (Amorphophallus konjac). It is composed of a
Regardless of the robust preclinical evidence available, β-1,4–linked D-mannose and D-glucose monomers, has a high
however, few clinical trials have been conducted using fuco- molecular weight, and is considered a soluble fiber [55].
xanthin. In a double-blind, placebo-controlled clinical trial, 31 Glucomannan is one of the most viscous dietary fibers known,
obese participants received supplementation with a combina- and it can absorb up to 50 times its weight in water. Because
tion of 100 mg of pomegranate seed oil and 0.8 mg of fuco- human salivary and pancreatic amylase cannot split β-1,4
xanthin or placebo for 16 weeks. No significant differences linkages, glucomannan passes relatively unchanged into the
regarding weight loss or body fat were observed between the colon, where it is fermented by the gut microbiota [56].
groups [48]. In another study, 151 obese premenopausal wom- Konjac has been used in indigenous Asia as an herbal remedy
en received a supplement with pomegranate seed oil extract and currently is being studied for its health-related effects on
and/or brown seaweed extract containing fucoxanthin at dif- weight reduction, dyslipidemia, and blood glucose, among
ferent doses for 16 weeks. The investigators reported that the others [56, 57].
group receiving a dosage of 300 mg of pomegranate seed oil Different mechanisms have been proposed to explain the
and 300 mg of seaweed extract containing 2.4 mg of fucoxan- effects of glucomannan on weight loss, including promotion
thin had a statistically significant reduction in body weight, of satiety through increased mastication efforts, delayed gas-
body fat, and waist circumference. Furthermore, the group tric emptying, and reduced small bowel transit. Fecal energy
receiving 8 mg of fucoxanthin showed an increase in resting loss also has been proposed as a mechanism, because soluble
energy expenditure, measured by indirect calorimetry [49]. fibers reduce fat and protein absorption.
Based on the results from these clinical trials, no recom- Glucomannan generally is well tolerated; the only serious
mendations can be made regarding the consumption of fuco- adverse events reported were the result of ingestion of
xanthin in the treatment of obesity. glucomannan tablets (which are no longer available) or jelly
candies [56]. So far, two meta-analyses evaluated the efficacy
of glucomannan as a weight loss dietary supplement. These
Raspberry Ketone studies analyzed nine clinical trials, six of which were includ-
ed in both analyses. Both studies reported significant hetero-
Raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] is an ar- geneity in their results [58, 59]. Sood et al. [59] found a sta-
omatic substance used by the food industry for flavoring [50]. tistically significant reduction in weight, −0.79 kg, among
In vitro studies using adipocytes have observed an increase in participants receiving glucomannan for a mean of 5.2 weeks.
fatty acid oxidation, suppression in lipid accumulation, and The more recent meta-analysis by Onakpoya et al. [58] re-
increased secretion of adiponectin [51]. On a molecular basis, vealed a non-statistically significant difference of −0.22 kg
studies found that raspberry ketone downregulates the expres- in weight loss between the glucomannan and placebo groups,
sion of transcription factors involved in adipogenesis, includ- contradicting the earlier meta-analysis. These conflicting re-
ing PPAR-γ, C/EBPα, adipocyte fatty acid–binding protein2, sults might be explained by the different inclusion criteria that
acetyl-CoA carboxylase1, fatty acid synthase, and steroyl-CoA the studies used to select the clinical trials analyzed. Although
desaturase1, while increasing the expression of genes involved Sood et al. [59] found a statistically significant reduction in
in fatty acid oxidation, including adipose triglyceride lipase, weight among study participants using glucomannan, this
hormone-sensitive lipase, and carnitine palmitoyltransferase weight loss is not necessarily clinically significant; thus, the
[52•]. Meanwhile, in vivo studies in rodents showed that rasp- results should be interpreted carefully.
berry ketone prevented high-fat diet–induced increases in body
weight and visceral adipose tissues. Possible mechanisms of
action include stimulation of the white and brown adipose β-Glucans
tissues and inhibition of pancreatic lipase activity [53].
Although raspberry ketone has been considered within al- Glucans are glucose polysaccharides classified according to
ternative weight loss management, no clinical evidence is their interchain linkage as α or β. β-Glucans consist of D-
available, and furthermore, raspberry ketone has the potential glucose monomers linked by β-glycosidic bonds, and their
adverse effect of cardiotoxicity as well as a teratogenic effect, structure consists of linear β1-3,1-4-D-glucans. Glucans are
as identified in silico [50]. present in cereal grains in the cell walls of the endosperm,
266 Curr Obes Rep (2016) 5:262–270

whereas in mushrooms, they are major structural components Therefore, current evidence does not support the use of
of the cell walls. β-Glucans are considered non-digestible guar gum as a dietary supplement for treating overweight or
dietary fiber, particularly soluble fiber, and are highly obesity.
fermented in the cecum and colon by the gut microbiota;
therefore, the effect of β-glucans as prebiotics has been pro-
posed [60–62]. The weight loss effects attributed to β-glucans Chitosan
derive from their being a soluble fiber, which may increase
satiety and total gastrointestinal transit time and slow glucose Chitosans are a family of deacetylated chitins. Although not
absorption. The effects of β-glucans in treating overweight naturally present in human tissue, chitosan is biodegradable,
and obesity have been studied mainly as secondary outcomes nontoxic, nonimmunogenic, and biocompatible. Currently,
in clinical trials evaluating the effects of β-glucans on dyslip- chitosan may be found among OTC products for treating obe-
idemia, blood pressure, and insulin resistance as primary out- sity, hypercholesterolemia, and hypertension.
comes. Overall, most of these trials reported no or non- The mechanism by which chitosan may exert a weight loss
significant effects on weight loss from β-glucans administered effect is by binding to negatively charged fat molecules within
at 3 to 10 g/day for 4 to 12 weeks [63–66]. Regarding satiety, the intestinal lumen, thus preventing its absorption [77].
most clinical trials have used subjective scores for satiety and Chitosan is considered an insoluble fiber of animal origin
appetite, reporting controversial results within the clinical tri- and exerts a bile acid resin effect, decreasing cholesterol ab-
als, possibly as a result of the nature of the subjective scores sorption [78]. Although several clinical trials and meta-
used. Therefore, no conclusions can be drawn regarding the analyses studied the effect of chitosan on weight loss, contro-
effects of β-glucan administration on satiety and/or appetite versial results have been found. In the first published meta-
[67–71]. Given these results, it may be concluded that β- analysis, Ernst and Pittler [79] reported a statistically signifi-
glucan administration does not appear useful in treating over- cant weight loss of 2.38 kg after 28 days of treatment; how-
weight or obesity. ever, more recent meta-analyses and systematic reviews have
not found the same results. A Cochrane meta-analysis includ-
ing 13 clinical trials found a weighted mean difference in body
weight of −1.7 kg after chitosan supplementation vs placebo,
Guar Gum which was statistically significant. However, when the inclu-
sion standards were increased and only high-quality trials
Guar gum, derived from the seeds of the Cyamopsis were analyzed, the reduction in estimated weight loss was
tetragonoloba plant, is a source of soluble fiber and is used only −0.6 kg, which nevertheless was still statistically signif-
as an emulsifier and thickener in diverse foods. It consists of icant [80].
high-molecular-weight polysaccharides of galactomannans in Given the fact that chitosan is supposed to increase fecal fat
the form of a linear chain of β1-4–linked D-mannopyranosyl excretion, clinical trials have evaluated this effect but have
units with α1-6 D-galactopyranosyl residues as side chains found only a non-significant difference in fecal fat excretion
[72]. Guar gum serves as a bulking agent; hence, its supple- after chitosan administration [81, 82]. Finally, one clinical trial
mentation has been used to decrease food intake and to in- compared the effects of orlistat (a pancreatic lipase inhibitor)
crease satiety [73]. vs chitosan on fecal fat excretion, finding that the latter did not
Several studies evaluated the effect of guar gum on inhibit dietary fat absorption [83].
weight reduction. A meta-analysis of 11 randomized, dou- Given the aforementioned results, it may be observed that
ble-blind, placebo-controlled clinical trials of guar gum although chitosan might have an effect on weight loss, that
given at dosages of 9 to 30 g/day for 3 weeks to 6 months loss is not clinically significant and therefore should be
found no significant difference in weight loss between pa- interpreted cautiously.
tients receiving guar gum and the placebo group [74].
Since that study was published, few clinical trials regard-
ing guar gum and weight loss have been reported. White Kidney Bean
However, a clinical trial in patients with type 2 diabetes
evaluated the effects of partially hydrolyzed guar gum on Phaseolus vulgaris extract is marketed as an OTC dietary
metabolic syndrome parameters; it found a significant re- supplement for weight loss because of its so-called
duction in waist circumference but no effect on weight loss Bcarbohydrate blocker^ actions, which refers to the fact that
[75]. Another study evaluated the effects of administering phaseolamin inhibits pancreatic amylase and thus digestion of
a combination of fibers, including guar gum, on appetite dietary starches. Indeed, proof-of-concept studies have
and energy intake in overweight humans and found no reported a dose-dependent decrease in glucose absorption
effect on appetite sensation or energy intake [76]. [84].
Curr Obes Rep (2016) 5:262–270 267

However, effects from dosages ranging from 1.5 to 6 g/day whey protein, etc., which actually are used as ergogenic aids).
were proven only in relatively small, short-term studies. For Nevertheless, these compounds need further investigation be-
example, a clinical trial including 60 overweight subjects re- cause no clear-cut evidence has been demonstrated in clinical
ported greater reductions in body weight, fat mass, and waist, practice and, moreover, because some are considered to exert
hip, and thigh circumference in those taking white kidney potential side effects.
bean extract versus the placebo group [85]. However, a In conclusion, none of the dietary supplements reviewed
meta-analysis found a statistically significant decrease in fat here can be recommended for OTC use [95] and, moreover,
mass but a non-significant difference in weight loss between both health professionals and their patients should acknowl-
the two cohorts. Nevertheless, the authors acknowledge that edge that therapeutic lifestyle changes remain the first-line
the studies that they included clearly show heterogenicity and treatment for weight loss, while other therapies are to be con-
serious methodologic flaws [86]. sidered as coadjuvant/complimentary.
In light of these results, accurate conclusions cannot be
drawn, and more robust clinical evidence, together with Compliance with Ethical Standards
long-term safety reports, is needed.
Conflict of Interest Alejandro Ríos-Hoyo and Gabriela Gutiérrez-
Salmeán declare that they have no conflict of interest.
Garcinia cambogia
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
Native to Asia, Australia, Africa, and Polynesia, Garcinia has
of the authors.
been associated with a wide variety of effects, including hy-
polipidemic, anti-inflammatory, antidiabetic, and
antineoplasic properties. Because extracts of its exocarp have
shown anorexigenic effects, Garcinia also has been studied
within the weight management scenario. Moreover, References
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highlighted as:
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