Obesity is now a major concern in the Western world, as it can lead to health problems such as diabetes, cardiovascular disease, hypertension and some forms of cancer. Here, Richard A Collins looks at the efficacy of hydroxycitric acid, one of the components in various over-the-counter weight-loss formulations and appetite-suppressor products.
Hydroxycitric acid
and weight loss

Losing weight has become a modern-day
obsession. Regardless of the personal

‘Obesity and overweight are factors that reasons for wanting to lose weight, there
is certainly a need for wider concern

about obesity and being overweight. A
person whose body mass index (BMI) is

greater than 25 kg/m2 is defined as
overweight, and over 30 kg/m2 is
regarded as obese. Globally, there are
more than one billion overweight adults,1
of whom at least 300 million are obese.

the healthcare system.2 Obesity places an some areas and is on the rise in others.
induce weight loss are illegal (amphetamines), Worldwide, about 22 million children under service, with the direct costs being at least dangerous (fenfluramine, ephedra), addictive five years of age are overweight. Obesity and £500 million per year.3 The cost of obesity- related healthcare varies with the degree (opioid antagonists, amylin) or are indicated diseases and disability, including type 2 of obesity. Overall, the healthcare costs for for other conditions (fluoxetine [Prozac] – diabetes, cardiovascular disease, hypertension an antidepressant). Few detailed studies on and stroke, and certain forms of cancer. double those of a person of normal weight.4 the safety or efficacy of other potentially contribute to the increase in the number induce weight loss and it is impossible to of overweight and obese individuals. Busy vast number of dietary regimes introduced laevorotatory optical isomer (L-hydroxycitric healthy meals or participating in regular over the decades. For those unable to stick acid or [-]-hydroxycitric acid) of which has exercise or sporting activities. Energy-dense food high in saturated fats and sugars are treatment of obesity, government agencies Hydroxycitric acid
have suggested that the direct and indirect which help regulate the sense of fullness, Hydroxycitric acid is purported to be one of costs associated with obesity may overwhelm and this results in reduced food intake. the active components in various over-the- gastrointestinal lipases. It acts in the lumen forming a covalent bond with the activeserine residue sites of gastric and pancreatic lipases. Thus, the inactivatedenzymes are unavailable to hydrolyse dietary fat (ie triglycerides) into absorbablefree fatty acids and monoglycerides, which control. Systemic absorption of the drug is not needed for activity. At the Fig 1. Chemical structure of
three times a day), orlistat inhibits dietary THE BIOMEDICAL SCIENTIST September 2006
counter weight-loss formulations andappetite-suppressor products. It is obtained Fig 2. Garcinia cambogia, is
from the rind of the fruit of Garcinia cambogia (also known as brindal berry, the rind by extraction into water at room temperature. The crude extract is loaded on an anion exchange to adsorb HCA, which is eluted with sodium/potassium hydroxide.
This fraction is then passed through a cation G. quaesita, G. zeylanica or exchange column to obtain the free acid. biologically active form. However, the acid sodium or calcium salts of HCA. The calcium sparingly soluble in water and are not well In a recent study, the peak plasma level of hydroxycitrate was 8.4 µg/mL two hours after the oral administration of 2 g G. cambogia extract to normal subjects.6 Hydroxycitric acid can be broken down by bile acids and fats in the intestine and can bind to fibre,pectin and other substances in the diet orsecreted during digestion. Hydroxycitric acid is an extremely popular dietary supplement. Between March 2000and September 2003, 225 tonnes of HCA, Proposed actions
Acetyl-CoA is the basic building block of G. cambogia and G. cambogia extract were fatty acids. It is produced by oxidation of glucose obtained from carbohydrates in the weight loss, including inhibition of fatty acid diet via the tricarboxylic acid (TCA) cycle or by oxidation of fatty acids. Both activities take place in the mitochondria and cytoplasmic acetyl-CoA is ultimately derived from citrate The recommended daily dose of G. cambogia Inhibiting fatty acid synthesis
exported across the mitochondrial membrane Hydroxycitric acid is a potent competitive, reversible inhibitor of ATP-citrate lyase Inhibiting production of acetyl-CoA would (also known as ATP citrate synthase, citrate also be expected to deplete the concentrations regulated by the Dietary Supplement Health cleavage enzyme) in vitro, and an inhibitor of subsequent metabolites in the fatty acid and Education Act in the USA. For dietary of fatty acid synthesis in rat liver in vivo.10,11 synthetic pathway. The second metabolite supplements marketed before October 1994, in the pathway, formed from acetyl-CoA, is no proof of safety is required for them to required for the synthesis of fatty acids and catalyses the following reaction: citrate + enzyme carnitine acyltransferase, which is CoA + ATP ➞ oxaloacetate + acetyl-CoA + needed for the oxidation of fat. Therefore, it is include contraindications for using HCA in proposed that reducing malonyl-CoA formation persons with diabetes, Alzheimer’s disease with HCA might stimulate fat metabolism. or dementia or in those who are pregnant or lactating. Potential drug interactions include gain and that inhibiting fat synthesis is the likely mechanism for the observed effect. β-adrenoreceptor blockers, potentiation of For example, male rats (n=24) had restricted access to food (10 g/day) for 10 days followed hypokalaemia, and risk of arrhythmia when by ad libitum energy-rich diet for the next combined with depolarising muscle relaxants 10 days. Half of the rats were supplemented Studies failed to demonstrate any changes body weight regain after substantial body in hepatic and testicular peroxidation, DNA weight loss; an effect the authors presumed fragmentation, histopathological changes, to be due to the inhibiting effect of HCA haematology or clinical chemistry in rats on lipogenesis.12 In human studies, however, whose feed was supplemented with 5% (w/w) THE BIOMEDICAL SCIENTIST September 2006
Fig 3. Simplified
Appetite suppression
Regulation of appetite is a complex process that is not fully understood. It consists of involves the integration by the brain of a variety of signals from peripheral organstransmitted by neurotransmitters, peptides,hormones and metabolites.14 Most anorecticdrugs act by central mechanisms and havemany disadvantages that include limited expression of serotonin receptor genes in days and performed endurance exercise.
effectiveness, side effects on the central abdominal fat tissues of rats fed low-dose Blood free fatty acid concentrations increased significantly and the respiratory exchange ratio (ratio of the amount of carbon dioxide hyperphagia (over-eating) on discontinuation ingestion, suggesting that short-term HCA been tested in animals that act by peripheral Thermogenesis
ingestion increases fat oxidation in untrained Thermogenesis is the metabolism of fat or other compounds to produce heat rather than that peripherally acting anorectic drugs metabolic energy in the form of ATP.
Evidence from trials
may provide new therapeutic approaches to Thermogenesis occurs in specialised fatty It is generally accepted that evidence of disorders of appetite regulation in humans. tissue known as brown adipose tissue (brown efficacy for pharmacological interventions is A patent for the use of HCA as an appetite fat). However, it is unclear how HCA exerts suppressant and an inducer of weight loss double-blind, placebo-controlled trial. The fact that such trials have been performed validated and detailed metabolic studies on indicated that HCA decreased food intake and this interesting hypothesis have not been such frequency and at such high doses for body weight gain. Body lipid levels decreased a condition that may lead to serious adverse but body protein levels remained unchanged.
In contrast, citrate had no such effect.16 In genetically obese Zucker rats, administration of HCA in the diet for 39 days reduced food significantly by short-term administration of mg HCA per day (n=66) or placebo (n=69) intake and body weight but had no effect on for 12 weeks.28 In addition, both groups were prescribed a high-fibre, low-energy diet.
decreased (P<0.05) during exercise.25 Similar About two-thirds of subjects in each group results were obtained in six untrained women completed the trial. Subjects in each group taking placebo on weight loss and appetite lost a significant amount of weight during suppression. Both groups lost weight, with The effects of HCA on fat oxidation during the 12-week treatment period (P<0.001); moderately intensity exercise in untrained greater reduction (3.7± 3.1 kg vs 2.4 ± differences were not statistically significant 2.9 kg). However, there was no difference ingested 500 mg HCA or a placebo for five (mean ± SD: 3.2 ± 3.3 kg vs 4.1 ± 3.9 kg; in appetite variables and the study did not support a satiety effect of HCA.18 The lack of effect of HCA on satiety was supported estimated percentage of body fat mass loss in a separate trial on 11 overweight males between treatment groups, and the fraction of weight loss as fat was not influenced by the treatment group. The authors concluded unaffected in 24 adults receiving 900 mg/day that G. cambogia failed to produce significant weight loss and fat mass loss beyond that while 24-hour energy intake was decreased placebo-controlled trial in 60 moderately serotonin after feeding are implicated in conducted in which HCA (2.8 g/day in three equal doses, given 30–60 minutes before THE BIOMEDICAL SCIENTIST September 2006
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BMI decreased by 5–6% in the HCA group.
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A marginal or non-significant effect was 20 Kovacs EM, Westerterp-Plantenga MS, de seen in all parameters in the placebo group.29 Vries M et al. Effects of 2-week ingestion Similar weight loss and beneficial effects on of (-)-hydroxycitrate and (-)-hydroxycitrate blood profiles were observed in studies of 82 obese subjects (BMI 30–50.8 kg/m2).23 National Cancer Institute. Garcinia triglycerides on satiety and food intake.
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21 Westerterp-Plantenga MS, Kovacs EM.
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