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Potassium Magnesium Hydroxycitrate at Physiologic Levels Influences Various Metabolic Parameters and Inflammation in Rats
Abstract
Using oral potassium-magnesium hydroxycitrate (KMgHCA) doses comparable to suggested human intake, effects on systolic blood pressure (SBP), glucose-insulin metabolism, inflammatory markers, blood chemistries and carageenan-induced paw edema were examined in rats. Initially, four groups of eight 8-week old male Sprague-Dawley Rats (SD) received diets supplying calories as 30% fats, 50% carbohydrates and 20% proteins. For 8 weeks, test arms received HCA (from KMgHCA) at 14 mg, 28 mg or 84 mg daily. In a second study, two groups of 6 spontaneously hypertensive rats (SHR) consuming normal rat chow mixed with 20% w/w sucrose were examined (Control or 84 mg HCA daily) to expand findings on SBP and glucose-insulin metabolism. In the first study, there were no significant differences in food intake or weight gain. The 28 mg and 84 mg doses significantly lowered SBP. In all test groups, circulating insulin levels were lower, but without significance due to variances in Control. The highest test dose significantly reduced paw edema and all doses strongly trended towards reduced CRP and TNF-alpha. There was no evidence of toxicity. In the second study, the intake of KMgHCA (84 mg daily) in genetically hypertensive rats quickly caused a significant decrease in SBP. Losartan challenge suggested the renin-angiotensin system was involved. Glucose tolerance and insulin challenges indicated that KMgHCA enhanced insulin sensitivity.
... Lowered CRP and TNF-γ without visible toxicity, raised systolic blood pressure, and alleviated carageenan-induced paw edema in Sprague-Dawley rats. The activity level was considered to be "moderate," particularly when contrasted with the sedentary control group (Clouatre and Preuss, 2008). ...
In the past, the extreme sourness of the Garcinia gummi-gutta fruit
rind, which is also called Garcinia cambogia (syn.), was often
utilized as a flavoring agent in fish curries. Other traditional uses in
the field of ethno-medicine include the treatment of eradication of
bowel problems, the digestive problems, rheumatism, and the intestinal
parasites. This little fruit, which looks quite similar to a pumpkin, is
commonly advertised and utilized as a technique of reducing extra
pounds in today’s society. In animal trials, it was revealed that both the
extracts and the major organic acid contained in the fruit rind, called (-)-
hydroxycitric acid, had anti-obese properties. These effects include a
reduction in food consumptions and body fat growth through changes in
the levels of satiety-related serotonin. Additionally, there is an increase in the
amount of fat that is oxidized, and there is a decrease in the amount of de
novo lipogenesis that takes place. The enzyme adenosine triphosphate-citrate
lyase, which is essential for the synthesis of triglycerides, cholesterol,
and fatty acids, is effectively inhibited by (-)-hydroxycitric acid.
This enzyme catalyzes the conversion of citrate to acetyl-coenzyme A and is responsible for the essential step of converting citrate to acetylcoenzyme
A. In in vivo and in vitro models, the crude extract or components
of the plant demonstrated anti-inflammatory, hypolipidemic, anthelmintic,
anticancer, hepatoprotective, and anticholinesterase actions. Other benefits
include lowering blood sugar and cholesterol levels, and protecting the liver.
In this chapter, a complete scientific assessment of Garcinia gummi-gutta is
provided with special focus dedicated to the plant’s phytochemistry, ethnobotanical
uses, pharmacological uses, and toxicity.
... 79 Insulin challenges and glucose tolerance tests showed that potassium magnesium hydroxy citrate (KMgHCA) improved insulin sensitivity in rats. 80 Overall, G. gummi-gutta can be used to treat diabetes by boosting insulin action, modulating glucose metabolism, promoting glycogenesis and β oxidation of fatty acids. 56 ...
Garcinia gummi-gutta, also known as Garcinia cambogia, is a member of the Guttiferae family. Garcinia is a polygamous genus consisting 200 species of trees and shrubs. It is found in different zones of the planet including Asia’s tropical regions. In India alone, around 30 species have been discovered. They are widely used as a flavoring agent to garnish fish curry in southern India, particularly in Kerala and Karnataka. The fruit rind of G. gummi-gutta has traditionally been used to treat gastrointestinal problems, diarrhoea, and ulcers. South Indian people have been utilizing it traditionally as evidenced by its ethnobotanical properties. In vivo and in vitro effects of the crude fruit extract showed anti-inflammatory, anti-cancer, anthelmintic, anti-microbial, and antioxidant activities. G. gummi-gutta fruit rind is medicinally significant and is frequently used in ayurvedic and traditional medicine for many diseases. Various secondary metabolites such as organic acids-hydroxycitric acid (HCA), flavonoids, terpenes, polysaccharides and polyisoprenylated benzophenones - garcinol, xanthochymol, guttiferone, benzophenone, xanthone, biflavonoids, alkaloids, tannins, phenols, and saponins isolated from the G. gummi-gutta have diverse pharmacological activities. This review provides a summary of G. gummi-gutta, including biological activities, phytochemistry, and ethnobotanical applications.
... Potassium-magnesium hydroxycitrate (KMgHCA) administered at doses of 28 and 84 mg/day p.o. improved systolic blood pressure and reduced carageenan-induced paw oedema in Sprague-Dawley rats by reducing CRP and TNF-α without any observed toxic effect. The activity was considered to be moderate when compared to that of the control group [105]. ...
... A promising botanical compound that may have beneficial effects on food intake, weight management, oxidative stress, and metabolic disease is Garcinia cambogia (Garcinia cambogia Desr.)-derived (−)-hydroxycitric acid (HCA). For example, previous animal studies have demonstrated that this compound affects insulin metabolism, leptin, glucocorticoid metabolism, and inflammation [18,19] . The majority of research on this botanical, however, has been conducted on rodents and short-term human trials without adequate control conditions [20][21][22][23][24][25][26][27][28] . ...
Garcinia cambogia, with its active component hydroxycitric acid (HCA), is widely used for weight loss due to its anorexigenic effect, increased fat oxidation, and regulation of endogenous lipid biosynthesis. The potential effectiveness of G. cambogia in reducing body weight and fat has been concluded in several studies in both experimental animals and humans. However, the results of some randomized placebo-controlled human clinical trials have either not reported the same outcome or there has been a marginal reduction in body weight on a short-term basis, not beyond 12 weeks. Other beneficial effects of Garcinia in experimental studies include antiinflammatory, antiulcerogenic, antioxidant, hepatoprotective, cytotoxic, erythropoietic, and miscellaneous other effects. Studies with G. cambogia conducted in experimental animals have not reported mortality or significant toxicity. Further, at doses usually recommended for humans no side effects have been reported. However, G. cambogia should not be concurrently used with other drugs to circumvent drug interactions. Currently, a large number of G. cambogia/HCA-containing dietary supplements are being marketed, although the reports of toxicity associated with the regular use of these supplements have raised concerns. In most cases complaints have been related to formulations containing multiple ingredients including G. cambogia. Another reason for adverse effects of G. cambogia/HCA can be related to idiosyncratic reactions by individual patients or other drugs used concurrently with these supplements resulting into in a drug/herb-induced toxic interaction.
Garcinia cambogia, with its active component hydroxy citric acid (HCA), is widely used for weight loss due to its anorexic effect, increased fat oxidation, and regulation of endogenous lipid biosynthesis. The potential effectiveness of G. cambogia in reducing body weight and fat has been concluded in several studies in both experimental animals and humans. However, results of some randomized, placebo-controlled human clinical trials either have not reported the same outcome or there has been marginal reduction in body weight on a short-term basis, not beyond 12 weeks. Other beneficial impacts of Garcinia in experimental studies include anti-inflammatory, antiulcerogenic, antioxidant, hepatoprotection, cytotoxic, antidiabetic, and erythropoietic effects. Studies with G. cambogia conducted in experimental animals have not reported mortality or significant toxicity. Further, at doses usually recommended for humans, no side effects have been reported. However, G. cambogia should not be concurrently used with other drugs to circumvent drug interactions.
Garcinia cambogia extract (GC) with its active component consisting of hydroxycitric acid (HCA) is widely utilized for weight loss. Various HCA salts are available, including calcium, magnesium, potassium and mixtures of these. Experimentally, these salts exhibit different properties with some, but not all, improving glucose tolerance and blood pressure. Recently, obesity-prone C57BL/6J mice were fed a high-fat diet (HFD, 45 kcal% fat) with or without GC (1%, w/w) for 16 wk. The active arm reduced visceral fat, adipocyte size and serum glucose, yet purportedly also exhibited hepatic collagen accumulation, lipid peroxidation and increased mRNA levels of genes related to oxidative stress. The latter findings are at odds with a large body of animal and human studies that have been conducted on the safety and efficacy of HCA. This literature shows HCA to be protective against the liver toxicity associated with ethanol and dexamethasone administration, and to maintain serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase at near normal levels. In both animal and clinical literature, elevated intakes of HCA per se have not led to signs of inflammation or hepatotoxicity. The compound has been found to reduce markers of inflammation in brain, intestines, kidney and serum.
Botanicals represent an important and underexplored source of potential new therapies that may facilitate caloric restriction and thereby may produce long-term weight loss. In particular, one promising botanical that may reduce food intake and body weight by affecting neuroendocrine pathways related to satiety is hydroxycitric acid (HCA) derived from Garcinia cambogia Desr.
The objective of this article is to describe the protocol of a clinical trial designed to directly test the effects of Garcinia cambogia-derived HCA on food intake, satiety, weight loss and oxidative stress levels, and to serve as a model for similar trials. A total of 48 healthy, overweight or obese individuals (with a body mass index range of 25.0 to 39.9 kg/m(2)) between the ages of 50 to 70 will participate in this double-blind, placebo-controlled, crossover study designed to examine the effects of two doses of Garcinia cambogia-derived HCA on food intake, satiety, weight loss, and oxidative stress levels. Food intake represents the primary outcome measure and is calculated based on the total calories consumed at breakfast, lunch, and dinner meals during each test meal day. This study can be completed with far fewer subjects than a parallel design.
Of the numerous botanical compounds, the compound Garcinia cambogia-derived HCA is selected for testing in the present study because of its potential to safely reduce food intake, body weight, and oxidative stress levels. We will review potential mechanisms of action and safety parameters throughout this clinical trial.
ClinicalTrials.gov (Identifier: NCT01238887).
Objective: To determine the modulating effect of Garcinia cambogia fruit extract on ethanol induced peroxidative damage in rats. Method: Male albino rats weighing 125 to 150g were administered ethanol (7.11g per kg body weight / day) for 45 days. Ethanol administered rats were treated concomitantly with Garcinia cambogia fruit extract (1g/kg body weight / day) orally for 45 days. After the experimental period the antioxidant enzymes, LPO, conjugated diene in the liver tissue, serum AST, ALT and alkaline phosphatase and lipid levels in both serum and liver tissue were estimated. Results: Co-treatment of the rats with Garcinia cambogia significantly inhibited the rise in lipid levels and also the peroxidative damage caused by ethanol, which is evident from the improved antioxidant status. The levels of serum AST, ALT and alkaline phosphatase were maintained at near normalcy in Garcinia cambogia treated rats. Conclusion: The imbalance in lipid metabolism could be the reason for increase in lipid peroxidation. In our present study the treatment with Garcinia cambogia fruit extract resulted in reduction of both serum and liver lipid to near normalcy. This hypolipidemic property of Garcinia cambogia in turn reduces the peroxidative damage, enhanced by ethanol.
Previous studies in our laboratories have demonstrated that niacin-bound chromium (NBC), Maitake mushroom and (-)-hydroxycitric acid (HCA-SX) can ameliorate hypertension, dyslipidemias and diabetes mellitus, and therefore may be useful in weight management. In the present study, we used aged, diabetic Zucker fatty rats (ZFR) (70-75 weeks) in order to determine whether NBC, fraction SX of Maitake mushroom (MSX) and 60% (-)-hydroxycitric acid (HCA-SX) from Garcinia cambogia, alone or in combination, can affect certain aspects of the metabolic syndrome. Syndrome X or metabolic syndrome has been described as a concurrence of disturbed glucose and insulin metabolism, overweight and abdominal fat distribution, mild dyslipidemia, and hypertension, which are associated with subsequent development of type 2 diabetes mellitus and cardiovascular disease. Four groups of eight ZFR were gavaged daily with different supplements. For the initial three weeks, the control group of ZFR received only water, the second group received NBC 40 mcg elemental chromium/day, the third group received MSX 100 mg/day and the last group received HCA-SX 200 mg/day. During weeks 4-6, the doses of each treatment were doubled. The control animals lost approximately 50 g body weight (BW) per rat over 6 weeks of treatment, which is characteristic of these animals in declining health. In contrast, eight ZFR receiving NBC lost approximately 9 g BW per rat, while rats consuming MSX lost 16 g BW per rat. However, ZFR receiving HCA-SX simulated the pattern in the control group because these animals lost approximately 46 g BW per rat. The wide individual variations resulted in a lack of statistical significance among groups. Nevertheless, 75% of the ZFR in the control group lost more than 50 g BW over the 6 weeks duration, whereas none of the ZFR receiving NBC, 25% of the ZFR receiving MSX and 57% of the ZFR receiving HCA-SX lost over 50 g BW over the 6 weeks of the study. ZFR in all 3 treatment groups showed significantly lower blood pressures as compared to control, which seemed to be dose related. The general trend was for renal and liver blood parameters, hepatic and renal lipid peroxidation and DNA fragmentation to improve due to the supplementation of these natural products. Treatment of animals with a combination of these three novel supplements resulted in a lower SBP and maintenance of BW compared to control animals. These results demonstrate that elderly diabetics and even aging individuals might benefit from a similar regimen.
Hydroxycitrate (HCA), a popular dietary supplement for weight loss, is a competitive inhibitor of ATP-citrate lyase, an extramitochondrial enzyme involved in the initial steps of de novo lipogenesis (DNL). Although animal studies have shown that HCA effectively inhibits DNL and induces weight loss, these findings have not been consistent in humans. This raises the possibility that the bioavailability of HCA may differ among species. We developed a new GC/MS method to measure HCA levels in blood, using [U-13C]citrate (CA*) as internal standard to account for losses associated with the isolation, derivatization, and measurement of HCA. HCA and CA* were derivatized with BSTFA + 10% TMCS and analyzed using PCI/GC/MS (CA*, m/z 471; and HCA, m/z 553). The plasma HCA concentration was measured over a 3.5-h period in four subjects having ingested 2 g of HCA. Their plasma HCA concentration ranged from 0.8 to 8.4 μg/ml 30 min and 2 h after ingestion, respectively. These results demonstrate that when taken acutely, HCA is absorbed, yet present in small quantities in human plasma. This simple method requiring minimal sample preparation is able to measure trace amounts of HCA with accuracy and precision.
Albino rats of Wistar strain were fed lipogenic diet with and without the addition of (−)hydroxycitrate for a period of 15 days. Daily food intake and weekly body weight gain of the animals were recorded during the feeding period. The animals were then sacrificed, blood, liver and epididymal fat were collected and analysed for selected parameters. It was observed that inclusion of (−)hydroxycitrate in the diet resulted in significant reduction in food intake, body weight, epididymal fat and serum triglyceride in the animals and also decrease in the feed efficiency ratio. The decrease in food intake, body weight gain and feed efficiency ratio brought about by (−)hydroxycitrate was dependent on the content of this compound in the diet.
The regulation of appetite is a complex process that we are just beginning to understand. It consists of both central and peripheral elements and involves the integration by the brain of a variety of signals from peripheral organs transmitted by neurotransmitters, peptides, hormones, and metabolites. All available anorectic drugs act by central mechanisms and have several disadvantages including limited effectiveness, side effects on the central nervous system, the development of tolerance, abuse potential, and rebound hyperphagia on discontinuance. Several appetite-modulating agents have been tested in animals that act by peripheral mechanisms and do not produce tolerance or rebound hyperphagia, which suggests that peripherally acting anorectic drugs may provide novel therapeutic approaches to disorders of appetite regulation in humans.
These studies were designed to determine the effect of (−)-hydroxycitrate upon the accumulation of lipid in the rat by examining appetite, wt gain, and total body lipid profiles. The chronic oral administration of a nontoxic dose of (−)-hydroxycitrate to growing rats for 11–30 days caused a significant reduction in body wt gain, food consumption, and total body lipid. The administration of equimolar amounts of citrate did not alter wt gain, appetite, or body lipid. No increase in liver size or liver lipid content occurred with either treatment. Pair feeding studies demonstrated that the reduction in food intake accounted for the decrease in wt gain and body lipid observed with (−)-hydroxycitrate treatment.
The purpose of these investigations was to ascertain the effect of (−)-hydroxycitrate on the accumulation of lipid in the
meal fed rat by examining the rates of lipogenesis after acute and chronic treatment. Oral administration of (−)-hydroxycitrate
depressed significantly the in vivo lipogenic rates in a dose-dependent manner in the liver, adipose tissue, and small intestine.
The hepatic inhibition was significant for the 8 hr period, when control animals demonstrated elevated rates of lipid synthesis.
The kinetics of this reduction of in vivo hepatic lipogenesis were identical after acute or chronic administration of (−)-hydroxycitrate.
However, in vitro rates of lipogenesis were elevated after chronic administration of (−)-hydroxycitrate for 30 days. Rats
receiving (−)-hydroxycitrate consumed less food than the untreated controls; however, this decreased caloric intake was not
responsible for the drug induced depression of hepatic lipogenesis, as shown by studies using pair fed rats.
This chapter discusses the stereochemistry and preparation of hydroxycitrate. In nonruminant mammals the acetyl-CoA used for lipogenesis is generated largely from citrate in a reaction catalyzed by ATP: citrate lyase. Hydroxycitrate is a competitive inhibitor of the reaction with respect to citrate. The de novo syntheses of long-chain fatty acids and 3-β-hydroxysterols are inhibited to about the same extent by hydroxycitrate. Both pathways are extramitochondrial and both use acetyl-CoA as a carbon source. In nonruminant mammals extramitochondrial acetyl-CoA is made predominantly via the citrate cleavage reaction. Hydroxycitrate can therefore be expected to inhibit both pathways. The degrees to which both pathways are inhibited will depend on the relative affinity of their acetyl-CoA-utilizing enzymes for acetyl-CoA. Metabolite analyses of perfused livers show that addition of either hydroxycitrate or oleate causes a crossover at the phosphofructokinase reaction. This indicates a slowing down of glycolysis, which is regulated through phosphofructokinase. It is found that ketone production by perfused livers from fed rats, which occurs at a considerably slower rate, is inhibited by hydroxycitrate.
Hydroxycitric acid, the active ingredient in the herbal compound Garcinia cambogia, competitively inhibits the extramitochondrial enzyme adenosine triphosphate-citrate (pro-3S)-lyase. As a citrate cleavage enzyme that may play an essential role in de novo lipogenesis inhibition, G cambogia is claimed to lower body weight and reduce fat mass in humans.
To evaluate the efficacy of G cambogia for body weight and fat mass loss in overweight human subjects.
Twelve-week randomized, double-blind, placebo-controlled trial.
Outpatient weight control research unit.
Overweight men and women subjects (mean body mass index [weight in kilograms divided by the square of height in meters], approximately 32 kg/m2).
Subjects were randomized to receive either active herbal compound (1500 mg of hydroxycitric acid per day) or placebo, and both groups were prescribed a high-fiber, low-energy diet. The treatment period was 12 weeks. Body weight was evaluated every other week and fat mass was measured at weeks 0 and 12.
Body weight change and fat mass change.
A total of 135 subjects were randomized to either active hydroxycitric acid (n = 66) or placebo (n = 69); 42 (64%) in the active hydroxycitric acid group and 42 (61%) in the placebo group completed 12 weeks of treatment (P = .74). Patients in both groups lost a significant amount of weight during the 12-week treatment period (P<.001); however, between-group weight loss differences were not statistically significant (mean [SD], 3.2 [3.3] kg vs 4.1 [3.9] kg; P = .14). There were no significant differences in estimated percentage of body fat mass loss between treatment groups, and the fraction of subject weight loss as fat was not influenced by treatment group.
Garcinia cambogia failed to produce significant weight loss and fat mass loss beyond that observed with placebo.
A method is described for measuring the acute blood glucose response to an insulin challenge which requires only 6 samples of 20 microl of blood collected over a 4 hour period. This evaluation of sensitivity to insulin was validated by comparing the effects of gliclazide, metformin and a novel antidiabetic imidazoline compound (S22068) on the blood glucose response. The test distinguished between the insulin-secreting and hypoglycaemic action of gliclazide and the insulin-sensitizing actions of metformin and S22068. The test has the advantage that it can be repeated in the same animal after a period of recovery and thus enables the overall sensitivity to insulin to be compared before and after acute or chronic dose regimes.