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Introduction
   The reputed effects of hydroxycitrate are based on its action as a potent inhibitor of the enzyme ATP citrate lyase (also known as citrate cleavage enzyme), which is required for the synthesis of fatty acids. The enzyme takes citrate, which has been exported from the mitochondria to the cytoplasm, and forms acetyl CoA and oxaloacetate from it. Coincidentally, this inhibitory effect was discovered in the laboratory of my Ph.D. mentor, Dr. John M. Lowenstein of Brandeis University (1). (Although my own research project did not involve hydroxycitrate, I can remember it being used in other ongoing studies in the Lowenstein laboratory while I was there in the 1970's.) Lowenstein has followed recent developments in the use of his discovery with great interest, and has shared his observations with me; some of his conclusions are presented in this article.
In the preparation of this article I am also indebted to Larry S. Hobbs, who devoted a chapter of his book The New Diet Pills (Pragmatic Press, 1994) to hydroxycitrate (2). Hobbs has corresponded extensively with the major researchers and promoters of hydroxycitrate, and has provided me with a considerable amount of information on the subject.
   Thomas J. Wheeler, Ph.D. is an Associate Professor of Biochemistry at the University of Louisville.

A Literature Review
   In mid-1995 I performed a search of the medical literature (Medline, National Library of Medicine) covering the period 1983 through May 1995, looking at the key words "hydroxycitrate," "hydroxycitric," "garcinia," and "cambogia." There were no articles found for "cambogia," and those obtained for "garcinia" all dealt with species other than cambogia and with compounds other than hydroxycitrate. References obtained for the keywords "hydroxycitrate" and "hydroxycitric" were nearly all to papers in which the compound was used as a research tool to manipulate metabolism in experimental animals or cell preparations. The only clinical study was a Russian-language article whose translated title was "Treatment of Patients with Food Toxinfection in Middle and Old Age."
   Thus, there were no studies in the regular medical literature documenting the usefulness of the compound for weight loss in humans.
Of the other papers identified in the search, two (3, 4) were review articles coauthored by Ann C. Sullivan of Hoffman-LaRoche, Inc., who was involved in many of the early animal studies. (Hoffman-LaRoche began studying the compound in the 1970's and held several related patents.) These articles, dealing with the general topic of appetite regulation by drugs and other compounds, summarized the results obtained with hydroxycitrate in animals (rats, mice, chickens). The authors proposed that hydroxycitrate acted primarily through its effects on the appetite, possibly involving increases in glycogen levels (see below).
   The other two articles were published in the journal Medical Hypotheses. One of these (5) briefly discussed the animal studies and described the presence of HCA in fruits of Garcinia species. It also mentioned, with no documentation of methodology, the author's personal success in using the compound for weight loss (claimed to be "about one pound per day without any dieting" and accompanied by "sustained increase in energy").
   The second of these (6) was a much longer article by Mark McCarty. He is vice-president of Nutrition 21, which manufactures chromium picolinate. The article reviewed theories of appetite control, as well as effects of hydroxycitrate and their possible mechanisms (see below). The author proposed that HCA might be combined with carnitine for a weight-loss program, the latter because of its alleged ability to promote fat oxidation - even though he acknowledged "a lack of clinical studies demonstrating its efficacy" in weight loss.
   He further proposed that the addition of chromium picolinate to a hydroxycitrate/carnitine mixture would be even better. A review of this popular "health food" item is beyond the scope of this article, but a recent critical review (7) gave reasons to be skeptical of the value of chromium supplements. For one thing, it is difficult to determine whether anyone is chromium deficient, and people who aren't deficient will not benefit from supplements.
   Also, clinical results supporting the use of chromium in reducing fat have not been replicated. In November, 1996, the Federal Trade Commission announced consent agreements with Nutrition 21 and two other marketers of chromium picolinate. The companies had been charged with making unsupported claims about the benefits of chromium.
   During final preparation of this article (December, 1996) I updated my literature search. The only new articles relevant to HCA supplements were three more by McCarty in Medical Hypotheses (8-10). These develop further the ideas that HCA may be useful in promoting fat oxidation and gluconeogenesis (see below).

Possible Modes of Action
   While the ability of hydroxycitrate to block ATP citrate lyase, and therefore fatty acid synthesis, has been established in experimental animals, this alone would not be expected to produce weight loss. First, calories consumed in one form (say, carbohydrates) would not simply disappear because they couldn't be converted to fat; they would be directed to other metabolic pathways (for example, storage as glycogen). Secondly, the major problem in obesity is not that too much fat is synthesized; rather, too much is consumed in the diet.
   Nevertheless, studies with rats and mice indicate that hydroxycitrate decreases weight gain. (It should be noted that unlike the adult humans for whom the compound is being promoted, these animals continue to grow throughout their life spans. Thus, it was a decrease in weight gain, rather than a loss of weight, which was measured. This difference in growth patterns emphasizes the need for human studies to confirm the effectiveness of the compound.)
   The most likely mechanism for the decreased weight gain seems to be a decrease in appetite (and animals consuming the compound do eat less), but the mechanism by which hydroxycitrate produces such an effect is unclear. One suggestion is that hydroxycitrate would divert calories toward the synthesis of liver glycogen (a polymer of glucose). Animal studies support increased gluconeogenesis (synthesis of glucose from compounds such as lactate and amino acids) and glycogen synthesis in response to HCA.
     The resulting increased glycogen, or possibly glucose itself, might then be involved in the satiety signal. However, there is no general agreement on how appetite is controlled, and some experts in the field reject the idea that glycogen is involved. (Related to glycogen, it has been suggested (11) that the increased glycogen could help maintain blood sugar, leading to an increased feeling of "energy," "for those with glycogen storage problems."
   Since the synthesis and breakdown of glycogen, as well as other pathways controlling the level of blood glucose, are highly regulated processes, there would appear to be no advantage in this respect for normal individuals.)
   A second suggested mode of action is that hydroxycitrate somehow increases thermogenesis (metabolism of fat or other compounds to produce heat rather than metabolic energy in the form of ATP). Normally, cells only consume fuels when needed to produce ATP; otherwise, the fuels are converted to stored energy in the form of fat or glycogen. However, in brown adipose tissue (brown fat), there is a type of fat consumption in which calories are converted to heat without producing ATP.
   I am unaware of any reason to think that hydroxycitrate would regulate this process. However, McCarty (6) advances the thermogenesis hypothesis based on comparisons of reduced weight gain in experimental animals to the reduced food intake, which suggests that extra calories were being disposed of in some way.
   McCarty also suggests that other metabolic effects could contribute to wasting of ATP, and therefore extra consumption of calories in the presence of hydroxycitrate. For example, gluconeogenesis consumes ATP energy, and if molecules are converted to glucose (and glycogen) rather than to fat, this would consume ATP. This seems unlikely to me.
   First, there is only a limited capacity for taking up extra carbohydrate in glycogen, so this would not produce much long-term effect on weight.
   Second, this pathway is also limited by the body's natural regulatory mechanisms; a rise in blood glucose would trigger release of insulin, and this in turn should inhibit gluconeogenesis.
   Third, converting the pyruvate to glucose would consume less ATP than converting it to fat (the process blocked by hydroxycitrate). (Clouatre and Rosenbaum (11) assert that the inhibition of ATP citrate lyase by HCA "uses up a significant amount of energy," but provide no rationale for this claim.)
   It has also been suggested (6) that HCA, since it inhibits the formation of acetyl CoA in the cytoplasm, would also inhibit the formation of the next compound in the pathway of fatty acid synthesis, malonyl CoA. Malonyl CoA is in turn an inhibitor of the enzyme carnitine acyltransferase, which is needed for oxidation of fat. Therefore, reducing malonyl CoA formation with HCA might stimulate fat metabolism (along this same line of reasoning, provision of carnitine is also proposed to enhance fat metabolism, so that McCarty (6) advocates joint administration of HCA and carnitine).
   However, as noted above, cells normally only metabolize fuels when they need to produce energy, so if more calories in the form of fat are being consumed, fewer carbohydrate calories will be disposed of. The shift in the relative use of carbohydrate and fat would not by itself result in weight loss unless the resulting increased carbohydrate levels cause a decrease in appetite, as discussed above.

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