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Institute of Animal Sciences, Swiss Federal Institute of Technology, CH-8603 Schwerzenbach, Switzerland
3To whom correspondence should be addressed. E-mail: monika.leonhardt{at}inw.agrl.ethz.ch.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • hydroxycitrate • rats • metabolism • meal patterns
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,2
), a key step in lipogenesis. Sullivan and colleagues (1
,3
) demonstrated that oral administration of HCA dose-dependently depressed in vivo lipogenesis in liver, adipose tissue and intestine of rodents. HCA also suppressed food intake and decreased body weight gain (4
–6
) when rats were fed diets high in soluble carbohydrates, which stimulate lipogenesis. Most animal studies were performed with young and growing rats. Recently, however, we demonstrated that HCA also reduces food intake and body weight regain in adult rats after substantial body weight loss, and this effect was particularly strong when HCA was given with a high glucose diet that contained 12 g/100 g fat (7
). This model may be of benefit in human obesity because it demonstrates that HCA is effective in combination with a nutritionally relevant level of dietary fat (24% of energy as fat) and because maintenance of reduced body weight after weight loss is usually a greater problem than weight loss itself, which many obese people are able to achieve by rigorous dieting, exercise and pharmacologic treatment (8
,9
). Because de novo lipogenesis also occurs in humans, albeit at a low rate (10
,11
), substances that block fatty acid synthesis such as HCA might be useful in the prevention of body weight gain.
In our previous study (7
) the period of ad libitum consumption lasted only 10 d. It is unclear whether HCA affects food intake and body weight regain for longer periods, which would be a requirement for any potential therapeutic use. We addressed this question in the present study. In addition, we further characterized the suppressive effect of HCA on feeding by recording meal patterns and circadian distribution of intake in addition to cumulative intake and body weight regain. We also began to address the mechanism of action of HCA by administering it as part of two different diets varying mainly in fat content, and by examining the effect of HCA on several metabolic variables.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The protocols for these experiments were approved by the Kanton of Zurich’s Animal Use and Care Committee. Male Sprague-Dawley rats (founder rats from Charles River Germany were maintained as a breeding colony under specified pathogen–free conditions in our facility in Schwerzenbach, Switzerland) were housed individually in plastic cages with grated stainless steel floors. The floor area of the cages was 35 x 20 cm2. The colony room was maintained at 22 ± 2°C and 60% atmospheric humidity, with a 12-h light:dark cycle. Before the experiments, rats had ad libitum access to water and a pelleted rodent diet (No 3430, Provimi Kliba, Kaiseraugst, Switzerland).
Experimental design.
Two experiments were performed in 23 and 24 different rats for Experiments 1 and 2, respectively. The rats’ initial body weights in Experiments 1 and 2 were 663 ± 12 and 616 ± 7 g, respectively. In each of the two experiments, the rats were fed only 10 g powdered standard rodent diet (No. 890, Nafag, Gossau, Switzerland) per day for 10 d; they were then divided into two groups (n = 11 or 12) matched for body weight loss and body weight, and were finally given free access to one of two diets [Experiment 1: 1% (g/100 g) fat diet = 81% carbohydrate, 10% protein and 1% fat; Experiment 2: 12% (g/100 g) fat diet = 76% carbohydrate, 9% protein and 12% fat] (Table 1
) for the next 22 d. The diet of one group was always supplemented with 3 g/100 g HCA (85 mmol/kg diet; Table 1
). Rats were fed from spill-resistant feeding cups fixed on scales (PM 300, Mettler-Toledo, Greifensee, Switzerland). Food was available from the beginning of the dark phase for the next 22 h. During the last 2 h of the light phase, when access to food was prevented, rats were weighed (±1 g) and food cups were refilled. The weight of the food cups was recorded (±0.1 g) each 30 s by an Olivetti personal computer, using custom-made software (VZM, Software-Entwicklung Albert Krügel, Munich, Germany). Meals were defined as weight decreases 
0.3 g maintained for 1 min with a minimum intermeal interval of 15 min. VZM used this meal definition to record the number of meals and their size (g).
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Analytical procedures.
Glucose, lactate, triacylglycerol (TG), total cholesterol, HDL cholesterol, free fatty acids and ß-hydroxybutyrate (BHB) were determined by standard colorimetric and enzymatic methods adapted for the Cobas Mira autoanalyzer (Hoffman LaRoche, Basel, Switzerland). Insulin was determined by a commercially available RIA kit (Insulin RIA 100, Pharma Diagnostics AB, Uppsala, Sweden).
Fat was extracted from a liver sample with a mixture of isopropanol/hexane (2:3, v/v). Solvent was evaporated and then the sample was dried to constant weight. The difference in weight was expressed as total fat.
Liver glycogen content was determined as previously described (12
). Briefly, a pulverized liver sample was mixed with potassium hydroxide solution and boiled for 30 min. Then, ethanol was added and the sample was centrifuged for 20 min at 4°C and 2000 x g. The sediment was dissolved with hydrochloric acid and neutralized with sodium carbonate. The filtrate was then used for glucose determination by a standard enzymatic method adapted for the Cobas Mira autoanalyzer (Hoffman LaRoche).
Data analysis.
Body weight regain was analyzed by repeated-measures ANOVA with blocking (rats were matched by body weight loss). An ANOVA was performed to determine the effect of HCA on daily food intake, cumulative food intake during the dark and light phase and meal patterns during the light phase. The energy conversion ratio [cumulative body weight regain (g)/cumulative food intake (MJ)]) after 22 d of ad libitum consumption and blood and liver variables for the control and the HCA groups were compared using Student’s t test. In Experiment 2, one control rat had to be eliminated because we could not record reliable feeding data. Differences with P < 0.05 were considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Rats lost 72 ± 3 and 75 ± 2 g body weight during the 10 d of restrictive feeding in Experiments 1 and 2, respectively. HCA reduced body weight regain in rats fed both diets throughout the period of ad libitum consumption (Fig. 1
). In Experiment 1 (1% fat diet), the cumulative body weight regain in rats fed HCA was significantly less than in controls from ad libitum d 2 (control: 17 ± 1 g, HCA: 12 ± 1 g) until ad libitum d 22, when control and HCA rats had regained 70 ± 6 g and 48 ± 3 g of body weight, respectively (overall P < 0.01). Thus, HCA-fed rats regained only 68 ± 4% of the control group’s body weight regain. On ad libitum d 22, the control group had almost compensated the body weight loss (body weight loss: 72 ± 3 g, body weight regain 70 ± 6 g), whereas the HCA group had not (body weight loss: 73 ± 2 g, body weight regain 48 ± 3 g, P < 0.001). In Experiment 2 (12% fat diet; Fig. 1
), the difference in cumulative body weight regain between the control and HCA groups was significant beginning on ad libitum d 4; after 22 d, the control and HCA groups had regained 81 ± 7 and 49 ± 6 g, respectively (overall P < 0.01). The latter was 61 ± 8% of the control group’s body weight regain. As in Experiment 1, the control group had compensated the body weight loss on ad libitum d 22 (body weight loss: 75 ± 3 g, body weight regain 81 ± 7 g), whereas the HCA group (body weight loss: 75 ± 3 g, body weight regain 49 ± 6 g, P < 0.01) had not.
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). In this experiment, cumulative food intakes after 22 ad libitum days in the control group and the HCA group were 559 ± 18 g and 491 ± 8 g (P < 0.01), respectively. Thus, HCA-treated rats ate 88 ± 2% of the control group’s intake.
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B). Circadian distribution of food intake and meal patterns during the light phase of the second experiment (12% fat diet).
HCA had a long-term feeding suppressive effect only in combination with the 12% fat diet (Experiment 2; Fig. 2
A). During the first ad libitum days of this experiment, the reduction of food intake occurred predominately during the dark phase, whereas later on, HCA was more effective in suppressing food intake during the light phase (Fig. 3
). A reduction in the number of meals during the light phase markedly contributed to this effect (overall P < 0.05) (Fig. 4
). Meal size during the light phase was not different (Fig. 4)
between groups; in addition, meal patterns during the dark phase were not affected by HCA.
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HCA did not affect the plasma concentrations of BHB and glucose after ad libitum d 1 and 6 of Experiment 2 (12% fat diet). Nevertheless, at the end of this experiment, the HCA group had a significantly reduced plasma TG level (control: 2.13 ± 0.20 mmol/L; HCA: 1.63 ± 0.12mmol/L; P < 0.05) and a significantly greater hepatic fat concentration (control: 5.8 ± 0.2 g/100 g wet weight; HCA: 7.2 ± 0.6 g/100 g wet weight; P < 0.05). All of the other blood and liver variables examined were not affected by HCA. In Experiment 1 (1% fat diet), none of the metabolic variables (plasma glucose, lactate, triacylglycerol, HDL, free fatty acids, ß-hydroxybutyrate, and insulin, hepatic fat and glycogen concentrations) examined at the end of the experiment differed significantly between HCA and control rats (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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HCA reduced body weight regain in rats for at least 22 d of ad libitum consumption after body weight loss due to restricted feeding, and in combination with the 1 and 12% fat diets. In contrast to controls, the HCA-treated rats did not in fact fully compensate for the body weight loss due to restrictive feeding. This confirms and extends the data of our previous study in which HCA suppressed body weight regain for 10 d (7
). In other long-term studies, HCA also reduced body weight gain (6
,13
,14
). For example, in growing, meal-fed female rats, chronic administration of HCA for 30 d reduced body weight gain (4
). Similarly, feeding HCA for > 13 wk suppressed body weight gain in mature female rats, in gold thioglucose–induced obese mice and in ventromedial hypothalamic–lesioned obese rats (5
). Nevertheless, we show here for the first time that HCA causes a long-term reduction of body weight regain after substantial body weight loss (11–12%), even when food intake was not reduced (in rats fed the 1% fat diet). These results suggest that HCA increased energy expenditure. This is in line with the finding that HCA reduced the energy conversion ratio in both experiments. A decrease in the energy conversion ratio by HCA has been reported previously (7
,13
). Results from pair-feeding studies (6
) and measurements of energy expenditure (14
) further support the idea that HCA affects body weight gain by increasing energy expenditure. Nevertheless, HCA did not seem to increase energy expenditure in one pair-feeding study (15
). The mechanism underlying the effect of HCA on energy expenditure is unclear. HCA may increase energy expenditure in part by increasing glycogen deposition through the indirect pathway, i.e., through extrahepatic glycolysis followed by hepatic gluconeogenesis, which is thermogenic (16
,17
). A decreased absorption of energy due to the 3 g/100 g HCA in the diet, however, could also be an explanation for the reduced energy conversion ratio. These results may be interesting for weight maintenance in formerly obese humans. As already mentioned, many obese people can achieve body weight loss, but they are often unable to maintain their reduced body weight (8
). Yet, the relevance of the present findings for the treatment of human obesity remains unknown because in humans, de novo lipogenesis is small even after a large carbohydrate load (16
) and because the amount of HCA (3 g/100 g diet) we used was quite high.
Food intake, circadian distribution of food intake, meal patterns and metabolic variables.
HCA reduced daily food intake for the first ad libitum days in both experiments, but reduced food intake over the whole ad libitum period only when given as part of the 12% fat diet. These results are consistent with our previous findings but not with other reports (4
–6
,13
) of a long-term suppression of food intake by HCA in combination with a high glucose, low fat diet. Nevertheless, in most studies, rats were meal-fed, and young growing rats or female rats were used. These differences might account for the inconsistent results because it has been shown that young rats have a higher rate of de novo lipogenesis than old rats (18
) and because the rate of de novo lipogenesis of women in the follicular phase exceeds that of men (19
).
To the best of our knowledge, this is the first study that examined the effect of HCA on the circadian distribution of food intake and on meal patterns during the dark and light phases. In the second experiment (12% fat diet), during the first ad libitum days, HCA reduced cumulative food intake predominately during the dark phase, whereas later, food intake was reduced during the light phase. In this experiment, meal patterns during the dark phase did not differ, and the reduced food intake during the light phase was due to a reduction of meal number.
The anorectic mechanism of HCA is unknown. It is unlikely that it is due to a bad taste of the HCA diets because such sensory effects are usually transient and HCA also decreased food intake after intragastric infusion (4
). A formed taste aversion based on malaise caused by the effects of HCA on lipid metabolism is also an unlikely cause of the hypophagia because the only effect of HCA on lipid metabolism was to reduce plasma triglyceride level and to increase the liver lipid content. Conjugated linoleic acid also decreased plasma triglyceride level (20
) and increased liver lipid content (21
) without affecting food intake.
One hypothesis is that the suppressive effect of HCA on feeding is related to an increase in hepatic fatty acid oxidation (7
) due to a suppressed formation of the carnitine palmitoyltransferase I inhibitor malonyl CoA (22
). An enhanced oxidation of long-chain fatty acids by HCA has been shown in pancreatic beta cells (23
) and in skeletal muscle cells (24
). Animal and human studies indicate that hepatic fatty acid oxidation is involved in the metabolic control of food intake (25
,26
). One rat study showed that mercaptoacetate (MA), an inhibitor of mitochondrial fatty acid oxidation, enhanced food intake (25
) by shortening the intermeal interval, whereas meal size was unaffected (27
). In addition, the effect of MA on food intake was more pronounced during the light than during the dark phase (25
), presumably because in rats, fatty acid oxidation is quantitatively less important during the dark phase (28
), and when rats were fed a 36% fat energy diet (27
). Therefore, it is tempting to speculate that an increase in hepatic fatty acid oxidation will reduce food intake predominately during the light phase by a prolongation of intermeal interval (reduced number of meals) especially when rats consume a diet with a nutritionally relevant level of fat. The observations that HCA caused a long-term reduction of food intake only when given with the 12% fat diet, and that this reduction occurred predominately during the light phase and was characterized by a decreased meal number, are therefore in line with the hypothesis that HCA suppressed food intake by an increased hepatic fatty acid oxidation.
Yet, the fact that HCA did not affect the plasma BHB concentration in Experiment 2 after ad libitum d 1 and 6 as well as at the end of the experiment (on ad libitum d 24) argues against a role of an increased hepatic fatty acid oxidation in the suppressive effect of HCA on feeding. Nevertheless, Brunengraber et al. (29
, 30
) reported that HCA in perfused rat liver decreased, did not change or even increased ketone synthesis, depending on the rat’ s nutritional state and on the infused substances. Also, acetoacetate can be used for de novo lipogenesis when cytosolic acetyl-CoA levels are low (24
, 31
), as is to be expected in response to HCA. Thus, HCA could increase hepatic fatty acid oxidation without a substantial increase in plasma ketone body levels. This possibility should be examined.
Loftus et al. (32
) showed that systemic and intracerebroventricular administration of a fatty acid synthase inhibitor reduced feeding in mice, and this effect was accompanied by an increase in malonyl-CoA concentration in brain and liver. This finding does not agree with the idea that HCA inhibits feeding by reducing malonyl CoA and, hence, increasing hepatic fatty acid oxidation. All in all, further studies are necessary to identify the mechanism of the anorectic effect of HCA.
As already mentioned, in Experiment 2 (12% fat diet) HCA decreased plasma triacylglycerol levels and increased the liver fat concentration. It appears paradoxical that after 12 h of food deprivation, when presumably most of the circulating TG were synthesized by the liver, TG levels were reduced and at the same time liver fat concentration was increased. The liver uses mainly fatty acids originating from the diet and the adipose tissue to meet its own energy needs, whereas the fatty acids derived from hepatic de novo lipogenesis are secreted as TG in lipoproteins (mainly VLDL) into the circulation (33
). A decrease in circulating TG levels with a concomitant increase in liver fat is usually caused by substances that markedly inhibit VLDL secretion (34
). Thus, the present results suggest that HCA inhibits VLDL secretion in addition to fatty acid synthesis, and that the former effect can somehow prevail, causing hepatic fat accumulation. The findings concerning the effects of HCA on plasma triacylglycerols and liver lipids are inconsistent. In line with our results, Nageswara Rao and Sakariah (13
) reported a decrease of plasma TG and a tendency for increased liver fat content in rats after HCA administration in combination with high glucose diets. On the other hand, Chee et al. (15
) showed that HCA had no effect on plasma TG in rats, but it increased plasma TG and liver lipid content in chickens. The main difference between the two studies (13
,15
) was that different rat strains were used and the initial weight of the rats was markedly different. In addition, Sullivan et al. (35
) demonstrated that HCA reduced the fructose-induced increase in serum TG. Therefore, further studies should examine the HCA effect on VLDL formation and secretion as well as on hepatic lipid accumulation under various conditions. Also, it should be clarified whether the observed lipid accumulation causes liver damage.
In both experiments, HCA had no long-term effect on liver glycogen content. This is consistent with previous findings by others (17
), but different from results obtained in short-term studies showing that HCA increased the liver glycogen content (17
,36
). Possibly, in long-term studies, the animal adapts to the HCA effect by increasing glucose and glycogen turnover.
HCA did cause a long-term reduction of body weight regain in rats fed both 1 and 12% fat diets, but it had a long-term suppressive effect on food intake only when given as part of the 12% fat diet. The feeding suppressive effect seemed to depend on a certain amount of dietary fat, occurred predominately during the light phase and was due to a reduction of meal numbers during the light phase. The fact that HCA did not affect plasma BHB levels does not support the hypothesis that increased hepatic fatty acid oxidation is involved in the food intake suppression by HCA.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by Novartis, Switzerland.
4 Abbreviations used: BHB, ß-hydroxybutyrate; HCA, hydroxycitrate; MA, mercaptoacetate; TG, triacylglycerol.
Manuscript received 8 November 2001. Initial review completed 20 December 2001. Revision accepted 11 April 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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P < 0.001.
