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* Department of Health and Nutrition Sciences and
Department of Psychology, Brooklyn College of the City University of New York, Brooklyn, NY 11210
3To whom correspondence should be addressed. E-mail: kaxen{at}brooklyn.cuny.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • dietary fat • obesity • energy restriction • Syndrome X
Diets with very low carbohydrate (<20% of energy), and therefore high fat, contents are advertised to the public, commercially and through mass media, for loss of body weight and improvement in health. Although high fat, low carbohydrate diets are claimed to lower risk factors for cardiovascular disease and type 2 diabetes (1,2), the American Diabetes Association (3) and the American Heart Association (4) recommend low fat, high complex carbohydrate intakes. Despite their contraindication for individuals at risk for obesity-related diseases, the use of high fat, low carbohydrate diets is widespread. Furthermore, there is lack of agreement on the effects of such diets on insulin resistance and dyslipidemia (5–8). These conditions, along with hypertension and abdominal obesity, are included in an aggregate of metabolic risk factors for cardiovascular disease and type 2 diabetes, known as metabolic Syndrome X (9,10).
Adherence to a high fat, low carbohydrate diet, like any dietary change, may affect physiologic function and health through a variety of alterations in an individual’s nutritional state. These alterations may include a decrease in energy intake, a decrease in sucrose intake, an increase in protein intake, and a change in the amounts and/or ratios of saturated, monounsaturated, and (n-3) and (n-6) PUFA. Furthermore, weight loss itself, independent of diet composition, has an effect on disease risk (11). Any of these changes, alone or in combination, can potentially alter biomarkers of diabetes and cardiovascular disease (12).
Although high fat, low carbohydrate diets, without restriction of energy intake, are promoted as weight loss regimens, rats that consume high fat, low carbohydrate diets ad libitum generally become obese (13,14). Therefore, to evaluate the effect of such a diet on Syndome X in rats, we restricted intake of a high fat (60% of energy), low carbohydrate (15% of energy) diet, in lean and obese rats, to a level that would prevent excessive weight gain. The level of energy restriction was designed to support normal weight gain in growing rats, not to produce weight loss, so that the effects of diet composition could be examined apart from those of weight loss. This design mimics the use of high fat, low carbohydrate diets to slow weight gain by growing obese or nonobese adolescents. As a control for the effects of low energy intake, comparisons were made using lean rats that consumed restricted amounts of a low fat, high carbohydrate diet. An essential feature of the study was the constancy of the type of fat and the protein level, as well as the virtual absence of sucrose in the diets, to control for their effects on blood levels of insulin and lipids (15) and glucose tolerance (16).
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Phase 1.
Male Sprague-Dawley rats (n = 24, age 6–7 wk, Charles River Laboratories, Wilmington MA) were individually housed in mesh-bottomed cages at 20–22°C, with a 12-h light:dark cycle. Rats were separated into two weight-matched groups; one group was fed a low fat (LF; 45 g fat/kg of diet, Table 1) high carbohydrate diet (13.8 kJ/g, 3.3 kcal/g) of Purina 5001 pellets (PMI Feeds, St. Louis, MO), and the other group was fed a high fat (HF; 347 g fat/kg diet) low carbohydrate diet (22.6 kJ/g, 5.4 kcal/g). The HF diet was comprised of powdered Purina 5001 and hydrogenated vegetable fat (Proctor & Gamble, Cincinnati OH), with casein, L-methionine, AIN vitamin mix, and AIN mineral mix (Bio-serv, Frenchtown, NJ) (17) added to provide equivalent protein concentrations (LF, 234 g/kg diet; HF, 331 g/kg diet) and equivalent vitamin and mineral contents for the two diets. The hydrogenated vegetable fat contained 
25% long-chain saturated, 44% monounsaturated and 28% PUFA, with 17% of total fat as trans fatty acids (manufacturer’s communication). This high fat, low carbohydrate diet was used because of the more pronounced obesity it has produced in rats in our laboratory than have several commercial high fat diets. Food and water were consumed ad libitum by all rats for 4 wk in Phase 1.
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In vivo measurements.
Food intakes, corrected for spillage, were measured twice a week; body weights were recorded once a week. During wk 4 of Phase 1, 6 HF and 6 LF rats were deprived of food for 16 h overnight before blood sampling; in Phase 2, these rats were evenly distributed among the four groups. Plasma samples, obtained from the tail, were analyzed for glucose, insulin and free fatty acid concentrations. These 12 rats, after overnight food deprivation on a separate day, were given an intraperitoneal (ip) injection of glucose (1 g/kg body weight, 50 g/100 mL solution); plasma was obtained preinjection and 15, 30 and 90 min postinjection for glucose determination. During wk 9 of the study (Phase 2), all 24 rats were subjected to collection of plasma in the food-deprived state as well as during an ip glucose tolerance test.
At the end of Phase 2 (wk 10–12 of the study), fed rats were anesthetized by ip injection with a mixture of ketamine (63 mg/kg) and xylazine (9.4 mg/kg) (Butler, Columbus OH). Pancreases were removed for isolation of islets by collagenase (Sigma, St. Louis MO) digestion (18). Blood obtained from the aorta was used for determination of plasma insulin and triglyceride levels; anesthetized rats were killed by exsanguination. Livers were excised and samples were stored at -80°C for later lipid measurement. Fat pads from three visceral fat regions (epidydimal, retroperitoneal + perirenal, and mesenteric + omental) were dissected from the rats. The mean age was the same for all groups at the end of the experiment.
In vitro measurements.
Pancreatic islets (50/chamber) were preincubated for 30 min at 3 mmol/L glucose in Krebs-Ringer bicarbonate buffer under 95% O2:5% CO2 at 37°C. Islets were perifused at a rate of 1 mL/min with 3 mmol/L glucose for 20 min. Samples of effluent were collected each minute and stored at -80°C for insulin assay.
Analyses.
Plasma insulin was measured using a double antibody RIA kit specific for rat insulin (Linco, St. Charles MO); a kit with human standard was used for perifusate samples (DPC, Los Angeles CA). Plasma free fatty acid concentration was assayed using a NEFA C kit (Wako, Richmond VA); plasma triglyceride level was measured using a GPO-Trinder kit (Sigma, St. Louis MO); plasma glucose levels were measured utilizing a YSI Biochemistry Analyzer (YSI, Yellow Springs OH); and liver lipid was extracted with chloroform-methanol (19). Statistical analyses were performed by ANOVA and the Newman-Keuls post-hoc test (Crunch 4, Crunch Software, Oakland, CA); differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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During Phase 1, rats consumed more energy from the HF than the LF diet (Fig. 1, P < 0.001), resulting in higher body weights in HF rats by wk 3 (Fig. 2, P < 0.002). During Phase 2, the food intake of rats continuing to consume HF ad libitum was highest, whereas intakes of the two groups consuming restricted amounts of HF (HFa-HFr and LFa-HFr) did not differ from one another but, by design, were lower than HFa-HFa; that of the LF rats consuming restricted amounts of LF (LFa-LFr) was lowest (P < 0.001). Although all groups of energy-restricted rats were given an amount of food providing the same amount of energy per day (equal to 90% of ad libitum LF consumption in Phase 1), the LFa-LFr group did not finish its daily ration. During Phase 2, rats in all groups continued to grow, and in the early part of Phase 2 (until wk 7 of the study), body weights generally reflected the previous diet (Fig. 2, effect of group according to Phase 1 diet, P < 0.01). However, by wk 9 of the study, body weights of the four groups paralleled the relationship for food intake (P < 0.01).
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Fat pad weight.
Visceral fat pad weights, analyzed either as individual pads or as the sum of the pads, were highest in HFa-HFa rats, intermediate and equivalent in the two groups consuming restricted HF intakes (HFa-HFr and LFa-HFr) despite different diets in Phase 1, and lowest in the group consuming restricted LF intake (P < 0.001, Fig. 3). The percentage of carcass weight due to these visceral pads followed the same pattern among groups (P < 0.001), with 9% of total body weight represented as dissected visceral fat mass in HFa-HFa, 6% in either HFa-HFr or LFa-HFr and 3% in LFa-LFr. The relationship among the weights of the individual pads was consistent among diet groups, with retroperitoneal-perirenal > epididymal > mesenteric-omental (P < 0.0001).
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Plasma glucose and insulin levels did not differ at wk 4 (end of Phase 1) between HF and LF rats in the fed or food-deprived states (Table 2). Plasma glucose levels in the fed or food-deprived states did not differ among the four groups at wk 9 (end of Phase 2). In the subset of rats for which samples were taken for glucose measurement in both Phases 1 and 2 (3 rats/Phase 2 group), plasma glucose levels in food-deprived rats did not change with time. However, plasma glucose levels of fed rats decreased (P < 0.05) from Phase 1 to Phase 2 in all groups except the lean group that consumed the energy-restricted, high fat diet in Phase 2 (LFa-HFr). Although plasma insulin levels in the fed state did not differ significantly among the four groups at the end of Phase 2, rats that had consumed HF during Phase 1 (HFa-HFa and HFa-HFr) had higher plasma insulin levels in the food-deprived state than did rats that had consumed LF (LFa-HFr and LFa-LFr) during Phase 1 (P < 0.02). Restriction of intake of the HF diet in obese rats did not lower their hyperinsulinemia in the fed or food-deprived state.
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Plasma free fatty acid concentration, measured after 16 h of food deprivation, did not differ among groups in either Phase 1 or Phase 2. Although plasma triglyceride levels of fed rats did not differ among the four diet groups at the end of Phase 2 (Table 2), when rats were grouped by their Phase 1 diet, plasma triglyceride levels were higher in rats fed HF (HFa-HFa and HFa-HFr) than in those fed LF (LFa-HFr and LFa-LFr) during Phase 1 (P < 0.03).
Total liver lipid content was higher in HFa-HFa and LFa-HFr rats (1.64 ± 0.19 and 1.57 ± 0.29 g; means ± SEM) compared with LFa-LFr (0.76 ± 0.07 g, P < 0.05), but liver lipid content of HFa-HFr (1.13 ± 0.23 g) did not differ from that of any other group. Liver lipid concentrations did not differ between HFa-HFa and LFa-HFr rats (0.10 ± 0.01 and 0.11 ± 0.02 mg/mg of liver) but were higher than those in HFa-HFr and LFa-LFr rats (0.08 ± 0.01 and 0.06 ± 0.01 mg/mg liver) (P < 0.01); livers of HFa-HFa rats were also heavier than those of LFa-LFr rats (17.03 ± 1.03 vs. 13.39 ± 0.64 g, P < 0.05).
In vitro insulin release.
Basal (3 mmol/L glucose) insulin release of isolated islets differed among groups (P < 0.002). Islets of HFa-HFa rats had higher secretion (295 ± 64 pmol/L, mean ± SEM) than those of LFa-HFr (172 ± 33 pmol/L) or LFa-LFr (102 ± 33 pmol/L) rats (P < 0.05); insulin release by HFa-HFr islets (185 ± 30 pmol/L) did not differ from that of any other group.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Ad libitum consumption of the high fat, low carbohydrate (HF) diet produced obesity during Phase 1; rats that continued to consume the HF diet ad libitum throughout the study had the greatest visceral fat pad mass, largest livers, highest liver lipid content, and the highest basal insulin release by their isolated islets. Similar high fat, low carbohydrate, sucrose-free diets have been shown to produce obesity (13,14) and insulin resistance (20) and in vitro basal hypersecretion of insulin (21) in rodents.
Human subjects consuming 20% of their energy intake as trans fatty acids have been shown to exhibit insulin resistance (22). Because 10% of the energy of the HF diet used in the present study was provided by trans fatty acids, they may have contributed to the diet’s effect on Syndrome X. It has been estimated that trans fatty acid intakes in the general population range from 3 to 7% of total fat intake (23) compared with 17% for rats consuming the HF diet. Although the actual trans fatty acid intake of people consuming high fat, low carbohydrate diets is not known, the shortening, oils, peanut butter and a variety of prepared foods that are permitted by these regimens would be expected to contribute to trans fatty acid intake.
The ratio of polyunsaturated to saturated fatty acids (P/S) in the HF diet was 1, a ratio that is recommended by the American Heart Association (4) for moderate (30% of energy) fat intakes. The P/S ratio of the HF diet matches (24) or exceeds (1) that reported for popular high fat, low carbohydrates diets. Like these diets, the total saturated fat content of the HF diet exceeded the recommended 10% of total energy intake. The HF diet was low in (n-3) PUFA, which may mitigate the atherogenic effects of a high fat diet (25).
Effect of energy-restricted HF diet on obese rats.
Compared with ad libitum HF intake, restriction of HF intake slowed the rate of weight gain by 30%. The mean weight gain of the rats was reduced from 31 to 24 g/wk. This latter rate of gain agrees with that predicted by the supplier for male rats of the same age and strain consuming a standard diet (Charles River Laboratories), indicating that the dietary restriction prevented weight gain in excess of normal growth.
Restriction of HF intake in rats previously consuming HF ad libitum decreased visceral fat mass, liver lipid content, and basal in vitro hypersecretion of insulin compared with that of rats continuing to consume the HF diet ad libitum. However, restriction of intake of the HF diet in rats failed to lower their elevated plasma insulin levels in the food-deprived state or plasma triglyceride levels in the fed state, or to diminish glucose intolerance, all of which are major features of Syndrome X. Although dietary fiber intake was higher in HFa-HFa rats compared with that of rats with restricted HF intake (HFa-HFr), it could not offset the effects of greater fat or energy intake; a high fiber diet has been reported to lower plasma insulin and postprandial glucose levels in obese rats (26).
Energy-restricted high fat, low carbohydrate diets that cause body weight loss have been reported to lower plasma glucose in food-deprived obese mice (27), as well as insulin (14) and triglyceride (28) levels, although these results are not observed consistently (14,27,29). At the same level of weight loss, however, a low fat diet has been shown to have a greater effect than a high fat diet in improving features of Syndrome X in rats (27). In human subjects, isoenergetic high fat diets have been reported to promote hyperinsulinemia (7) and insulin resistance (5); a high fat diet that yielded weight loss was reported to lower plasma insulin and triglyceride levels (6). These studies collectively support the importance of weight loss and not a high fat diet in lowering risk factors associated with Syndrome X.
In the present study, a mildly restricted level of intake (90% of previous ad libitum consumption of LF) of the high fat, low carbohydrate, sucrose-free (2% of energy) diet by growing rats failed to produce the improvements in Syndrome X promised in the popular literature (1,2). The percentage of energy consumed as fat was within the range of 50–66% reported for people self-selecting such diets (1,8,24). A 4- to 6-wk period of dietary change (Phase 2) represents 4% of the rat’s 2.5 y life-span and thus would correspond to a substantial period of dieting in humans.
Effect of the energy-restricted HF diet on lean rats.
Consumption of the energy-restricted HF diet during Phase 2 by either obese (HFa-HFr) or lean (LFa-HFr) rats resulted in the same visceral fat pad mass, which was greater than that of the lean rats consuming the energy-restricted LF diet (LFa-LFr). Although LFa-HFr rats initially gained weight at a slower rate than did HFa-HFr for the first half of Phase 2, they had an increased rate of weight gain later in Phase 2 (Fig. 2). Because visceral fat pad weights of the two groups were similar at the end of the experiment, there appears to have been an adaptation to the diet. Lean rats fed high fat (48% of energy), sucrose-containing diets for 6 wk in an amount restricted to match that of low fat-fed controls have been shown to have increased visceral adiposity vs. lower fat-fed rats (30), supporting the idea that diet composition and not simply energy intake influences fat deposition. Plasma glucose and insulin levels of fed rats in that study did not differ among groups with differing visceral fat mass. In the present study, LFa-HFr rats were the only group that did not have a significant decrease in plasma glucose level in the fed state between Phases 1 and 2; this decrease could have been an effect of age or handling. The lack of such an effect in LFa-HFr rats in the fed state suggests that despite lower carbohydrate intake, their increased fat intake during Phase 2 may have made this group more insulin resistant.
Rats consuming the LF diet during Phase 1 (LFa-HFr and LFa-LFr) did not differ in body weight until wk 8 when the glucose tolerance test was administered; thus, they received the same amount of glucose. All rats consuming HF diets in Phase 2, including LFa-HFr, had elevated plasma glucose levels 15 and 30 min after the glucose load compared with LFa-LFr and with their own Phase 1 results, whereas the plasma glucose response of the LFa-LFr group did not differ from the LF response in Phase 1. These findings indicate that even a restricted intake of the high fat, low carbohydrate diet impairs glucose tolerance in lean rats. Because insulin levels among groups did not differ at 15 min, all three groups of HF-fed rats, including lean rats fed the energy-restricted HF diet, were relatively insulin resistant.
Regardless of diet or body weight in Phase 1, consumption of the HF diet in Phase 2 was associated with a higher liver lipid content. The group originally consuming the LF diet in Phase 1 but fed the restricted HF diet in Phase 2 (LFa-HFr) had a high liver lipid concentration similar to that of HFa-HFa rats at the end of the study. In contrast, fed LFa-HFr rats had lower plasma triglyceride levels than those of HFa-HFa rats. These observations suggest that there is a period of adaptation to the HF diet, even at restricted intake, in which uptake of dietary fat from the blood is still high (providing lower plasma triglyceride levels in fed rats), whereas export or suppression of hepatic triglyceride synthesis still may be low, thereby elevating hepatic lipid concentration.
Effect of fat content of energy-restricted diet on lean rats.
Restricted feeding of the LF diet to rats previously consuming the LF diet ad libitum produced the lowest body weights at the end of the study and the lowest fat pad masses. This group (LFa-LFr) consumed less food than the other diet-restricted groups, although they were provided with the same amount of energy, apparently because of their lower acceptance of the powdered version of the LF diet.
Consumption of the LF diet during Phase 2 permitted lean rats to maintain their normal glucose tolerance (unchanged from Phase 1). In contrast, lean rats consuming the restricted HF diet in Phase 2 had impaired glucose tolerance, even though all lean rats weighed the same at the time of the test. The LFa-LFr rats had the lowest basal insulin release in vitro or in vivo, along with normal glucose levels, suggesting higher insulin sensitivity than the HF diet groups.
The impaired glucose tolerance and insulin resistance of LFa-HFr rats were associated with increased visceral fat mass, as well as an elevated liver lipid content compared with LFa-LFr rats. This association is consistent with the characteristics of Syndrome X (9). The energy-restricted high fat, low carbohydrate diet produced higher values in lean rats for these indices of disease risk than did the energy-restricted low fat, high carbohydrate diet.
In summary, restricted feeding of a high fat, sucrose-free, low carbohydrate diet failed to improve a number of features of Syndrome X in obese rats, despite a significant slowing of weight gain. In addition, the same dietary regimen increased the level of disease risk factors in growing lean rats, including visceral fat mass, glucose intolerance and liver lipid content. These findings support the conclusion that, in the absence of weight loss, a high fat, low carbohydrate diet not only may be ineffective in decreasing risk factors for cardiovascular disease and type 2 diabetes but may promote the development of disease in previously lower risk, nonobese individuals.
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FOOTNOTES |
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2 Supported by PSC-CUNY Research Award 669238.
4 Abbreviations used: HF, high fat; HFa, high fat consumed ad libitum; HFr, high fat consumed in restricted amounts; ip, intraperitoneal; LF, low fat; LFa, low fat consumed ad libitum; LFr, low fat consumed in restricted amounts.
Manuscript received 1 November 2002. Initial review completed 2 January 2003. Revision accepted 12 March 2003.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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