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University of Washington School of Medicine, Veterans Affairs Puget Sound Health Care System, and Harborview Medical Center (D.S.W., D.E.C., P.D.N., P.A.B., R.S.F., C.C.M., H.S.C.), Seattle, Washington 98104; and Oregon Health and Science University (J.Q.P.), Portland, Oregon 97201
Address all correspondence and requests for reprints to: David S. Weigle, M.D., Endocrinology, Box 359757, Harborview Medical Center, 325 Ninth Avenue, Seattle, Washington 98104. E-mail: weigle{at}u.washington.edu.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Recent evidence suggests that circulating ghrelin may work in concert with leptin as an adiposity signal in the CNS. Ghrelin, the endogenous ligand for the GH secretagogue receptor, is an acylated peptide secreted into the bloodstream primarily by the stomach (9, 10). Ghrelin rapidly stimulates food intake in both rats (11, 12, 13) and humans (14) when administered peripherally in doses that produce physiological increments in plasma levels. Loss of body fat mass due to cancer (15), cardiac cachexia (16), or anorexia nervosa (17, 18) is associated with increased circulating ghrelin levels. We have recently shown that hypocaloric diet-induced weight loss produces a coordinated decrease in plasma leptin levels and increase in plasma ghrelin levels (19). These changes in peripheral adiposity signals could help to explain the robust compensatory increase in appetite that contributes to the poor long-term maintenance of weight loss achieved by caloric restriction.
Reducing dietary fat intake without intentionally restricting energy intake may also bring about weight loss. In contrast to individuals on a hypocaloric diet, subjects consuming an ad libitum low fat diet generally experience a reduction in fat mass without increased hunger (20, 21, 22, 23). It is possible that dietary fat restriction produces weight loss by increasing CNS sensitivity to leptin, allowing energy intake, adipose mass, and leptin levels to fall without a compensatory increase in appetite. This possibility is supported by animal data showing that high fat diets promote leptin resistance and that a reduction of dietary fat intake restores normal leptin action in the CNS (24, 25, 26, 27).
An alternative possibility is that dietary fat restriction produces weight loss by increasing circulating leptin levels, thereby delivering a stronger satiety message to the CNS and reducing energy intake. This possibility is supported by a study in which human subjects were placed on diets containing either 60% or 20% of total calories as fat during alternate 24-h periods (28). Fat calories were replaced by carbohydrate calories on the low fat diet, and protein content was held constant. The authors of this study found that the proportional rise of plasma leptin levels above baseline over the course of the study was greater on the 20% fat diet and speculated that increased amplitude of the leptin signal, if sustained, could contribute to weight loss following dietary fat restriction.
The goal of the present study was to determine whether dietary fat reduction for periods greater than 24 h leads to weight loss by increasing plasma leptin levels or by a mechanism more consistent with increased leptin sensitivity in the CNS. A secondary goal of the study was to determine whether subjects who lose weight on a low fat diet experience the same increase in circulating ghrelin levels as subjects who lose weight by caloric restriction. Fat intake was decreased from the level present in the typical American diet to a level that is often employed in obesity therapy. Volunteers were studied both under weight-stable conditions and during spontaneous weight loss while consuming the low fat diet to satiety.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eighteen healthy adults were recruited by newspaper advertisement. The median age of the subjects was 48 yr, and their characteristics at the time of enrollment are summarized in Table 1
. All subjects were weight-stable for at least 3 months before enrollment and at their lifetime maximal weight. Exclusion criteria included body mass index greater than 30 kg/m2, regular aerobic exercise (>30 min, three times per week), tobacco use, consumption of more than two alcoholic beverages per day, and the presence of diabetes, chronic medical illness, or pregnancy. Prospective subjects were informed that this was not a weight reduction study and were not enrolled if they expressed a desire to lose weight. Subjects provided informed written consent before enrollment. All procedures and meal preparation took place at the General Clinical Research Center (GCRC), and the protocol was approved by the human subjects review committee of University of Washington.
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After enrollment, subjects completed a 3-d food record and were interviewed by a GCRC dietitian. Individuals were excluded from the study at this point if they typically consumed a diet containing >55% or <35% of total calories from carbohydrate. Subjects were then placed for 2 wk on a baseline, moderate fat diet consisting of 35% of total daily energy as fat, 45% as carbohydrate, and 20% as protein. All meals were prepared in the Nutrition Research Kitchen of the GCRC and consisted of typical foods found in a mixed American diet (29). A 3-d cycle menu was used, with the macronutrient distribution provided over the course of each day. Subjects visited the GCRC twice weekly to be weighed, meet with the dietitian, and pick up frozen prepared meals for the next 3 or 4 d. Subjects maintained a daily log recording all food items consumed. Subjects were instructed to eat all food items, and daily caloric intake was adjusted to stabilize body weight to within 1.0 kg of baseline weight. On the last day of this 2-wk period, subjects were admitted to the GCRC (visit CRC1) where an iv catheter was placed, and the study diet for that day of the cycle was administered in three meals given at 0800, 1200, and 1730 h, with a snack at 2000 h. Blood was drawn into EDTA tubes at 30-min intervals from 0800–2100 h and then hourly until 0800 h the next morning, at which time subjects were discharged from the GCRC. Plasma was separated and stored at -70 C.
During the 2 wk immediately following CRC1, subjects were placed on a low fat, high carbohydrate, isocaloric diet consisting of 15% fat, 65% carbohydrate, and 20% protein, with a 3-d cycle menu. Daily caloric intake was fixed at the level resulting in a stable weight on the baseline diet, and subjects were instructed to eat all food provided. Subjects continued to keep a daily food log and visit the GCRC twice weekly to meet with a dietitian, be weighed, and pick up meals for the next 3 or 4 d. Subjects were readmitted to the GCRC (visit CRC2) on the last day of this 2-wk period. The study diet for that day of the cycle was provided, and blood was sampled as during CRC1. All subjects underwent body composition assessment by dual energy x-ray absorptiometry (DEXA) scanning.
After discharge from CRC2, the dietary macronutrient distribution remained fixed at 15% fat, 65% carbohydrate, and 20% protein; however, subjects were instructed to eat only as much of the diet as they wished (ad libitum phase). Specifically, they were told to eat when hungry, stop eating when satisfied, and avoid making any conscious effort to modify food intake, physical activity, or body weight. Three additional menu days were added to those of the second dietary period to provide a 6-d cycle menu. Sufficient food was provided on this ad libitum 15% fat diet to allow subjects to consume up to 15% more than their weight-maintaining daily caloric intake. Subjects maintained the same daily food logs and twice weekly GCRC visits described above. At each GCRC visit subjects returned their food log, which included appetite questions, and all uneaten food items from the previous visit to permit accurate determination of the number of daily calories and macronutrients actually consumed. Particular attention was paid to the consistency of each subject’s reported and calculated food intake and the relationship between energy consumption and trends in body weight. Based on this ongoing analysis, one subject was believed to be concealing active caloric restriction, and another subject was believed to be eating food in excess of that provided by the GCRC. The data for these two subjects were excluded from analysis of the results on the ad libitum diet. Subjects were readmitted to the GCRC (visit CRC3) after 12 wk of ad libitum 15% fat meal consumption. The study diet for that day of the cycle was provided, and the blood sampling and DEXA scanning procedures were identical to those employed during CRC2.
Examples of the 35% fat and 15% fat menus are given in Table 2. The macronutrient composition of the diets was calculated using the ProNutra database and is given in Table 3. Total dietary fiber averaged 9 g/1000 kcal for the 35% fat diet and 14 g/1000 kcal for the 15% fat diets. The average fatty acid composition of the diets as a percentage of total energy content was 11.9 ± 1.0% saturated, 12.5 ± 0.3% monounsaturated, and 8.3 ± 0.8% polyunsaturated for the 35% fat diet, and 4.9 ± 0.3% saturated, 5.7 ± 0.3% monounsaturated, and 2.9 ± 0.2% polyunsaturated for the 15% fat diets. The average percentage of total energy supplied by individual carbohydrates for which data are available was 6.4 ± 0.5% sucrose, 4.4 ± 0.5% fructose, 4.3 ± 0.6% glucose, 20.8 ± 1.5% starch, 5.5 ± 0.3% lactose, and 0.5 ± 0.1% maltose for the 35% fat diet, and 12.2 ± 0.9% sucrose, 7.8 ± 0.8% fructose, 7.5 ± 0.7% glucose, 25.4 ± 1.9% starch, 5.9 ± 0.5% lactose, and 0.9 ± 0.1% maltose for the 15% fat diets. Individual carbohydrate content was calculated using Nutrition Data System for Research (version 4.04, Nutrition Coordinating Center, University of Minnesota).
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Plasma insulin was measured using a double-antibody RIA (30). The lower and upper limits of detection were 2.2 and 300 µU/ml, respectively, and the intraassay coefficient of variation was less than 10%. Leptin was measured using a commercially available RIA (Linco Research, Inc., St. Charles, MO) with lower and upper detection limits of 0.5 and 100 ng/ml, respectively, and an intraassay coefficient of variation of 5%. Plasma immunoreactive ghrelin was measured using a commercially available RIA (Phoenix Pharmaceuticals, Inc., Belmont, CA) with lower and upper detection limits of 80 and 2500 pg/ml, respectively; an intraassay coefficient of variation of 8.7%; and an interassay coefficient of variation of 14.6%. All insulin and leptin samples from a single individual were run in duplicate in a single assay. Ghrelin samples from CRC1, CRC2, and CRC3 were run in duplicate in separate assays that were normalized to one another using internal standards as described previously (31).
Statistical analysis
Concentrations of all plasma hormones or fuel molecules, body weight, and caloric intake data are expressed as the mean ± SE unless noted otherwise. Nadirs of leptin time series data were defined as the average of the two lowest consecutive values, and peaks were defined as the average of the two highest consecutive values occurring over a 24-h period. Due to the more rapid variation in plasma ghrelin levels, nadirs of ghrelin time series data were defined as the single lowest value following a meal, and peaks were defined as the single highest value preceding a meal. Periprandial 
ghrelin was calculated as the average of the postmeal ghrelin nadir minus the premeal ghrelin peak values for the three meals consumed by a subject during each CRC admission. Periprandial percent ghrelin was calculated as the average of the percent change in postmeal nadir relative to premeal peak ghrelin values for the three meals consumed by a subject during each CRC admission. Values for 24-h integrated area under the curves (AUC) of plasma concentrations vs. time were calculated using the trapezoidal rule. AUC values for leptin, insulin, glucose, and ghrelin time series data were calculated above the zero concentration. In addition, AUC was calculated for the plasma leptin concentration minus the morning nadir value ( leptin), and leptin was calculated as a percentage of the morning nadir value (% leptin) to allow comparison with previously published results (28). Within-subject comparisons among variables measured at CRC1, CRC2, and CRC3 were made using repeated measures ANOVA, with pairwise post hoc comparisons made using Fisher’s protected least significant difference test. Within-subject comparisons between variables measured only at CRC2 and CRC3 were made using paired two-tailed t tests. Relationships between pairs of variables were assessed by univariate regression analysis using either a linear or an exponential model as appropriate. Data were considered significant at a level of P = 0.05. All statistical analyses were carried out using StatView 5.0.1 software.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Subjects uniformly noted in their visits to the dietitians that they felt uncomfortably satiated during wk 3 and 4, when dietary fat content was dropped to 15% of the total daily energy, but isocaloric food intake was enforced. Daily energy intake decreased by a mean of 16% within 24 h after discharge from CRC2 when subjects were allowed to consume the low fat diet on an ad libitum basis. There was no significant recovery toward baseline daily energy intake, and body weight dropped without inflection throughout the 12-wk ad libitum diet phase. Group mean body weight and energy intake data for CRC1, CRC2, and CRC3 are summarized in Table 4.
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, and the parameters characterizing these profiles are summarized in Table 5. Isocaloric substitution of dietary carbohydrate for fat over 2 wk caused no change in nadir, peak, amplitude, or area for the leptin, leptin, or percent leptin profiles. In contrast, 12 wk of ad libitum 15% fat diet consumption produced a fall in nadir, peak, and AUC-leptin that was highly significant compared with values on both the 35% and 15% fat isocaloric diets (Fig. 2A). In absolute terms, the average peak minus nadir value and the area of the leptin curve above nadir (AUC- leptin) were significantly lower during CRC3 than during CRC1 or CRC2 (Fig. 2B). The proportional amplitude of the 24-h plasma leptin profile (28) was assessed both asthe percent change from nadir to peak and as area under thecurve of leptin values expressed as a percentage ofthe nadir (AUC-% leptin). The percent change in leptin from nadir to peak was significantly increased during CRC3 relative to CRC1, and there was an insignificant trend toward an increase in AUC-% leptin during CRC3 relative to CRC1 and CRC2 (Fig. 2C).
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) and body fat mass (Fig. 3B) between CRC3 and CRC1 were performed. As shown in the figures, there was a highly significant correlation between the increase in proportional amplitude of the 24-h plasma leptin profile and loss of both body weight and body fat mass. Equally significant relationships were found when changes in body composition between CRC3 and CRC1 were correlated with changes in AUC-% leptin (data not shown).
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). Thus, the integrated plasma leptin level remained exactly proportional to body fat content under conditions of both weight stability and active weight loss on the low fat diet.
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and Table 6. AUC-insulin values did not differ between CRC1 and CRC2. In contrast, AUC-insulin decreased significantly during CRC3, despite the fact that more total carbohydrate was consumed on the ad libitum 15% fat diet than on the 35% fat diet. The 24-h plasma glucose profiles (Fig. 6) and AUC-glucose values (Table 6) were unaffected by the study diet. These observations along with the finding that fasting insulin levels were significantly lower during CRC3 suggest that insulin sensitivity was increased by dietary fat reduction with or without a subsequent weight loss. Although it did not reach statistical significance, there was a trend toward lower fasting free fatty acid levels during CRC2 and CRC3 that would also be consistent with increasing insulin sensitivity.
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, and the parameters characterizing these profiles are summarized in Table 6
. All profiles displayed preprandial increases, postprandial decreases, and an overall rising diurnal rhythm in circulating ghrelin levels similar to the patterns that we have reported previously (31). Although suppression of plasma ghrelin levels tended to be greater after breakfast than after lunch or dinner on all of the study diets, this finding reached significance only during CRC1 (data not shown). The average absolute suppression of plasma ghrelin levels (periprandial ghrelin) and percent suppression of plasma ghrelin levels (periprandial percent ghrelin) for all three meals was greatest during CRC2, the day during which subjects consumed the largest total amount of carbohydrate. There were no significant differences among AUC-ghrelin values at any of the CRC visits.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Despite the reduction in absolute plasma leptin levels, there was an increase in the proportional amplitude of the 24-h leptin profile after 12 wk on the ad libitum 15% fat diet, and this increase correlated strongly with the loss of body weight and body fat. As suggested by Havel and co-workers (28), it is possible that the proportional amplitude of the diurnal leptin rhythm is also sensed by the CNS and further augments the increased satiety signal that is presumed to arise from enhanced leptin sensitivity on a low fat diet. Although Havel and co-workers (28) found an increase in diurnal leptin amplitude with isocaloric substitution of carbohydrate for dietary fat in their study of 19 women, we did not observe this phenomenon during the isocaloric phase of our study, which also involved predominantly female subjects. A possible explanation for the different outcomes of the 2 studies is that we measured plasma leptin levels after 2 wk on each isocaloric study diet, as opposed to the 24-h study periods employed by Havel and co-workers. It is conceivable that this previously demonstrated effect of isocaloric macronutrient manipulation on leptin secretion is transient and also occurred in our subjects during the first 1–2 d of consuming the low fat diet. In addition, we lowered dietary fat content from the typical American value of 35% of total daily calories to 15% of total daily calories, a reduction that might be employed in the therapy of obesity. Havel and co-workers (28) varied dietary fat content from 60% to 20% of total daily calories, a range double that employed in our study. Finally, we did not observe an increase in integrated 24-h plasma insulin and glucose levels as noted by Havel and co-workers with isocaloric substitution of carbohydrate for dietary fat. Thus, any contribution of increased insulin-mediated glucose uptake to additional leptin secretion by adipocytes (34) may have been lacking in our study.
Raben and co-workers (35) also found that an 18% increase in dietary carbohydrate calories (as a percentage of total daily intake) relative to fat calories for 14 d had no effect on area under the 8-h serum insulin vs. time curve. We believe that there are two possible explanations for the failure of AUC-insulin and AUC-glucose levels to rise when our subjects were placed on the low fat, high carbohydrate diet. First, because our low fat diet conformed to American Dietetic Association guidelines it included an increase in fruit. This increase combined with an increase in sucrose resulted in an overall increase of 6.3% of total daily calories as fructose and 11.1% of total daily calories as glucose. It is possible that this increase in glucose was too small to provide a significant stimulus to additional insulin secretion. Second, it is likely that there was an increase in insulin sensitivity on the low fat diet that took longer than 24 h to develop (36). An increase in insulin sensitivity is suggested by the trend for both fasting insulin and free fatty acid levels to fall with time spent on the low fat diet. In addition, we noted a significant correlation between lower fasting insulin levels and lower AUC-insulin during both CRC2 and CRC3 (data not shown). Increased intracellular phosphatidylinositol-3-hydroxykinase levels on the 15% fat diet could enhance sensitivity to both insulin and leptin, with insulin signaling in the hypothalamus contributing to increased satiety after dietary fat reduction (37, 38, 39, 40).
A growing body of evidence demonstrates that loss of fat mass causes an increase in circulating ghrelin levels that coincides with decreasing leptin levels (15, 16, 17, 18, 19). Because ghrelin is a potent orexigenic signal (11, 12, 13, 14), and leptin is a satiety signal at the level of the CNS, this coordinated change in hormone levels should elicit a strong compensatory increase in appetite. Our data demonstrate that weight loss induced by a low fat, high carbohydrate diet fails to trigger an increase in AUC-ghrelin, in contrast to the clear increases that accompany weight loss due to anorexia nervosa (17, 18), congestive heart failure (16), cancer (15), or caloric restriction (19). We speculate that stable AUC-ghrelin may have contributed to the lack of an increase in appetite accompanying weight loss in our study. We further speculate that the failure of AUC-ghrelin to rise may itself be a manifestation of enhanced leptin action. This speculation is based on the observation that leptin administration to both lean and ob/ob mice significantly suppresses ghrelin mRNA expression in the stomach with a concomitant decrease in food intake and body weight (41). Our data are also the first to show that isocaloric substitution of dietary carbohydrate for fat causes lower postprandial ghrelin levels in humans, a change that might diminish appetite.
The hypothesis that leptin resistance in the CNS is proportional to dietary fat content has been directly tested in animals (24, 25, 26, 27). Several studies have demonstrated that high fat feeding attenuates the ability of peripherally injected leptin to cause a reduction in the consumption of a test meal. This leptin resistance is seen within 5 d after increasing dietary fat, before significant weight gain occurs (24). Returning animals to their baseline low fat diets restores normal leptin sensitivity (24). Administering leptin directly into the cerebroventricular system may completely (25) or partially (26) restore the effect of leptin in the setting of high fat feeding, suggesting that both impaired leptin signal transduction and impaired transport of leptin across the blood-brain barrier may contribute to leptin resistance. It is noteworthy that in dogs, high fat feeding reduces insulin transport into the CNS (42). Although impaired leptin transport from blood into cerebrospinal fluid has been documented in obese subjects (43, 44), the effect of high fat feeding on this process has not yet been studied in humans.
In conclusion, we found that an ad libitum low fat diet produced progressive weight loss in human subjects without a compensatory increase in ghrelin levels or food consumption despite reduced absolute 24-h plasma leptin levels. An increase in the proportional amplitude of the diurnal leptin profile occurring with weight loss may have contributed to the effect of dietary fat restriction. These observations suggest that dietary fat restriction enhances leptin sensitivity in the CNS and the periphery, an inference that remains to be proven by future studies in which leptin is administered directly to humans consuming diets of differing fat content. Presumably, if our subjects were returned to a 35% fat diet at the end of the study, their increased sensitivity to leptin action would have rapidly abated, and their ghrelin levels and appetite would have increased. In this preobese state, they would be poised to regain fat mass until an increase in the integrated 24-h plasma leptin level restored energy balance. We believe that the model of dietary fat manipulation can be generalized to other genetic and acquired conditions that promote obesity by diminishing leptin signaling in the CNS.
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Acknowledgments |
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Footnotes |
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Abbreviations: AUC, Area under the curve; C, carbohydrate; CNS, central nervous system; DEXA, dual energy x-ray absorptiometry; F, fat; GCRC, General Clinical Research Center; P, protein.
Received August 12, 2002.
Accepted January 8, 2003.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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