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American Journal of Clinical Nutrition, Vol. 81, No. 4, 762-772, April 2005
© 2005 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

Carbohydrate-restricted diets high in either monounsaturated fat or protein are equally effective at promoting fat loss and improving blood lipids1,2,3

Natalie D Luscombe-Marsh, Manny Noakes, Gary A Wittert, Jennifer B Keogh, Paul Foster and Peter M Clifton

1 From the Department of Medicine, University of Adelaide, Adelaide, Australia (NDL-M and GAW), and Health Science and Nutrition, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Adelaide, Australia (MN, JBK, PF, and PMC).

2 Supported in part by the National Health and Medical Research Council of Australia (grant 150812).

3 Reprints not available. Address correspondence to PM Clifton, Department of Medicine, University of Adelaide, Adelaide BC, South Australia, Australia 5000. E-mail: peter.clifton{at}csiro.au.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: When substituted for carbohydrate in an energy-reduced diet, dietary protein enhances fat loss in women. It is unknown whether the effect is due to increased protein or reduced carbohydrate.

Objective: We compared the effects of 2 isocaloric diets that differed in protein and fat content on weight loss, lipids, appetite regulation, and energy expenditure after test meals.

Design: This was a parallel, randomized study in which subjects received either a low-fat, high-protein (LF-HP) diet (29 ± 1% fat, 34 ± 0.8% protein) or a high-fat, standard-protein (HF-SP) diet (45 ± 0.6% fat, 18 ± 0.3% protein) during 12 wk of energy restriction (6 ± 0.1 MJ/d) and 4 wk of energy balance (7.4 ± 0.3 MJ/d). Fifty-seven overweight and obese [mean body mass index (in kg/m2): 33.8 ± 0.9] volunteers with insulin concentrations >12 mU/L completed the study.

Results: Weight loss (LF-HP group, 9.7 ± 1.1 kg; HF-SP group, 10.2 ± 1.4 kg; P = 0.78) and fat loss were not significantly different between diet groups even though the subjects desired less to eat after the LF-HP meal (P = 0.02). The decrease in resting energy expenditure was not significantly different between diet groups (LF-HP, –342 ± 185 kJ/d; HF-SP, –349 ± 220 kJ/d). The decrease in the thermic effect of feeding with weight loss was smaller in the LF-HP group than in the HF-SP group (–0.3 ± 1.0% compared with –3.6 ± 0.7%; P = 0.014). Glucose and insulin responses to test meals improved after weight loss (P < 0.001) with no significant diet effect. Bone turnover, inflammation, and calcium excretion did not change significantly.

Conclusion: The magnitude of weight loss and the improvements in insulin resistance and cardiovascular disease risk factors did not differ significantly between the 2 diets, and neither diet had any detrimental effects on bone turnover or renal function.

Key Words: Weight loss • protein • low-carbohydrate diet • energy restriction • insulin resistance • lipids • energy expenditure • appetite • bone turnover • humans


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Obesity, particularly when central, is associated with a cluster of metabolic disturbances that include elevated plasma insulin and triacylglycerol concentrations, low HDL-cholesterol concentrations, high blood pressure, and impaired glucose tolerance (1). Prospective studies have established that these metabolic disturbances increase the risk of cardiovascular disease and type 2 diabetes (2–4). The Diabetes Prevention Study showed that modest weight loss improves the metabolic disturbances and reduces the risk of developing type 2 diabetes (5). Although a plethora of dietary prescriptions have gained popularity, it remains unclear which, if any, of these popular diets can be complied with long term or confer benefits in weight loss and reduced risk factors.

Many popular weight-loss diets focus on carbohydrate restriction of various degrees, with the energy from carbohydrate replaced by different proportions of protein or fat. The shift from the traditional high-carbohydrate, low-fat diet may be the consequence of modest weight loss and poor long-term compliance (6, 7). Moreover, some argue that in the absence of weight loss, high- compared with moderate-carbohydrate diets worsen glycemic control (8–10) and the plasma triacylglycerol and HDL-cholesterol profile (11, 12). Alternate dietary approaches currently being examined include a high-fat, moderate-carbohydrate, standard-protein diet that derives a large proportion of its energy from sources rich in monounsaturated fat, or a low-fat, moderate-carbohydrate, high-protein diet.

Short-term, randomized, energy-matched studies in which {approx}10–25% of the energy from dietary carbohydrate was replaced with fat, predominantly monounsaturated fat, have shown greater reductions in body weight (13) and concentrations of glucose, insulin, triacylglycerols, and VLDL cholesterol (10, 11, 14–16). Similarly, when energy intake is matched and dietary fat is restricted to ≤30% of energy, the replacement of a moderate percentage of energy from carbohydrate with protein (ie, 15% of energy) has been shown to enhance weight loss (17, 18) and fat loss (17, 19) and to spare lean mass (20–23). Moreover, numerous reports exist of greater improvements in postprandial glycemic control (18, 23–25), insulin sensitivity (17, 18, 20), and the blood lipid profile (17, 19, 23, 24, 26–28) after weight loss with high-protein diets than after standard-protein diets. A pertinent question arising from these later studies is whether, in the context of carbohydrate-restricted diets, the high-protein or the high-fat modification is potentially better at improving cardiovascular and diabetes risk. Accordingly, the objective of the present study was to compare the short-term effects of 2 isocaloric, energy-restricted, carbohydrate-matched diets that were either low-fat, high-protein (LF-HP) or high-fat, standard-protein (HF-SP; monounsaturated-fat enriched) on weight loss, body composition, energy expenditure, appetite, glucose, insulin, and lipid metabolism in subjects with insulin concentrations >12 mU/L. The short-term effects of the 2 moderate-carbohydrate dietary prescriptions on markers of bone turnover, inflammation, and renal function were also examined.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Seventy-three obese men and women were recruited through public advertisement. A screening session was conducted, and subjects were included if they were aged between 20 and 65 y, were nondiabetic, had a fasting serum insulin concentration >12 mU/L, and a body mass index (in kg/m2) between 27 and 40. Volunteers were excluded if they had diabetes mellitus; had microalbuminuria; had a history of liver, unstable cardiovascular, respiratory, or gastrointestinal disease; had malignancy; or were pregnant or lactating. The protocol and potential risks and benefits of the study were fully explained to each subject before he or she provided written informed consent. All experimental procedures followed the ethical standards of and were approved by the Human Ethics Committees of the Commonwealth Scientific Industrial Research Organisation (CSIRO) and the Royal Adelaide Hospital.

Subject randomization and dropout throughout the study are shown in Figure 1Go. Subjects taking antihypertensive or lipid-lowering medication were asked to maintain all medications and supplements at prestudy doses. Most subjects were sedentary at baseline and were asked to continue their usual physical activity levels and to refrain from drinking >2 standard glasses of alcohol per week throughout the study.



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  		FIGURE 1. Flow diagram of subject enrollment, random assignment, and completion of the 16-wk study protocol. The 73 subjects accepted for participation in the study were sorted into pairs matched for fasting serum insulin, BMI, age, and sex. The resulting matched groups were randomly assigned to either the low-fat, high-protein (LF-HP) diet or the high-fat, standard-protein (HF-SP) diet. The 16-wk intervention was divided into a 12-wk period of energy restriction followed by 4 wk of energy balance. At weeks 0, 2, 4, 6, 8, 10, 12, 14, and 16, measurements of body weight were made and diet counseling was given. At weeks 0, 4, 8, 12, and 16, measurements of blood pressure were made and venous blood was collected. In addition, at weeks 0 and 16, 24-h urine samples were collected, body composition and energy expenditure were measured, and a meal tolerance test was conducted for the determination of postprandial glucose and insulin responses.

 
Diets
The prescribed diets were: 1) a LF-HP diet containing 30% of energy as fat (46 g/d) and 40% of energy as protein (136 g/d), and 2) a HF-SP diet containing 50% of energy as fat (76 g/d) and 20% of energy as protein (67 g/d). For each diet, the percentages of energy derived from carbohydrate and saturated fat were matched; carbohydrate was restricted to 30% of energy ({approx}110 g/d), and saturated fat was restricted to <10% of energy. The fiber content of each diet was similar (21 g/d in the LF-HP diet and 27 g/d in the HF-SP diet). To achieve the composition of the prescribed diets, the subjects followed fixed-menu plans and were supplied with key foods that made up 60% of their energy intake. The prescribed menu plans and foods supplied to each subject are shown in Table 1Go. Foods were provided at 2 weekly intervals when the subjects visited the research unit for dietary counseling.


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  		TABLE 1 Prescribed diets and foods supplied to subjects1

 
The subjects were counseled by a dietitian on the dietary protocol and on how to keep daily dietary intake checklists for all foods eaten. The subjects’ body weights and dietary intake checklists were monitored every 2 wk, and dietary adjustments were made if the food specified was too little or too much. Three consecutive days (1 weekend day and 2 weekdays) of the checklists from each 2-wk period were analyzed with the use of DIET/1 NUTRIENT CALCULATION software (1998; Xyris Software, Highgate Hill, Australia), a computerized database of Australian foods. Recipes were entered as proportions of the original ingredients. The database has been extensively modified by our group to include new foods and recipes.

Experimental protocol
The study was conducted on an outpatient basis over 16 wk. Both dietary groups underwent 12 wk of energy restriction ({approx}6000 kJ/d, or 30% restriction of total energy) followed by 4 wk in energy balance with the same macronutrient composition. If an individual was not achieving the desired weight loss of 0.5–1 kg/wk during the energy-restricted phase, or if during the energy-balance phase he or she did not maintain a stable weight, minor adjustments in food intake were made at the fortnightly diet counseling sessions. Numerous weight-loss studies conducted at CSIRO have found this method of dietary counseling to be sufficient for successful weight loss and weight maintenance. On 2 consecutive days at weeks 0, 4, 8, 12, and 16, body weight, blood pressure, and venous blood samples were taken in the morning after the subjects had fasted overnight for measurement of blood glucose, insulin, and lipid concentrations; the average of the 2 values was used in the statistical analysis. At weeks 0 and 16, a single venous blood sample was taken for the determination of serum creatinine, and a 24-h urine sample was collected for the assessment of the ratio of urea to creatinine to determine dietary compliance. Calcium and sodium excretion, as well as ratios of deoxypyridinoline to creatinine and of pyridinoline to creatinine (biomarkers of bone turnover) were assessed from the 24-h urine sample at weeks 0 and 16. Also at weeks 0 and 16, measurements of body composition and total energy expenditure and a 3-h meal tolerance test using meals that were representative of the diet to which the subjects were assigned were performed. Venous blood samples for the determination of glucose, insulin, and free fatty acid concentrations were taken before the subjects consumed the LF-HP (2636 kJ, 37% of energy as protein, 30% fat, 32% carbohydrate) or HF-SP (2586 kJ, 18% of energy as protein, 49% fat, 32% carbohydrate) test meal, as well as 30, 60, 120, and 180 min after the meal. Resting energy expenditure (REE), the thermic effect of feeding (TEF), respiratory quotient (RQ), and appetite sensations (hunger, satiety, fullness, and desire to eat) were also measured before and after the meal at these time points.

Measurements
Body weight and body composition
Body weight (model AMZ14 digital scale; A&D Mercury, Kinomoto, Japan) was recorded while the subjects were wearing light clothing without shoes. Total fat mass and total lean mass were assessed by whole-body dual-energy X-ray absorptiometry (densitometer XR36; Norland Medical Systems, Fort Atkinson, WI; CVs of 2.3 ± 0.7% for total-body fat mass and 2.1 ± 0.4% for lean mass).

Resting energy expenditure, the thermic effect of feeding, and respiratory quotient
Thirty subjects (6 men and 8 women from the LF-HP group and 6 men and 10 women from the HF-SP group) were recruited to participate in the energy expenditure measurements performed at weeks 0 and 16. The methods used to assess REE, TEF, and RQ have been described in detail elsewhere (29). All energy expenditure measurements were performed on the same day of the week and at the same time of day after the subjects had fasted overnight. The subjects were asked to refrain from participating in planned exercise, drinking alcohol, and smoking for ≥12 h before the measurement of resting energy expenditure. The intraindividual CVs for the measurement of REE, TEF, and RQ in obese subjects were 1.7 ± 0.41%, 7.8 ± 1.5%, and 3.10 ± 0.8%, respectively.

Appetite responses
Hunger, fullness, satiety, desire to eat, and the amount of food desired to eat were assessed by using a 100-mm visual analogue scale before and 30, 60, 120, and 180 min after the test meal (30–32). The subjects were asked to make a single vertical mark on each scale somewhere between the 0- and 100-mm extremes (eg, hungry to not hungry) to indicate their feelings at that time point. The subjects did not discuss their ratings with each other and could not refer to their previous ratings when marking the scale.

Biochemical analyses
Fasting blood samples were collected in tubes containing either serum clotting activator for the measurement of insulin, lipids, fatty acids, and creatinine or sodium fluoride-EDTA for the measurement of glucose. Plasma or serum was isolated by centrifugation at 600 x g for 10 min at 4 °C (GS-6R centrifuge; Beckman, Fullerton, CA) and was frozen at –20 °C until analyzed. Total cholesterol, HDL cholesterol, triacylglycerols, fatty acids, glucose, and creatinine were measured on a Hitachi centrifugal analyzer (Roche, Indianapolis, IN) with the use of standard enzymatic kits (Roche, New South Wales, Australia). Assays for insulin, HDL cholesterol, and LDL cholesterol are described in detail elsewhere (19). All biochemical assays were performed in a single run at the end of the 16-wk study. Homeostatic model assessment (HOMA) was used as a surrogate measure of insulin sensitivity and was calculated as fasting serum insulin (mU/L) x fasting plasma glucose (mmol/L)/22.5 (33). Total (glucose and insulin) and net (visual analogue scores for appetite) areas under the curve during the 3-h meal tolerance test were calculated geometrically by using the trapezoidal rule (34). Twenty-four–hour urine samples were collected, the volume was recorded, and aliquots were frozen until analyzed (in one run at the end of the study) for the measurement of urea and creatinine concentrations with the urease enzymatic assay (35) and the Jaffe reaction technique (36), respectively. Urinary pyridinium and deoxypyridinium cross-links (markers of bone turnover) were measured by using HPLC (37). Creatinine clearance was computed from plasma and 24-h urine creatinine excretion as follows: creatinine clearance = [(urine creatinine concentration in mmol/L) x (urine volume in mL/1140 min)/(plasma creatinine concentration in (µmol/L) · 1000 mL–1 · min–1)] x 0.7.

Statistical analyses
Two subjects were excluded from the lipid analysis because they ceased taking lipid-lowering medications; 3 subjects were unable to have a dual-energy X-ray absorptiometry scan completed at week 16. Statistical analysis was performed by using SPSS for WINDOWS 10.0 software (SPSS Inc, Chicago, IL). Baseline measurements were assessed by using two-factor analysis of variance (ANOVA) with diet and sex as the fixed factors. The effect of the diet intervention was assessed by using repeated-measures ANOVA; for each dependent variable, the measurements at weeks 0, 4, 8, 12, and 16 are the within-subject factor (ie, time) and diet and sex are the between-subject factors. In specific analyses, baseline weight, cholesterol, total fat mass, and total lean mass were included as covariates. Week 0 and 16 response curves after the test meals were compared by using repeated-measures ANOVA with week and blood sampling time as the within-subject factors and diet and sex as the between-subject factors. When significant interactions of time-by-diet or time-by-diet-by-sex were found, paired t tests were used to find where the differences lay. The study had 80% power ({alpha} = 0.05) to detect differences between dietary groups of 3.6 kg in body weight, 0.9 kg in lean and fat mass, 3 mU/L in fasting insulin, 0.2 mmol/L in LDL cholesterol, and 7% in REE. Significance was set at P < 0.05. All data are presented as means ± SEMs unless stated otherwise.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subject compliance with the diets
No significant differences existed in subject characteristics between treatment groups at baseline (Table 2Go). For body weight, there was a main effect of sex such that the men were heavier than the women (P < 0.001). There was also a diet-by-sex interaction (P = 0.04) such that the men in the HF-SP group weighed more than did the men in the LF-HP group (P = 0.03). Fasting plasma glucose was higher in the men than in the women (main effect of sex, P = 0.018).


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  		TABLE 2 Subject characteristics at baseline1

 
Both diets were well tolerated, with no adverse events or effects reported. The energy and macronutrient contents derived from the subjects’ daily weighed-food checklists are shown in Table 3Go and did not differ from those of the prescribed diets. The percentage of energy derived from the macronutrients of both diets was not significantly different during the energy-balance compared with the energy-restricted phase.


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  		TABLE 3 Dietary intake from daily weighed-food records1

 
From weeks 0 to 16, there was a time-by-diet interaction for urea:creatinine (P = 0.05) such that the ratio increased by 37.6 ± 7.2% with the LF-HP diet (40.8 ± 2.3 to 52.6 ± 1.8, main effect of time P < 0.001) but remained unchanged with the HF-SP diet (42.8 ± 6.0 to 41.9 ± 1.2).

Body weight and body composition
After 12 wk of energy restriction and 4 wk of energy balance, weight loss did not differ between subjects in the LF-HP and HF-SP groups; the amounts of fat and lean mass that were lost also did not differ (all main effects of diet were nonsignificant). There were no time-by-diet or time-by-diet-by-sex interactions for any of these variables (Table 4Go). The reduction in body weight after 16 wk was 9.5 ± 0.9%, or 9.2 ± 0.7 kg (main effect of time, P < 0.001; 10.2 ± 1.4 kg for the HF-SP diet, 9.7 ± 1.1 kg for the LF-HP diet). As shown in Table 4Go, all the weight loss occurred during the energy-restricted phase of the diet (from week 0 to week 12); no further weight loss occurred during the energy balance phase. The men lost 2% more of their body weight than did the women (time-by-sex interaction, P = 0.03). From week 0 to week 16, the reduction in fat mass was 13.9 ± 1.5% and the decrease in abdominal fat mass was 17.1 ± 2.0% (main effects of time, P < 0.001). Lean mass was reduced by 6.0 ± 0.6% (main effect of time, P < 0.001).


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  		TABLE 4 Body weight, BMI, and total fat, lean, and abdominal masses of subjects in the high-fat, standard-protein (HF-SP) and low-fat, high-protein (LF-HP) diet groups1

 
Glycemic control, insulin sensitivity, and fatty acids
Fasting concentrations of plasma glucose remained unchanged throughout the 16 wk in both the LF-HP and HF-SP groups (main effect of diet, NS; Table 5Go). Improvements in fasting serum insulin, the HOMA index of insulin resistance, and in fasting serum free fatty acids were also not significantly different in the LF-HP and HF-SP groups. There were no time-by-diet or time-by-diet-by-sex interactions for any of these variables (Table 5Go). After 16 wk, the decrease in fasting serum insulin was 25 ± 4.2% (main effect of time, P < 0.001) and the HOMA insulin resistance index was reduced by 34 ± 8.8% (P < 0.001). There was a main effect of time on fasting serum FFA concentrations (P < 0.001); the effect was due to a 26.7 ± 7.3% increase from week 0 to week 12 (P = 0.009), but by week 16 the concentration had fallen and was not significantly different from that at week 0 (P = 0.34).


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  		TABLE 5 Fasting glucose, insulin, free fatty acid (FFA), and lipid concentrations and areas under the glucose and insulin response curves (AUCs) to the test meals in the 2 diet groups1

 
At week 16, the increase in plasma glucose in response to the test meals was less than that at week 0 (Figure 2Go). There was no significant effect of diet or any time-by-diet or time-by-diet-by-sex interactions on plasma glucose responses. The same results were observed for the serum insulin responses to the test meals (Figure 2Go). The areas under the curve for both glucose and insulin responses did not differ significantly after the LF-HP and HF-SP meals at both weeks 0 and 16 (Table 5Go).



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  		FIGURE 2. Mean (±SEM) plasma glucose and insulin concentrations at baseline and 30, 60, 120, and 180 min after the ingestion of a high-fat, standard-protein (HF-SP; n = 28) or a low-fat, high-protein (LF-HP; n = 26) test meal, which was representative of the subjects’ study diet, at weeks 0 and 16. Week 0 and 16 data were compared by use of a repeated-measures ANOVA with week and blood sampling time as the within-subject factors and diet and sex as the between-subject factors. There was no main effect of diet, and there were no significant week-by-diet, week-by-diet-by-sex, week-by-time-by-diet, or week-by-time-by-diet-by-sex interactions on plasma glucose or insulin responses. There was a significant main effect of week for both glucose and insulin, P < 0.001.

 
Lipids
One subject in the LF-HP group ceased taking lipid-lowering medication during the 16 wk and was therefore excluded from the analysis of plasma lipids. Improvements in fasting serum lipid concentrations did not differ significantly between the LF-HP and HF-SP groups, and there were no time-by-diet or time-by-diet-by-sex interactions for any of these variables (Table 5Go). Total cholesterol was reduced by 6.6 ± 1.4% at week 12 compared with week 0, and it remained reduced by 2.9 ± 1.4% at week 16 (main effect of time, P < 0.001). LDL cholesterol was reduced by 3.4 ± 1.9% at week 12 and by 0.7 ± 2.3% at week 16 (P = 0.005). HDL cholesterol was increased by 6.8 ± 2.0% at week 12, and at the end of week 16 it remained 10.1 ± 2.1% above baseline (P < 0.001). The serum triacylglycerol concentration was reduced by 23.1 ± 3.6% by week 12 and by 15.9 ± 4.3% at week 16 (main effect of time, P < 0.001).

Resting energy expenditure, the thermic effect of feeding, and respiratory quotient
The reduction in REE (regardless of whether it was expressed as an absolute value or was adjusted for body composition) did not differ significantly between the LF-HP and the HF-SP group, and there were no time-by-diet or time-by-diet-by-sex interactions for REE (Table 6Go). The decrease in REE (expressed as an absolute value) from week 0 to week 16 was 4.0 ± 1.6% (main effect of time, P = 0.055). When adjusted for lean mass, the decrease in REE reached 16.8 ± 3.7% (from 3501 to 2847 kJ/d at week 0 compared with week 16; P < 0.001). After 12 wk of energy restriction and 4 wk of energy balance, the TEF of the subjects in the HF-SP group was reduced by 3.6 ± 0.7%, whereas in the LF-HP group, the decrease was only 0.32 ± 1% (time-by-diet interaction, P = 0.015; Table 6Go). There was no diet-by-sex or time-by-diet-by-sex interaction for the TEF. For fasting RQ, there was a significant time-by-diet-by-sex interaction (P = 0.02); for men, the RQ of the HF-SP group remained unchanged from week 0 to week 16 (0.82 ± 0.002 and 0.82 ± 0.001, respectively), whereas it increased by 6.6% (from 0.75 ± 0.001 to 0.80 ± 0.002) in the LF-HP group (P = 0.047). Postprandial RQ after the test meal did not differ significantly between the LF-HP and the HF-SP group, and there were no diet-by-time or time-by-diet-by-sex interactions (Table 6Go). Postprandial RQ increased from week 0 to week 16 by 1.8 ± 0.7% (P = 0.007).


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  		TABLE 6 Energy expenditure and respiratory quotient (RQ) at weeks 0 and 161

 
Appetite responses
The subjects did desire less to eat after the LF-HP meal than after the HF-SP meal at both week 0 and week 16 (main effect of diet, P = 0.02; Figure 3Go). There was a significant reduction in the 3-h hunger response from week 0 to week 16 (main effect of time, P = 0.018). In addition, there was a trend for desire to eat (P = 0.06) and the amount desired to eat (P = 0.07) to be reduced after 16 wk. Satiety after the meals was unchanged from week 0 to week 16 (P = 0.5). There were no diet-by-sex or time-by-diet-by-sex interactions for any of the appetite responses.



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  		FIGURE 3. Mean (±SEM) subjective ratings for hunger, desire to eat, and the amount of food desired at baseline and 30, 60, 120, and 180 min after the ingestion of a high-fat, standard-protein (HF-SP; n = 27) or a low-fat, high-protein (LF-HP; n = 23) test meal, which was representative of the subjects’ study diet, at weeks 0 and 16. Week 0 and 16 data were compared by use of a repeated-measures ANOVA with week and appetite rating time as the within-subject factors and diet and sex as the between-subject factors. There was no main effect of diet, and there were no significant week-by-diet, week-by-diet-by-sex, week-by-time-by-diet, or week-by-time-by-diet-by-sex interactions on any measured appetite variables. There was a significant main effect of week (from week 0 to week 16) on hunger, P = 0.018. There was a trend for desire to eat and the amount desired to eat to be reduced from week 0 to week 16 (main effect of week, P = 0.06 and P = 0.07, respectively). There was a significant main effect of diet on amount desired to eat, P = 0.02.

 
Urinary calcium and sodium, markers of bone turnover, serum creatinine, C-reactive protein, and blood pressure
There was no effect of diet composition on urinary calcium or sodium excretion, concentrations of bone-turnover markers, C-reactive protein (CRP), or blood pressure. Urinary calcium and sodium excretion remained unchanged from week 0 to week 16 (3.5 ± 0.4 and 4.1 ± 0.4 mmol/24 h for week 0 and week 16 calcium values, respectively, and 181 ± 31 and 158 ± 11 mmol/24 h for week 0 and week 16 sodium values), as did concentrations of the bone-turnover markers (94 ± 5.1 and 102 ± 5.2 nmol/mmol for week 0 and week 16 pyridinoline:creatinine values, respectively, and 26 ± 1.3 and 28 ± 1.4 nmol/mmol for deoxypyridinoline:creatinine values). CRP fell by 24.0 ± 20.2% (from 3.9 ± 0.4 mg/L at week 0 to 3.1 ± 0.4 mg/L by week 12; main effect of time, P = 0.001), but by week 16 the reduction from baseline (6.7 ± 15.0%) was not significant (week 16 CRP: 3.4 ± 0.37 mg/L). Systolic blood pressure decreased from 130 ± 1.89 mm Hg at week 0 to 123 ± 1.5 mm Hg at week 16 (main effect of time, P < 0.001), but diastolic blood pressure remained unchanged (72 ± 1.3 mm Hg at week 0 and 71 ± 1.0 mm Hg at week 16). For serum creatinine, there was no main effect of time or diet, but there was a time-by-diet-by-sex interaction (P = 0.01); for men, the concentration decreased from 91.5 ± 2.9 to 85.6 ± 3.3 µmol/L in the SP group (P = 0.005) but remained unchanged in the HP group (85.3 ± 2.3 and 85.7 ± 3.0 µmol/L). Creatinine clearance did not change with time in either diet group (117 ± 13 and 124 ± 15 mL/min at weeks 0 and 16, respectively, in the HF-SP group, and 121 ± 10 and 141 ± 12 mL/min at weeks 0 and 16, respectively, in the LF-HP group).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Recent short-term studies (lasting 4–6 mo), including our own, have shown positive effects of diets in which protein is increased at the expense of carbohydrate on weight loss and markers of cardiovascular disease risk, such as insulin resistance and lipid metabolism (17–19, 23, 24, 26, 28, 38). None of these studies, however, were designed to determine whether the beneficial effects, particularly on markers of cardiovascular disease risk, resulted from the reduced carbohydrate or the increased protein content of the diets. The present study therefore matched the carbohydrate content of 2 isocaloric, energy-restricted diets and manipulated the protein-to-fat ratio.

The main finding of the present study was that the LF-HP diet (which was based on lean meat, poultry, and low-fat dairy foods) and the HF-SP diet (which was based on lean meat, poultry, higher-fat milk, and oil and nuts high in monounsaturated fat) were both well accepted, as evident from the similar dropout rates in the 2 diet groups and compliance with the dietary prescriptions. The experimental diets had no deleterious effects on renal function, blood pressure, or markers of bone turnover and were equally effective at reducing body weight, improving insulin resistance, and improving cardiovascular disease risk factors. This finding contrasts with the results of 2 of our previous studies of subjects with moderately elevated insulin concentrations and type 2 diabetes, which showed statistically greater improvements in postprandial glucose responses, fasting lipid concentrations, and fat loss and lean mass preservation in women after 16 wk of a low-fat, moderate-carbohydrate, high-protein diet than after an isocaloric low-fat, high-carbohydrate, standard-protein diet (19, 23). Our finding also differs from those of Layman et al (28) and Piatti et al (20), who both showed that the fat-to-lean mass loss ratio (an indicator of fat utilization and preservation of lean mass) is greater for women after a high-protein, moderate-carbohydrate diet.

Thus, it appears that restriction of carbohydrate in a low-fat, moderate-carbohydrate, high-protein diet may be beneficial in improving body composition compared with a low-fat, high-carbohydrate, standard-protein diet, perhaps by reducing insulin and enhancing lipolysis of stored fat. However, an analysis of 94 weight-loss interventions found that total weight loss or changes in fasting plasma glucose and serum lipid concentrations were not independently associated with the reduced carbohydrate intake (39), although body composition was examined in few of these interventions. Most studies have shown that energy intake and not macronutrient composition is the key determinant of total weight loss (19–24, 40–44).

Available data from animal (45–47) and human epidemiologic (48–50) studies suggest that high-fat diets, particularly those high in saturated fat, are associated with insulin resistance and the onset of type 2 diabetes. Accordingly, there is concern that replacing carbohydrate with fat may adversely affect insulin resistance and plasma lipids, although unsaturated fat probably does not have this adverse effect (45, 51). In the present study, the increased fat content of the HF-SP diet did not have any detrimental effect on insulin resistance or the lipid profile of the subjects, who showed weight-loss-related improvements. This finding is consistent with those of others who showed improvements in the lipid profile of subjects who were hypercholesterolemic (52) or had type 1 diabetes (53) after they were placed on high-monounsaturated-fat diets.

As well as having moderately elevated insulin concentrations, the subjects in the present study had elevated plasma CRP concentrations at baseline. CRP is a plasma protein that when increased is associated with an increased risk of future cardiac events and that is also associated with insulin resistance and the development of type 2 diabetes (54, 55). Interestingly, in the present study, CRP was reduced significantly during active weight loss by 24%; during the weight maintenance phase, however, CRP rose and the final reduction of 14% was not statistically significant. An effect of energy intake on CRP has not been noted before, although weight loss has been shown to reduce CRP (56). In both of these low-carbohydrate diets, fasting free fatty acids were modestly elevated during the active weight-loss phase, consistent with greater use of fat as an energy source and enhanced mobilization of fat during energy restriction.

Our group, and others, have consistently shown that a high-protein compared with a standard-protein meal increases the TEF and may also reduce the decrease in the TEF after weight loss (29, 57–60). Similarly, in the present study, we observed that the decrease in the TEF after weight loss was {approx}3.3% smaller in the LF-HP diet group than in the HF-SP group. Even though over the short-term, the TEF does not appear to enhance weight loss, it may have some effect, albeit minimal, on weight maintenance. For example, over 6 mo, assuming subjects are in energy balance and are consuming 7.8 MJ/d (or 3 x 2.6-MJ meals), a difference in the TEF of {approx}82 kJ/3 h (or 246 kJ/d) may equate to a difference in weight gain of {approx}3 kg between the 2 diets. In this study, REE was reduced after weight loss but the reduction was not affected by the protein-to-fat ratio of the diet, a finding that is consistent with our previous results (29, 57). The few studies reporting preservation in REE after weight loss with increased protein diets were performed in small populations (8–13 subjects), and the absolute amounts of protein used were greater than in our studies (17, 61).

Data from an ad libitum feeding study (38) suggest that the satiating effects of protein-rich foods, such as lean meat and low-fat dairy products, are responsible for the reduced energy intake (by {approx}20%) that leads to greater weight loss (by 3.3 kg) after 6 mo of a LF-HP diet (30% fat, 25% protein) than after a LF-SP diet (30% fat, 12% protein). In the present study, the amount of food desired to eat over the 3-h period after the test meal was less after the LF-HP meal than after the isocaloric HF-SP meal, which is consistent with a greater satiating effect of protein.

In summary, in obese subjects with moderately elevated insulin concentrations, after 12 wk of energy restriction and 4 wk of energy balance, the magnitude of weight loss and the improvements in insulin resistance and lipid metabolism that were achieved with carbohydrate-restricted diets that contained either moderately increased amounts of protein or monounsaturated fat were not significantly different. Nevertheless, the higher-protein meals had the advantage of blunting the decrease in the TEF observed after weight loss, and they also reduced the amount of food desired at the next meal. Whether these mechanisms lead to differential weight loss under ad libitum conditions needs to be explored over the long term. The implication of these findings is that protein from meat, poultry, and dairy foods or fat from food sources rich in monounsaturated fatty acids are both suitable options to replace some dietary carbohydrate, at least in the short term, and the choice of weight-loss diet can be tailored to individual preferences.


   ACKNOWLEDGMENTS
 
We gratefully acknowledge Anne McGuffin, Kathryn Bastiaans, and Julia Weaver for coordinating the trial; Rosemary McArthur for her nursing expertise; and Mark Mano, Cherie Keatch, and Candita Sullivan for performing the biochemical assays.

PMC, MN, and GAW conceived and designed the study and contributed to data analysis and manuscript writing; NDL-M coordinated the study, measured the energy expenditure, and wrote the manuscript; and PF and JBK designed and supervised the diets and contributed to the manuscript. None of the authors had a conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication June 25, 2004. Accepted for publication November 23, 2004.




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