The results of this study challenge the notion that a calorie is a calorie from a metabolic perspective. During isocaloric feeding following weight loss, REE was 67 kcal/d greater with the VLC diet compared to the LF diet. TEE differed by about 300 kcal/d between these two diets, an effect corresponding to the amount of energy typically expended in 1 hour of moderate-intensity physical activity.
The physiological basis for the differences in REE and TEE remains subject to speculation. T3 was lowest with the VLC diet, consistent with previously reported effects of carbohydrate restriction;26
thus, changes in thyroid hormone concentration cannot account for the higher energy expenditure on this diet. The thermic effect of food (TEF, the increase in energy expenditure arising from digestive and metabolic processes) dissipates in the late postprandial period and would not affect REE measured in the fasting state. Because TEF tends to be greater for carbohydrate than fat27, 28
it would also not explain the lower TEE on the LF diet. Although protein has a high TEF,19
the content of this macronutrient was the same for the LF and LGI diets and contributed only 10% more to total energy intake with the VLC diet compared to the other two diets. Furthermore, physical activity as assessed by accelerometry did not change throughout the study. Alternative explanations for the observed differences in REE and TEE may involve intrinsic effects of dietary composition on the availability of metabolic fuels16, 17
or metabolic efficiency; changes in hormones (other than thyroid) or autonomic tone affecting catabolic or anabolic pathways; and (for TEE) skeletal muscle efficiency, as regulated by leptin.29–32
Regarding the last possibility, the ratio of energy expenditure to leptin concentration has been proposed as a measure of leptin sensitivity,33
and this ratio varied as expected in our study (VLC > LGI > LF).
Although the VLC diet produced the greatest improvements in most metabolic syndrome components examined here, we identified two potentially deleterious effects of this diet. Twenty-four hour urinary cortisol excretion, a hormonal measure of stress, was highest with the VLC diet. Consistent with this finding, Stimson et al34
reported increased whole-body regeneration of cortisol by 11β-HSD1 and reduced inactivation of cortisol by 5α-and 5β-reductases over 4 weeks on a VLC vs. a moderate-carbohydrate diet. Higher cortisol levels may promote adiposity, insulin resistance, and cardiovascular disease, as observed in epidemiological studies.35–37
In a 6-year prospective population-based study of older adults in Italy, individuals in the highest vs. lowest tertile of 24-hour cortisol excretion, with or without preexisting cardiovascular disease, had a 5-fold increased risk of cardiovascular mortality.38
CRP also tended to be higher on the VLC diet in our study, consistent with the findings of Rankin and Turpyn.39
Other studies also have found reductions in measures of chronic inflammation, including CRP with a low-GI diet.40–42
A main strength of this study was use of a controlled feeding protocol to establish weight stability following weight loss. Other strengths include a cross-over design to allow for within-individual comparisons, examination of three physiologically sustainable diets spanning a wide range of prevailing macronutrient compositions, control for dietary protein between the LF and LGI diets, state-of-the-art methods to assess TEE under free-living conditions, collection of other study outcomes under direct observation during inpatient hospital admissions to a metabolic ward, and use of observed respiratory quotient (RQ) by indirect calorimetry to verify macronutrient differences among the diets.
Main study limitations are the relatively short duration of the test diets and the difficulty extrapolating findings from a feeding study to a more natural setting, in which individuals consume self-selected diets. The VLC diet, in particular, involved more severe carbohydrate restriction than would be feasible for many individuals over the long term. Therefore, the study may overestimate the magnitude of effects that could be obtained by carbohydrate restriction in the context of a behavioral intervention. In addition, participants in the study were selected for ability to comply with the rigors of a 7-month feeding protocol and may not represent overweight and obese individuals in the general population. While we could not assess compliance during the outpatient phases of the study, good maintenance of weight loss throughout the test phase provides some reassurance on this point.
A methodological issue in cross-over feeding studies involves the possibility of carryover effects between test diets. However, random assignment of participants to a diet sequence and statistical control for order effects would diminish this possibility. In addition, we used compartmental modeling for analysis of TEE, to correct for residual tracer and possible variations in dilution spaces and water kinetics among study periods. Another limitation relating to TEE measurement involves reliance on several assumptions, including the food quotient (FQ) of the test diets. However, sensitivity analysis demonstrated that our results would withstand plausible inaccuracies in estimates of FQ, and qualitatively similar results were obtained when substituting measured RQ for calculated FQ. Finally, we did not assess physiological differences among participants, for example involving insulin secretion,43, 44
that might influence individual responses to the test diets.
In summary, this study demonstrates that commonly consumed diets can affect metabolism and components of the metabolic syndrome in markedly different ways during weight loss maintenance, independent of energy content. The LF diet produced changes in energy expenditure and serum leptin45–47
that would predict weight regain. In addition, this conventionally-recommended diet had unfavorable effects on most of the metabolic syndrome components studied here. In contrast, the VLC diet had the most beneficial effects on energy expenditure and several metabolic syndrome components, but this restrictive regimen may increase cortisol excretion and CRP. The LGI diet appears to have qualitatively similar, though smaller, metabolic benefits to the VLC diet, possibly without the deleterious effects on physiological stress and chronic inflammation. These findings suggest that a strategy to reduce glycemic load, rather than dietary fat, may be advantageous for weight loss maintenance and cardiovascular disease prevention. Ultimately, successful weight loss maintenance will require behavioral and environmental interventions to facilitate long-term dietary adherence. But such interventions will be most effective if they promote a dietary pattern that ameliorates the adverse biological changes accompanying weight loss.