The authors have declared that no competing interests exist.
Conceived and designed the experiments: DSL CBE. Performed the experiments: CBE RLM JFS COW. Analyzed the data: HAF. Wrote the paper: COW CBE DSL.
The major circulating metabolic fuels regulate hunger, and each is affected by dietary composition. An integrated measure of postprandial energy availability from circulating metabolic fuels may help inform dietary recommendations for weight maintenance after weight loss.
We examined the effect of low-fat (LF, 60% of energy from carbohydrate, 20% fat, 20% protein), low-glycemic index (LGI, 40%–40%-20%), and very low-carbohydrate (VLC, 10%–60%-30%) diets on total postprandial metabolic fuel energy availability (EA) during weight loss maintenance.
Eight obese young adults were fed a standard hypocaloric diet to produce 10–15% weight loss. They were then provided isocaloric LF, LGI, and VLC diets in a randomized crossover design, each for a 4-week period of weight loss maintenance. At the end of each dietary period, a test meal representing the respective diet was provided, and blood samples were obtained every 30 minutes for 5 hours. The primary outcome was EA, defined as the combined energy density (circulating level×relative energy content) of glucose, free fatty acids, and β-hydroxybutyrate. Secondary outcomes were individual metabolic fuels, metabolic rate, insulin, glucagon, cortisol, epinephrine, and hunger ratings. Respiratory quotient was a process measure. Data were analyzed by repeated-measures analysis of variance, with outcomes compared in the early (30 to 150 min) and late (180 to 300 min) postprandial periods.
EA did not differ between the test meals during the early postprandial period (p = 0.99). However, EA in the late postprandial period was significantly lower after the LF test meal than the LGI (p<0.0001) and VLC (p<0.0001) test meals. Metabolic rate also differed in the late postprandial period (p = 0.0074), with higher values on the VLC than LF (p = 0.0064) and LGI (p = 0.0066) diets.
These findings suggest that an LF diet may adversely affect postprandial EA and risk for weight regain during weight loss maintenance.
ClinicalTrials.gov
Circulating levels of the major fuels the body uses for metabolic processes, including glucose, free fatty acids (FFA), and ketones, are tightly regulated by hormonal mechanisms. When circulating levels are high, insulin promotes deposition of glucose and fatty acids into muscle, liver and adipose and suppresses their production and release from storage sites. Conversely, when circulating metabolic fuels are low, counter-regulatory hormones (especially glucagon, and also cortisol, epinephrine and growth hormone) stimulate lipolysis, glycogenolysis, gluconeogensis, and ketone formation
Many studies have shown that circulating levels of the individual fuels affect appetite
We previously proposed that high glycemic load diets reduce availability of metabolic fuels in the postprandial period by eliciting a high insulin to glucagon ratio, leading to excessive hunger and overeating
This postprandial study was conducted in the setting of a larger clinical trial, comprising run-in and test phases
Participants were recruited from the greater Boston area using flyers, newspaper advertisements, and Internet postings that described the study as an opportunity for weight loss with provision of meals. Inclusion criteria were: 18–40 years of age, body mass index ≥27 kg/m2, medical clearance from a primary care provider, and willingness to eat and drink only the foods and beverages on the study menu for the duration of the study. Exclusion criteria included: weight >160 kg, change in body weight greater than ±10% over preceding year, use of medications that might affect study outcomes, current smoking, diabetes mellitus (fasting plasma glucose level ≥126 mg/dl), or other major illness as assessed by a medical history and laboratory screening tests (thyroid stimulating hormone, complete blood count, blood urea nitrogen, creatinine, and alanine aminotransferase). For females, additional exclusion criteria included irregular menstrual cycles, pregnancy or lactation during the 12 months prior to enrollment, and change in birth control medication in the three months prior to enrollment. Participants received $500 at the end of the run-in phase and $2000 at the end of the test phase. This report is based on the first 8 participants to complete the larger clinical trial
The study was approved by the Institutional Review Boards at Boston Children’s Hospital and Brigham and Women’s Hospital. Written informed consent was obtained from each participant. The study was registered at ClinicalTrials.gov, with identifier NCT00315354.
Energy needs were estimated using the Mifflin-St Jeor equation
Standardized test meals are described in
LF | LGI | VLC |
Instant oatmeal 53 g | Steel cut oats 45 g | Egg, sausage, and cheese bake: |
Turkey sausage 40 g | Egg, whole raw 70 g | Egg, whole raw 110 g |
Promise margarine 8 g | Cottage cheese, 1% 90 g | Egg whites 50 g |
Milk, nonfat 205 g | Promise margarine 22 g | Pork sausage 80 g |
Water, from tap 227 g | Water, from tap 236 g | Cream 20 g |
Grape juice 77 g | Pink grapefruit, fresh 75 g | Light shredded cheddar cheese 20 g |
Raisins 15 g | Fructose sweetener 10 g | Orange, fresh 70 g |
Sugar 6 g |
All food was weighed prior to cooking.
A pork-free VLC option with the same macronutrient content was available for participants with religious restrictions on pork consumption.
LF = low-fat, LGI = low-glycemic index, VLC = very low-carbohydrate.
LF | LGI | VLC |
|
Energy (kcal) | 500 | 501 | 497 |
Carbohydrate (%) | 59.9 | 39.7 | 10.2 |
Glycemic Index | 65.2 | 40.5 | 48.0 |
Glycemic Load | 44.0 | 16.7 | 3.1 |
Protein (%) | 20.1 | 19.6 | 29.8 |
Fat-total (%) | 20 | 40.7 | 60 |
Fat-Saturated (%) |
3.7 | 10 | 22.3 |
Fat-Monounsaturated (%) | 5.3 | 13.6 | 23.8 |
Fat- Polyunsaturated (%) | 6.5 | 15.4 | 8.9 |
Fat- trans (%) | 0.5 | 0.4 | 0.1 |
Fat- other (%) | 4.1 | 1.2 | 4.9 |
Cholesterol (mg) | 41 | 304 | 545 |
Dietary Fiber (g) | 5.8 | 5.3 | 1.7 |
A pork-free VLC option with the same macronutrient content was available for participants with religious restrictions on pork consumption.
Fat percentages refer to percent of total kcal from that fat source.
LF = low-fat, LGI = low-glycemic index, VLC = very low-carbohydrate.
Nutrient composition of the test meals was calculated using Food Processor Software (Food Processor SQL; ESHA Research; Salem, OR, version 9.8). The glycemic index values for carbohydrate-containing foods were assigned using published values with a glucose reference, and overall glycemic load for the meal was calculated using the following equation:
Study staff and laboratory technicians who collected outcome data were masked to diet order.
Each participant underwent inpatient postprandial testing at the end of the fourth week on the three respective isocaloric diets. Participants were admitted at 5 pm the night before testing, and a nurse placed an intravenous line for blood sampling. The following morning, participants were awakened at 6∶30 am following a 10-hour fast for measurement of resting energy expenditure and a baseline blood draw. Participants then ate a breakfast, containing 25% of estimated daily energy needs and reflecting the diet composition of the respective test diet, within 15 minutes. Every 30 minutes for 5 hours, blood was drawn and participants rated hunger on a 10 cm visual analogue scale, using the prompt: “How hungry are you right now?” (with verbal anchors ranging from “Not at all hungry” to “Extremely hungry”). Metabolic rate was assessed at regular intervals throughout the postprandial period as described below. Admissions for female participants occurred during the follicular phase of the menstrual cycle to minimize potential confounding of metabolic outcomes.
The primary outcome, total EA from metabolic fuels, was calculated as the sum, in kcal/L, of energy from glucose, FFA, and BHB, measured using standard laboratory methodology:
Several assumptions were made in the calculation of EA. Consistent with previous studies
Metabolic rate was measured by indirect calorimetry at rest and then during the postprandial period using a dilution canopy system (Vmax Encore 29 N; VIASYS Healthcare Inc.; Yorba Linda, California). REE was measured while the subject was lying awake and still in a temperature-regulated room with minimal light and noise. During the postprandial period, a DVD with calm programming (i.e., travelogue) was shown to prevent boredom and sleep. At rest and following the test meal, oxygen consumption and carbon dioxide production were measured for 30 minutes of every hour. Using data averaged over the last 20 minutes of each measurement interval, energy expenditure was calculated using the Weir equation
Secondary outcomes were glucose, FFA, BHB, glucagon, insulin, cortisol, epinephrine, metabolic rate, and hunger ratings. Respiratory quotient was included as a process measure, with possible values generally ranging from 0.7 (total fat oxidation) to 1.0 (total carbohydrate oxidation).
Assuming 80% power and a Bonferroni-corrected Type I error rate 0.05/3, the detectable pairwise difference between diets with 8 participants was calculated to be between 0.89 and 1.55 standard deviations, based on whether the intrasubject correlation was strong or weak. Post-hoc power analysis indicated that a new, identically designed crossover study with 8 participants would have more than 98% power to detect differences of the observed magnitude between the LF and other two diets.
In light of prior work suggesting differing patterns of EA in the early versus late postprandial period
The baseline characteristics of the eight participants are shown in
Mean ± SD | ||
Age (years) | 30.8±6.4 | |
Body Mass Index (kg/m2) | Pre-weight loss | 33.4±4.8 |
Post-weight loss | 29.4±4.0 | |
Body fat (%) | Pre-weight loss | 33.5±7.9 |
Post-weight loss | 29.6±9.1 | |
Blood pressure (mmHg) | Systolic | 115±14.2 |
Diastolic | 70±7.3 | |
Fasting blood glucose (mg/dL) | 91.2±10.6 | |
Fasting lipids (mg/dL) | Total cholesterol | 177±34.9 |
Triglycerides | 154±97.7 | |
HDL cholesterol | 47.5±11.0 | |
LDL cholesterol | 98.4±24.3 | |
|
||
Sex | Male | 4 (50) |
Female | 4 (50) | |
Race | Black | 3 (37.5) |
White | 1 (12.5) | |
Asian | 2 (25) | |
Other (Caribbean) | 1 (12.5) | |
No response | 1 (12.5) | |
Ethnicity | Hispanic | 1 (12.5) |
Not Hispanic | 7 (87.5) |
Unless otherwise specified, data are from pre-weight loss baseline testing. Body fat percent was measured by dual-X ray absorptiometry.
Postprandial EA is shown in
EA is calculated as the total energy densities of glucose, free fatty acids, and β-hydroxybutyrate. Error bars represent the standard error of the mean from fitted repeated-measures model.
Metabolic rate is shown in
Respiratory quotient values ranged from 0.88–0.94 after the LF meal, 0.80–0.88 after the LGI meal, and 0.77–0.80 after the VLC meal. All pairwise comparisons for respiratory quotient indicated significant differences over the entire curve, with respiratory quotient higher with the LF diet vs. the LGI (p<0.0001) or VLC (p<0.0001) diet, and with the LGI vs. VLC diet (p = 0.0002).
Circulating levels of individual metabolic fuels are shown in
The figures show levels of glucose (Panel A, mg/dL), free fatty acids (Panel B, mEq/L), β-hydroxybutyrate (Panel C, mmol/L), insulin (Panel D, mcIU/mL), and glucagon (Panel E, pg/mL), and hunger ratings (Panel F). Error bars represent the standard error of the mean from fitted repeated-measures model.
For glucose, there was a significant effect of diet (p = 0.036), as well as a diet×time interaction (p = 0.0001). In the early postprandial period the three diets differed significantly (p = 0.0002), with glucose higher with the LF diet than the VLC diet (p<0.0001). The other two comparisons fell short of the Bonferroni criterion for significance, with glucose showing a higher response to the LF diet vs. the LGI diet (p = 0.048) and the LGI diet vs. the VLC diet (p = 0.031). There was no effect of diet on the level of the glucose curves in the late postprandial period (p = 0.66).
With both FFA and BHB, there was a significant effect of diet over the whole curve (FFA p<0.0001, BHB p = 0.024), and a diet×time interaction (FFA p = 0.0002, BHB p<0.0001). Over the whole curve, the FFA level was lower with the LF diet than with the LGI (p<0.0001) and VLC (p<0.0001) diets, and lower by a marginally non-significant amount with the LGI versus the VLC diet (p = 0.018). The BHB level over the whole curve was lower with the LF diet compared with the VLC diet (p = 0.007).
The FFA:BHB ratio differed between diets. At baseline (t = 0), the ratio differed between diets (p = 0.02); it was higher with the LF diet than with the LGI diet (p = 0.015), and higher with the LF than with VLC diet, with borderline significance (p = 0.02). The ratio also differed over the entire postprandial curve (p = 0.02) in the other direction; the ratio was lower with the LF diet than with LGI diet (p = 0.007), and lower with the LF diet than with the VLC diet with borderline significance (p = 0.04).
Postprandial insulin and glucagon are shown in
For cortisol, there was a significant effect of time (p<0.0001) over the entire period, but no effect of diet (p = 0.37) and no diet×time interaction (p = 0.72). For epinephrine, there was no significant effect of time (p = 0.27) or diet (p = 0.20), and no diet×time interaction (p = 0.39).
Hunger ratings are shown in
In this study, we examined the postprandial effects of three common dietary patterns in young adults during a period of weight maintenance after weight loss. We proposed a novel outcome measure, EA, which combines the relative energy available from three major metabolic fuels (glucose, FFA, and BHB) and hypothesized that an LF meal would lower total metabolic fuel availability and energy expenditure in the late postprandial period by causing a high insulin to glucagon ratio secondary to a high dietary glycemic load.
As hypothesized, the LF meal led to lower EA in the late postprandial period compared with the LGI and VLC meals. Consistent with previous studies
Similarly to EA, metabolic rate did not differ after the three test meals in the early postprandial period but differed significantly in the late postprandial period, with higher metabolic rate after a VLC meal than an LF or LGI meal. This sustained high postprandial metabolic rate after the VLC meal may contribute to the findings that total energy expenditure decreases less after weight loss on a VLC diet than on an LF or LGI diet
There was no significant effect of diet on hunger ratings. Unlike prior work examining the effect of similar test meals on postprandial hunger
A strength of the current study is the novelty of the primary outcome, a composite measure of EA comprising the relative availability of energy from glucose, FFA, and ketones. In addition, the protocol was conducted in a highly controlled setting allowing for accurate formulation of the test diets and collection of outcome data. Furthermore, the significant separation of respiratory quotient values, and the differences in glucose and insulin as expected based on calculated dietary glycemic load, show that we achieved the desired physiologic differentiation between diets. For these reasons, we can confidently assume that the data reflect the physiologic effect of the planned dietary interventions. Other strengths include the use of a crossover design in which each participant served as his or her own control, thereby limiting variability and mitigating the effect of the small sample size, and the selection of diets that span the full range of prevailing macronutrient compositions.
This study also has several limitations. Despite the strength of crossover design and the high power, the sample size was small, limiting generalizability. Several assumptions were made in calculating EA, though these assumptions rest upon physiological principles and withstand sensitivity analysis (in the case of FFA). The analysis did not include lactate, a labile metabolite that may be higher after an LF meal than a VLC meal
In conclusion, this study finds that EA in the postprandial state differs among diets, and may have implications for weight maintenance after weight loss. This finding does not support the use of LF diets, as presently endorsed by many organizations
The authors would like to acknowledge the study staff Hope Forbes, Sarah Kalil, and Erica Garcia-Lago for assistance with data collection and management; Karen Yee, Rachel Froelich, and Lisa Bielak for implementation of the dietary interventions; and Meredith Beard for administrative support. Additionally, we are grateful to the Harvard Medical School branch of the Doris Duke Clinical Research Fellowship for its support of the primary author for this project.