Caloric restriction alters the metabolic response to a mixed-meal: results from a randomized, controlled trial

Abstract

Objectives: To determine if caloric restriction (CR) would cause changes in plasma metabolic intermediates in response to a mixed meal, suggestive of changes in the capacity to adapt fuel oxidation to fuel availability or metabolic flexibility, and to determine how any such changes relate to insulin sensitivity (S(I)).

Methods: Forty-six volunteers were randomized to a weight maintenance diet (Control), 25% CR, or 12.5% CR plus 12.5% energy deficit from structured aerobic exercise (CR+EX), or a liquid calorie diet (890 kcal/d until 15% reduction in body weight)for six months. Fasting and postprandial plasma samples were obtained at baseline, three, and six months. A targeted mass spectrometry-based platform was used to measure concentrations of individual free fatty acids (FFA), amino acids (AA), and acylcarnitines (AC). S(I) was measured with an intravenous glucose tolerance test.

Results: Over three and six months, there were significantly larger differences in fasting-to-postprandial (FPP) concentrations of medium and long chain AC (byproducts of FA oxidation) in the CR relative to Control and a tendency for the same in CR+EX (CR-3 month P = 0.02; CR-6 month P = 0.002; CR+EX-3 month P = 0.09; CR+EX-6 month P = 0.08). After three months of CR, there was a trend towards a larger difference in FPP FFA concentrations (P = 0.07; CR-3 month P = 0.08). Time-varying differences in FPP concentrations of AC and AA were independently related to time-varying S(I) (P<0.05 for both).

Conclusions: Based on changes in intermediates of FA oxidation following a food challenge, CR imparted improvements in metabolic flexibility that correlated with improvements in S(I).

Trial registration: ClinicalTrials.gov NCT00099151.

Trial registration: ClinicalTrials.gov NCT00099151 NCT00427193.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Flow of Participants through the CALERIE trial at Pennington Biomedical Research Center.

This Figure has been published previously , .

Figure 2. Trajectories of Fasting to Postprandial Metabolic Intermediate Concentration Changes over Time by Intervention Group.

Fasting to postprandial difference (FPPD) scores were computed as postprandial minus fasting concentration. Difference scores were used in principal component analyses and single component solutions were retained as described in Results. FPPD component scores in Figures A-C were calculated as: (1) FPPD = S1*(I1)+S2*(I2) +… Sk*(Ik); where: I1-ik are the k individual items used in the principal components analysis; S1–Sk are standardized scoring coefficients from the principal component analysis; and, I1-Ik are entered as (I/SdI) for each item. With equation 1, the FPPD component score is the average of the mean post-preprandial differences across items with each item weighted by its standardized scoring coefficient. Mean difference are expressed in standard deviation units. Significant trends (PA. Free Fatty Acids (FFA). (CR * 3 months P = 0.07) B. Acylcarnitines (AC). (CR * 3 months P = 0.02; CR * 6 month P = 0.002; CR+EX * 3 month P = 0.09; CR+EX * 6 month P = 0.08) C. Amino Acids (AA).

Figure 3. Baseline to Month Three Changes in Insulin Sensitivity: Average Group Improvements Despite Varied Individual Responses.

Each bar represents insulin sensitivity improvements for participating individuals. A. By intervention group. CR = Caloric restriction; CR+EX = Caloric restriction with exercise; Control = Healthy weight maintenance diet; LCD = Liquid calorie diet B. Intervention groups combined.

Figure 4. Correlation Between Fasting to Postprandial Component Changes and Predicted SI Change Over Time.

As described in Methods, fasting and postprandial concentrations of amino acids and acylcarnitines were measured at baseline, three months, and six months, and fasting to postprandial components were generated. SI was determined from insulin and glucose concentrations measured during a frequently sampled intravenous tolerance test at each of baseline, three, and six months. Linear models were used to relate time varying concentrations of fasting to postprandial amino acid and acylcarnitine component to time varying insulin sensitivity (SI). Scatter plots depict the relation between fasting to postprandial component scores and predicted SI. A. Relation between Acylcarnitines (AC) Fasting to Postprandial Component Scores and Predicted SI Over Time. Since postprandial AC concentrations are larger than fasting, more negative fasting to postprandial differences represent more metabolic flexibility. B. Relation between Amino Acid (AA) Fasting to Postprandial Component Scores and Predicted SI Over Time.

Figure 5. Preprandial and postprandial concentrations of acylcarnitines in response to caloric restriction (CR).

Baseline and three month acylcarnitine concentrations are shown for both fasting (preprandial) and postprandial assessments. The six acylcarnitines that had the largest loadings on the acylcarnitine factor (see Table 1) are shown.

Figure 6. Preprandial and postprandial concentrations of amino acids for those with the highest and lowest insulin sensitivity changes.

Baseline and three month amino acids concentrations are shown for both fasting (preprandial) and postprandial assessments. The five amino acids that had the largest loadings on the amino acid factor (see Table 1) are shown. Leu/Ile = leucine/isoleucine, Phe = phenylalanine, Met = Methionine, His = Histidine, Val = Valine.