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. Author manuscript; available in PMC: 2024 Jan 1.
Published in final edited form as: Obesity (Silver Spring). 2022 Dec 5;31(1):139–149. doi: 10.1002/oby.23584

The Association between Gut Hormones and Diet-induced Metabolic Flexibility in Metabolically Healthy Adults

Yigit Unlu 1, Karyne L Vinales 1,2, Tim Hollstein 1,5, Douglas Chang 1, Tomás Cabeza de Baca 1, Mary Walter 3, Jonathan Krakoff 1, Paolo Piaggi 1,4,*
PMCID: PMC9780166  NIHMSID: NIHMS1835207  PMID: 36471908

Abstract

Objective:

We investigated whether inter-individual variance in diet-induced metabolic flexibility is explained by differences in gut hormone concentrations.

Methods:

Sixty-nine healthy participants with normal glucose regulation underwent 24-h assessments of respiratory quotient (RQ) in a whole-room indirect calorimeter during eucaloric feeding (EBL; 50% carbohydrate, 30% fat) and then, in a crossover design, during 24-h fasting and three normal-protein (20%) overfeeding diets (200% energy requirements). Metabolic flexibility was defined as the change in 24-h RQ from EBL during standard (50% carbohydrate), high-fat (60%), and high-carbohydrate (75%) overfeeding diets. Plasma concentrations of GLP-1 and PYY after an overnight fast were measured prior to and after each diet.

Results:

Compared to EBL, on average 24-h RQ decreased by ~4% during high-fat overfeeding, while increasing by ~4% during standard overfeeding and by ~9% during high-carbohydrate overfeeding. During high-carbohydrate overfeeding, but not during any other overfeeding diet or fasting, increased GLP-1 concentration was associated with increased RQ (r=0.44, p<0.001), higher/lower carbohydrate/lipid oxidation rates (r=0.34 and r=−0.51, both p<0.01), respectively, and increased insulin concentration (r=0.38, p=0.02).

Conclusion:

Increased GLP-1 concentration following high-carbohydrate overfeeding associated with a greater shift to carbohydrate oxidation, suggesting that GLP-1 may be implicated in diet-induced metabolic flexibility to carbohydrate overload.

Keywords: respiratory quotient, carbohydrate oxidation, fat oxidation, metabolic flexibility, overfeeding, substrate oxidation

INTRODUCTION

The global prevalence of obesity and overweight individuals has reached pandemic proportions(1). Weight gain leads to obesity as the result of chronic positive energy balance caused by relatively higher total energy intake vs. energy expenditure(2), or relatively higher macronutrient intake (e.g., fat intake) vs. its respective oxidation rate (e.g., lipid oxidation(3)) Our research group has previously demonstrated that relatively lower lipid oxidation rate both during isocaloric(4) and overfeeding(5) conditions is associated with subsequent weight gain. Specifically, individuals able to acutely alter substrate oxidation in response to changes in macronutrient composition of a given diet are considered to have a greater “metabolic flexibility”(6, 7). Physiologic factors such as diet-related hormones, degree of insulin action, and skeletal muscle efficiency may explain the inter-individual variability in the extent of diet-induced metabolic flexibility which is associated with weight change (6, 8).

Glucagon-like peptide 1 (GLP-1) is a post-prandially secreted gut hormone mediating glucose-stimulated insulin secretion (incretin effect) and central induction of satiety (anorexigenic effect) (9, 10). Peptide YY (PYY) is an anorexigenic hormone within the Neuropeptide Y receptor family regulating energy balance by slowing gastric emptying and reducing food intake (11, 12, 13). There is emerging evidence indicating that these hormones act beyond the gut-brain axis signaling of satiety as they also affect substrate utilization partitioning and, hence, metabolic flexibility(14, 15, 16, 17, 18, 19). Although overfeeding-induced metabolic flexibility has been studied in healthy individuals before (5, 20), the majority of studies investigating the role of gut hormones on metabolic flexibility have been conducted in rodents(14, 19, 21, 22, 23) or by exogenous hormone administration (16, 18, 24, 25, 26) rather than on physiological levels in response to diet. Therefore, the aim of our current study was to assess whether physiologic changes in gut hormones (GLP-1 and PYY) induced by acute, short-term fasting and overfeeding diets with different macronutrient proportions (high-carbohydrate vs. high-fat diets) are implicated in the physiological mechanisms of diet-induced metabolic flexibility assessed for 24 hours via whole-room indirect calorimetry.

METHODS

Study Volunteers

The data utilized for this analysis was obtained from a concluded clinical trial (ClinicalTrials.gov identifier: NCT00523627) which aimed to determine the effects of acute dietary interventions on energy metabolism and future weight change. All volunteers provided written informed consent before beginning the study. This study was approved by the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health. A total of 69 individuals aged 19–54 years completed the study from 2008–2015 and had available measurements of plasma GLP-1 and PYY concentrations (Supporting Information Figure S1). Participants self-reported a stable weight within the previous 6 months and were healthy based on history, physical examination, and routine blood tests upon admission. The experimental protocol is shown in Supporting Information Figure S2. On admission to the clinical research unit, participants were placed on a standard normal-protein weight maintaining diet (WMD; 50% carbohydrate, 30% fat, and 20% protein) for at least three days prior to any metabolic testing. Body weight was recorded daily and was maintained within 1% of the weight on admission day by modifying the daily caloric intake by ±200 kcal/day when needed. On day 2, dual-energy X-ray absorptiometry (Lunar Prodigy, enCORE 2003 software version 7.53.002, GE Lunar, Madison, WI, USA) was used to determine body composition measures including percentage body fat, fat mass, and fat free mass. All participants had normal glucose regulation according to ADA criteria (27) based on a standard 75-g oral glucose tolerance test performed at least 3 days on the WMD.

Energy Expenditure Measurements

A whole-room indirect calorimeter (respiratory chamber) was used for the assessment of 24-hour energy expenditure (EE) and respiratory quotient (RQ, an index of substrate oxidation). In this equipped room, O2 consumption (VO2) and CO2 production (VCO2) were measured on a minute-by-minute basis and used to calculate the average 24-h RQ defined as the ratio between the average VCO2 and the average VO2 calculated over 24 hours. The rate of 24-h EE was calculated based on average 24-h VO2 and RQ values using the Lusk’s equation (28). Carbohydrate (CARBOX) and lipid (LIPOX) oxidation rates were derived from the 24-h RQ after accounting for protein oxidation estimated from measurement of 24-h urinary nitrogen excretion (29). Similar results were obtained when CARBOX and LIPOX were derived using the formula of Elia and Livesey (30).

After an overnight fast and following breakfast (20% of total daily calories) at 7am, participants entered the chamber around 8 am. Three meals were then provided through an airtight interlock at 11am (lunch, accounting for 27.5% of total calories), 4pm (dinner, 27.5%), and 7pm (evening snack, 20%). Food that was not eaten was returned and weighed to determine the actual energy intake during each 24-hour session. The air temperature of the chamber was maintained constant at 24.0±1.4°C by an air conditioning system. Volunteers resided in the chamber for each dietary session for about 23.25 hours. Quality control assessments were performed monthly during the period of this study by burning instrument-grade propane and demonstrated average recoveries of predicted VO2 and VCO2 equal to 98±3% (coefficient of variation, CV=3.4%) and 99±3% (CV=3.6%), respectively.

Dietary Interventions

The experimental protocol for dietary interventions is shown on Supporting Information Figure S2 (31). Two consecutive 24-h EE measurements were performed in eucaloric conditions inside the whole-room calorimeter to calculate 24-h energy needs in this setting. During the first session, the total caloric intake was determined by a unit-specific formula(29). Two days following the first eucaloric chamber session, participants underwent a second eucaloric chamber session when the total caloric intake was set to the 24-h EE obtained during the first eucaloric chamber session. The 24-h EE and RQ measurements calculated during the second eucaloric chamber session were considered as the baseline values. The baseline 24-h EE was doubled to obtain the caloric intake for the subsequent chamber sessions when subjects were provided the following overfeeding diets in random order: standard overfeeding (50% carbohydrate and 30% fat), high-carbohydrate (75% carbohydrate and 5% fat), and high-fat (60% fat and 20% carbohydrate) overfeeding diets, all containing double the protein calories given for the eucaloric (baseline) diet. A 24-h fasting chamber session was also conducted when participants fasted for 24-h, during which only water and non-caloric beverages were permitted. Participants were fed a eucaloric standard diet (i.e., WMD) for three days in between these dietary interventions to minimize the effects of the previous diets on energy metabolism. The wash-out period was sufficiently long so there were no significant carry-over effects for any of the variables analyzed (all p >0.14). Chamber sessions in which the volunteer consumed less than <95% of the caloric requirement of the diet were excluded from the data analysis. For each participant, the overall extent of diet-induced metabolic flexibility (5) was quantified as the difference between the average 24-h RQ during each overfeeding and fasting intervention minus the average 24-h RQ during energy balance conditions, thus including both the daytime and nighttime periods. Changes in CARBOX and LIPOX during each dietary intervention with respect to their values during energy balance conditions were similarly calculated. Thus, metabolic flexibility represents the inter-individual changes in these parameters to the diets.

Hormone Measurements

Plasma for gut hormones measurements was collected in the morning after an overnight fast in EDTA-containing tubes at entry (pre-diet measurement) and at exit (post-diet measurement) from the calorimeter before and after each 24-h dietary condition, respectively. Samples were treated with aprotinin and dipeptidyl peptidase IV (DPP-IV) inhibitor (EMD Millipore Corporation, Billerica, MA, USA), and then frozen to −70°C for later measurements. Total GLP-1 and PYY were measured using immunoassay kits from Meso Scale Discovery (MSD) (Rockville, MD) with lower limits of detection of 0.98 pg/mL and 68 pg/mL, respectively. The intra- and inter- assay CV were 3.3% and 5.0% (GLP-1) and 2.5% and 3.1% (PYY), respectively. The limits of detection for the GLP-1 kit were 0.005–38.4 pg/mL and all measurements were within the acceptable range for this assay. In a subset of 34 individuals, plasma insulin concentrations were measured both prior to and after each dietary intervention by an automated immunoenzymometric assay (Tosoh Bioscience Inc., Tessenderlo, Belgium).

Statistical analysis

Statistical analyses were performed using SAS 9.4 software (SAS Institute, Cary, NC). Data are presented as mean with standard deviation or with 95% confidence interval (CI). For each hormone, the intra-class correlation coefficient (ICC) was calculated using all pre-diet measurements to assess reproducibility of baseline levels. For each individual, all pre-diet measurements were then averaged to calculate the baseline concentration of each gut hormone. Differences in baseline concentrations between sexes and races/ethnicities were evaluated using Student’s unpaired t-test and ANOVA, respectively. The Spearman’s correlation index was used to assess the effect of storage time on baseline concentrations.

The individual change (Δ) in gut hormone concentrations after each 24-h dietary intervention was calculated as the post-diet measurement minus the pre-diet measurement. Changes in hormone concentration following dietary interventions were analyzed by Student’s paired t-test. The relationships between diet-induced changes in hormone concentrations and the changes in 24-h RQ, EE and substrate oxidation rates during each overfeeding/fasting condition compared to energy balance conditions (e.g., metabolic flexibility) were analyzed using the Pearson’s correlation index. Multivariate regression analyses including both GLP-1 and PYY as predictors were performed to evaluate the independent effects of each hormone on the changes in RQ and EE after accounting for covariates (age, sex, and percentage body fat). Statistical significance was considered for a two-tailed p<0.05. Sensitivity analyses were conducted including only in men and similar results were obtained (data not shown).

RESULTS

Clinical characteristics of the study cohort are shown on Table 1. The ICC values of baseline (pre-diet) concentrations of GLP-1 and PYY were 0.64 and 0.65 (all p<0.001), respectively, indicating consistency of baseline hormone measurements within individuals. Plasma concentrations of GLP-1 correlated with storage time (ρ=−0.46, p<0.001, Supporting Information Figure S6), therefore the analyses of baseline GLP-1 concentration were performed after adjustment for storage time. No associations with anthropometric, demographic, and OGTT measurements were found for baseline GLP-1 and PYY concentrations (all p>0.05). Similarly, no associations were found between baseline gut hormone measurements and 24-h EE and RQ during energy balance conditions (all p>0.05).

Table 1.

Participant characteristics.

Whole cohort n=69 Men n=53 Women n=16
Age (years) 35.5±10.5 (19.2–54.0) 36.8±10.6 (19.2–54.0) 31.5±9.2 (20.3–45.4)
Race / Ethnicity BL 15, W 20, H 12, NA 22 BL 10, W 15, H 10, NA 18 BL 5, W 5, H 2, NA 4
BMI (kg/m 2 ) 26.5±4.2 (17.7–39.2) 26.3±3.6 (18.2–36.8) 27±6.1 (17.7–39.2)
Weight (kg) 79.1±13.7 (47.5–107.8) 80.7±11.8 (52.8–104.8) 73.7±18.0 (47.5–107.8) *
Body Fat (%) 28.1±10.2 (6.9–53.8) 24.8±8.1 (6.9–38.3) 39.0±8.8 (24.2–53.8) *
FM (kg) 22.8±10.8 (4.9–56.9) 20.6±8.7 (4.9–37.2) 30.2±13.9 (13.6–56.9) *
FFM (kg) 56.2±9.8 (33.8–79.4) 60.1±7.3 (43.4–79.4) 43.5±5.0 (33.8–53.2) *
Fasting Glucose (mg/dL) 91.0±5.15 (79.5–99.5) 91.2±5.2 (80.0–99.5) 90.4±4.9 (79.5–97.5)
2-hr OGTT glucose (mg/dL) 105±19 (65–138) 104±20 (65–138) 108±17 (80–132)
Fasting Insulin (μU/mL) 8.0 ± 5.1 (1.2–32) 7.5 ± 5.1 (1.2–32) 9.8 ± 4.9 (4.5–23.5)
2-hr OGTT Insulin (μU/mL) 50.7 ± 41.5 (4–222) 47.4 ± 38.4 (4–185) 62.8 ± 51.2 (20–222)
24-h energy intake during energy balance (MJ /day) 8.6 ± 1.3 (6.3–12.2) 8.9 ± 1.2 (6.8–12.2) 7.6 ± 1.1 (6.3–9.4) *
24-h EE during energy balance (MJ/day) 8.48±1.28(5.97,11.76) 8.78±1.21(6.59,11.76) 7.47±1.01(5.97,9.59)
24-h RQ during energy balance (ratio) 0.86±0.03(0.80–0.93) 0.86±0.03 (0.80–0.93) 0.86±0.03 (0.81–0.91)
24-h energy balance (kJ/day) 84.9 ± 320.5 (−811.7–707.1)) 81.2 ± 328.0 (−811.7–644.3) 97.5 ± 304.6 (−338.9–707.1)
Baseline# plasma total GLP-1 (pg/mL) 9.6±4.2 (2.0–27.3) 9.7±3.5 (3.1–16.8) 9.4±6.2 (2.0–27.3)
Baseline# plasma total PYY (pg/mL) 31.8±12.5 (9.7–69.6) 32.0±12.7 (9.7–69.6) 31.2±12.3 (13.5–60.9)
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Data are presented as mean ± SD (minimum, maximum) unless otherwise indicated.

*:

Statistically significant difference between males and females by Student t-test.

#:

Baseline measurements were calculated for each individual by averaging all pre-diet concentrations.

Abbreviations: BL: Black; W: White H: Hispanic; NA: Native American; BMI: body mass index; EE: energy expenditure; FFM: fat free mass; FM: fat mass; RQ: respiratory quotient; GLP-1: Glucagon like Peptide-1; PYY: Peptide YY; OGTT: Oral Glucose Tolerance Test

Changes in gut hormone concentrations after 24-hour dietary interventions

The changes in plasma concentrations of gut hormones after each 24-h dietary intervention are reported in Table 2, in Figure 1, and in Supporting Information Figure S5. Both GLP-1 and PYY concentrations showed significant changes after 24-h fasting and overfeeding diets with altered macronutrient content as detailed below, whereas no overall changes were observed after 24-h standard overfeeding (both p>0.20).

Table 2.

Changes in plasma hormone concentrations after 24-h dietary interventions.

Diet Pre-diet Post-diet Absolute Change Percent Change p-value
24-h fasting
Total GLP-1 (pg/mL) 10.1±4.9 (0.9,26.7) 12.8±6.8 (1.7,36.6) 2.7±6.0 (–11.4,29.4) 26.5% (12.0%, 41.0%) p<0.001
Total PYY (pg/mL) 36.0±17.1 (7.7,107.5) 25.4±17.7 (2.3,95.5) −10.7±14.1 (−35.8,25.5) −29.6% (−39.7%, −19.5%) p<0.001
Insulin (μU/mL) 7.6±3.2 (3.3,17.3) 3.8±2.1 (0.1,10.0) −3.8±3.0 (−10.9,0.3) −50.4% (−64.1%, −36.7%) p<0.001
24-h High Carbohydrate Overfeeding
Total GLP-1 (pg/mL) 9.7±4.9 (2.1,24.7) 8.8±4.2 (1.1,22.7) −1.0±3.5 (−11.7,6.8) −9.9% (−19.0%, −0.8%) p=0.03
Total PYY (pg/mL) 32.1±15.2 (7.7,78.4) 38.6±21.6 (10.5,145.5) 6.5±16.4 (−29.5,67.1) 20.3% (7.2%, 33.3%) p=0.003
Insulin (μU/mL) 7.0±2.3 (3.9,11.7) 10.3±5.4 (5.0,26.3) 3.3±4.4 (−1.9,16.8) 46.7% (24.8%, 68.5%) p<0.001
24-h High Fat Overfeeding
Total GLP-1 (pg/mL) 9.8±7.2 (1.6,44.5) 11.0±6.1 (2.2,31.4) 1.2±4.6 (–13.7,16.6) 12.1% (0.2%, 24.1%) p=0.04
Total PYY (pg/mL) 32.3±13.0 (12.2,73.7) 38.8±19.8 (10.7,88.5) 6.4±13.8 (−20.6,41.4) 19.9% (8.8%, 31.1%) p=0.007
Insulin (μU/mL) 8.4±3.6 (3.7,16.2) 8.4±3.5 (3.6,17.0) −0.03±3.6 (−8.4,8.0) −0.4% (−16.1%, 15.2%) p=0.95
24-h Standard Overfeeding
Total GLP-1 (pg/mL) 9.1±3.9 (1.3,18.8) 9.7±5.7 (1.0,37.2) 0.7±4.2 (–5.3,22.5) 7.3% (−5.1%, 19.6%) p=0.24
Total PYY (pg/mL) 31.9±15.0 (2.9,71.8) 35.8±17.3 (5.3,76.7) 3.9±13.5 (−26.3,59.0) 12.3% (1.3%, 23.4%) p=0.29
Insulin (μU/mL) 7.7±3.5 (3.3,18.7) 11.0±5.5 (4.2,26.4) 3.3±3.3 (−2.7,10.2) 42.6% (26.2%, 59.1%) p<0.001
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Data are presented as mean±SD (minimum, maximum), except for percentage changes that are reported as mean with 95% CI. Significant changes (p<0.05) by Student’s paired t-test are reported in bold.

Figure 1. Changes in gut hormone concentrations after each 24-h dietary intervention.

Figure 1.

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Changes in plasma GLP-1 and PYY concentrations after each 24-hour dietary intervention. The individual change in hormone concentrations on the y-axis was calculated as the difference between the post-diet minus the pre-diet values. Error bars represent 95% CI of the mean. Asterisks represent the significant changes in hormone concentrations with a p <0.05 by Student’s paired t-test. Diet composition: standard overfeeding diet (50% carbohydrate, 30% fat, 20% protein), high-carbohydrate overfeeding diet (75% carbohydrate, 5% fat, 20% protein), high-fat overfeeding diet (20% carbohydrate, 60% fat, 20% protein).

Fasting

After 24-h fasting, on average GLP-1 increased by ~26% (CI: 12–41, p<0.001) whereas PYY concentration decreased by ~30% (CI: −40% to −19%, p<0.001). The change in GLP-1 after 24-h fasting was positively associated with the concomitant changes in PYY within the same individual (r=0.45, p<0.001, Supporting Information Figure S3 panel A). Similar results were obtained after adjustment for age, sex, and body fat (partial r=0.40, p=0.01).

High-carbohydrate overfeeding

After 24-h of high-carbohydrate overfeeding diet, on average GLP-1 decreased by ~10% (CI: −19% to −1%, p=0.03) whereas PYY increased by 20% (CI: 7–33%, p=0.003). The change in GLP-1 after 24-h high-carbohydrate overfeeding was positively associated with the concomitant changes in PYY within the same individual (r=0.57, p<0.001, Supporting Information Figure S3 panel B). Similar results were obtained after adjustment for age, sex, and body fat (partial r=0.50, p<0.001). Plasma insulin concentration increased on average by 47% (CI: 25–68%, p<0.001) following 24-h high-carbohydrate overfeeding. The increase in plasma insulin was positively correlated to the increase in GLP-1 (r=0.38, p=0.02, Figure 2).

Figure 2. Relationship between the change in GLP-1 and the change in insulin concentrations following 24-h high-carbohydrate overfeeding.

Figure 2.

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Positive relationship between changes in plasma GLP-1 concentration and changes in plasma insulin concentration following 24-h high-carbohydrate overfeeding. The strength of association was quantified by the Pearson’s correlation index.

High-fat overfeeding

After 24-h high-fat overfeeding diet, both GLP-1 and PYY increased (12%, CI: 0.2–24%; 20%, CI: 9–31%, respectively, both p<0.05) with both changes being correlated within each individual (r=0.45, p<0.001, Supporting Information Figure S3 panel C). Similar results were obtained after adjustment for age, sex, and body fat (partial r=0.38, p<0001).

Relationships between diet-induced changes in gut hormones and metabolic flexibility

The 24-h RQ increased from eucaloric conditions during standard overfeeding (Δ = 3.5%, CI: 2.8–4.2%, p<0.001) and high-carbohydrate overfeeding (Δ = 8.6%, CI: 7.7–9.5%, p<0.001), reflecting an increase in carbohydrate oxidation rate (Δ = 32%, CI: 26.4–37.6% and Δ = 72.5%, CI: 64.9–80.1%, respectively, all p<0.001) and a decrease in lipid oxidation rate (Δ = −32.9%, CI: −41.1% to −24.6%, and Δ = −76.3%, CI: −86.8% to −65.8%, respectively, all p<0.001). During high-carbohydrate overfeeding, four individuals had evidence of de novo lipogenesis (lipid synthesis: 396±138 kcal/day, range: 311–602). Conversely, the 24-h RQ decreased from eucaloric conditions during high-fat overfeeding (Δ = −3.9%, CI: −5.1% to −2.8%, p<0.001) and 24-h fasting (Δ = −8.9%, CI: −9.6% to −8.2%, p<0.001), reflecting a decrease in carbohydrate oxidation rate (Δ = −20.5%, CI: −28.5% to −12.6%, and Δ = −54.8%, CI: −59.6% to −50.0%, respectively, all p<0.001) and an increase in lipid oxidation rate (Δ = 35.1%, CI: 24.0–46.2%, and Δ = 70.7%, CI: 62.3–79.2%, respectively, all p<0.001). The 24-h measurements of energy expenditure and substrate oxidation rates/balances and the correlations between macronutrients intake and 24-h RQ during each dietary intervention are reported in Supporting Information Tables S1 and S2, respectively. The associations between macronutrients intake and hormonal changes during each dietary intervention are shown in Supporting Information Table S3.

Despite on average GLP-1 concentration decreased after 24-h high-carbohydrate overfeeding, the individual change in GLP-1 was positively associated with the concomitant change in RQ (r=0.44, p<0.001, Figure 3A), such that an increase of 3 pg/mL in GLP-1 was associated with an average increase in RQ by 0.01 during 24-h high-carbohydrate overfeeding. The change in GLP-1 after the high-carbohydrate overfeeding diet was positively associated with increased CARBOX (r=0.34, p=0.006, Figure 3B) and negatively associated with LIPOX (r=−0.51, p<0.0001, Figure 3C), such that a change of 1 pg/mL in GLP-1 was associated with an average higher CARBOX by 26 kcal/day and lower LIPOX by 35 kcal/day during high-carbohydrate overfeeding. The relationships persisted after adjustment for covariates (age, sex, and body fat, data not shown).

Figure 3. Relationships between changes in GLP-1 and changes in RQ, carbohydrate and lipid oxidation rates during 24-h high-carbohydrate overfeeding.

Figure 3.

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Relationships between changes in plasma GLP-1 concentration and changes in 24-h RQ and macronutrient oxidation rates during high-carbohydrate overfeeding. Changes in 24-hour RQ and macronutrient oxidation rates shown on the y-axis of each panel were calculated as difference from the respective values during energy balance conditions. The strength of association was quantified by the Pearson’s correlation index. CARBOX, carbohydrate oxidation rate; LIPOX, lipid oxidation rate; RQ, respiratory quotient.

The individual change in PYY following the high-carbohydrate overfeeding diet was also positively associated with the concomitant change in RQ (r=0.25, p=0.05, Figure 4A), such that a change of 25 pg/mL in PYY was associated with an average increase in RQ by 0.01 during 24-h high-carbohydrate overfeeding. The change in PYY after the high-carbohydrate overfeeding diet was positively associated with the increase in CARBOX (r=0.24, p=0.06, Figure 4B) and negatively associated with the decrease in LIPOX (r=−0.32, p=0.001, Figure 4C), such that a change of 10 pg/mL in PYY was associated with an average increase in CARBOX by 40 kcal/day and decreased LIPOX by 48 kcal/day. The relationships persisted after adjustment for covariates (age, sex, and body fat, data not shown). In a multivariate analysis including both changes in GLP-1 and PYY after high-carbohydrate overfeeding, only the change in GLP-1 (p=0.01), but not in PYY (p=0.60), was independently associated with the changes in RQ during 24-h high-carbohydrate overfeeding. Similar results were obtained for macronutrient oxidation rates (data not shown).

Figure 4. Relationships between changes in PYY and changes in RQ, carbohydrate and lipid oxidation rates during 24-h high-carbohydrate overfeeding.

Figure 4.

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Relationships between changes in plasma PYY concentration and changes in 24-hour RQ and macronutrient oxidation rates during high-carbohydrate overfeeding. Changes in 24-hour RQ and macronutrient oxidation rates shown on the y-axis of each panel were calculated as difference from the respective values during energy balance conditions. The strength of association was quantified by the Pearson’s correlation index. CARBOX, carbohydrate oxidation rate; LIPOX, lipid oxidation rate; RQ, respiratory quotient.

Compared to eucaloric conditions, on average 24-h EE increased during each overfeeding diet, with the largest increase being after high-carbohydrate overfeeding (Δ = 13.5%, CI: 12.1–14.9%, p<0.001) and the smallest increase being after high-fat overfeeding Δ = 7.6%, CI: 6.2–9.1%, p<0.001). Conversely, an overall reduction in 24-h EE was observed during 24-h fasting (Δ = −7.7%, CI: −9.0% to −6.5%, p<0.001). No associations were observed between the changes in gut hormone concentrations and the changes in 24-h EE during any of dietary interventions (all p>0.05), except for GLP-1 being associated with the changes in 24-h EE during high-fat overfeeding (r=0.31, p=0.02, Supporting Information Figure S4).

DISCUSSION

In the present study including healthy subjects with normal glucose regulation, we sought to assess the impact of gut hormones GLP-1 and PYY on the extent of metabolic flexibility assessed over 24h during acute dietary interventions such as 24-h fasting and 200% normal-protein overfeeding diets with varying carbohydrate and fat content, which have been previously shown to identify metabolic phenotypes associated with long-term weight change(5, 32). Plasma concentrations of GLP-1 and PYY showed significant changes only after 24 hours of macronutrient-imbalanced overfeeding diets (high-carbohydrate and high fat diets) and 24-h fasting, but not following 24 hours on the macronutrient-balanced overfeeding diet. However, changes in hormone concentrations were associated with changes in 24-h RQ and in 24-h carbohydrate and lipid oxidation rates only during the high-carbohydrate (75%) overfeeding diet, suggesting that the gut hormones GLP-1 and PYY are involved in diet-induced metabolic flexibility to high-carbohydrate dietary challenge.

Metabolic Flexibility is the ability to adapt whole-body energy metabolism by sensing, utilizing, and storing nutrients based on substrate availability and metabolic requirements. Metabolic flexibility is essential to maintain energy homeostasis in settings of both caloric excess (5) and deprivation (33) and has been linked to the individual predisposition to future weight gain. Specifically, reduced fat oxidation rate overnight following 140% overfeeding for three days predicted greater free-living weight gain after five years (34). Similarly, we previously showed that impaired metabolic flexibility to acute high-fat overfeeding (e.g., relatively lower lipid oxidation rate during overfeeding) is associated with long-term weight gain in free-living conditions (5). Because the physiological mechanisms underlying metabolic flexibility have not been fully elucidated, we investigated changes in plasma concentration of gut hormones (GLP-1 and PYY) in response to acute fasting and overfeeding diets with diets with different macronutrient content. While the average change in RQ that quantifies metabolic flexibility is highly dependent on the macronutrient composition of the overfeeding diet (e.g., high-carbohydrate diets lead to increased RQ while the opposite is observed when the diet is rich in fats), there is a wide variability in the extent of metabolic flexibility even when the overfeeding diet is standardized among individuals (5). Accordingly, in the present study we aimed to evaluate whether the gut hormones response to acute overfeeding diets and fasting explain part of the inter-individual variability in diet-induced metabolic flexibility.

Both GLP-1 and PYY are predominantly secreted in response to the ingestion of meals from the L cells located in the distal gut. Peripheral GLP-1 is most commonly associated with gastrointestinal secretion and motility and augmentation of insulin secretion, such that ~50% of the total glucose-dependent insulin secretion is ascribable to the effects of GLP-1, the so-called “incretin” effect (35, 36). Further, GLP-1 induces satiety by acting on appetite centers within the hypothalamus that receive and integrate afferent signals, which ultimately modulate food intake (37). These centers include high concentrations of the following neurons that either have an orexigenic or anorexigenic effect when signaled: Neuropeptide Y [NPY], Agouti Related Peptide [AgRP] (increase food intake when signaled) and Pro- Opiomelanocortin [POMC] and Cocaine & Amphetamine Regulated Transcript [CART] (decreases food intake when signaled). PYY also acts on these appetite-regulating nuclei and induces satiety by delaying gastric emptying upon food ingestion(21). Beyond participating in the gut-brain axis signaling of satiety and delaying of gastric emptying, both GLP-1 and PYY also influence substrate utilization partitioning(14, 15, 16, 17, 19). Plasma GLP-1 is associated with increased lipid oxidation and decreased RQ both during resting (fasting) conditions when administered exogenously (17) (15, 16), although not all studies have demonstrated this effect(26). Acute and chronic administration of PYY to rodents stimulates lipid oxidation over carbohydrate oxidation (14, 19). To the best of our knowledge, there are not any studies conducted to test whether physiologic secretion of gut hormones induced by macronutrient-imbalanced diets mediate metabolic flexibility. Specifically, we obtained hormonal and metabolic measurements in four different dietary conditions given for 24 hours including 24-h fasting and three overfeeding diets with varying macronutrients content.

Plasma PYY decreased on average by ~30% after 24-h fasting while GLP-1 increased by approximately the same amount. The increase in GLP-1 following prolonged fasting was contrary to the current understanding of GLP-1 being a post-prandial hormone(38). We suspect that the strict timing of meals in our study entrainment (meal anticipation) may have led to this increase, a phenomenon mainly described in rats that is thought to facilitate subsequent consumption of a large meal(39). The decrease in plasma PYY concentration after prolonged fasting was expected as PYY is a post-prandially gut hormone secreted in proportion to ingested calories. Despite these changes in gut hormones following 24-h fasting, neither was associated with concomitant changes in substrate oxidation rate or energy expenditure observed during prolonged fasting conditions.

We found positive associations between the changes in gut hormone concentration and metabolic flexibility during the high-carbohydrate overfeeding diet. Compared to the eucaloric diet, this overfeeding diet had twice the total caloric content of which 75% were carbohydrates (as opposed to 50% as in the eucaloric diet), thus the actual carbohydrate intake in this overfeeding diet was three times that of the baseline (eucaloric) diet. Due to this large dietary carbohydrate load, carbohydrate oxidation rate increased substantially (mean=+73%) and lipid oxidation rate decreased (mean=−77%) reflecting the necessity to switch substrate for oxidation to compensate for greater carbohydrate intake. On average, plasma GLP-1 concentration decreased following 24-h high-carbohydrate overfeeding although the magnitude of this decrease was small (mean=−10%). The lack of increase in plasma GLP-1 concentration following 24-h high-carbohydrate overfeeding could be partly due to the timing of blood draw, which took place after a 12-h overnight fast and could not capture the acute post-prandial increase in GLP-1 expected following high-carbohydrate hypercaloric meals. The lack of an increase in GLP-1 following high-carbohydrate overfeeding compared to high-fat overfeeding could also be due to a previously described attenuation of GLP-1 response to oral carbohydrates in individuals with obesity(40, 41, 42, 43), which is commonly attributed to an increase in plasma non-esterified fatty acids at baseline in these individuals(40, 41, 43). Nevertheless, the individual change in plasma GLP-1 concentration following 24-h high-carbohydrate overfeeding was positively associated with concomitant increases both in RQ and carbohydrate oxidation rate, and negatively associated with the change in lipid oxidation rate. We found a positive relationship between the increase in plasma GLP-1 concentration and the increase in plasma insulin following high-carbohydrate overfeeding, such that individuals with increased GLP-1 concentration in response to this dietary challenge had higher increases in insulin concentration, 24-h RQ and carbohydrate oxidation rate. Although our study design cannot prove causality, these results are in line with the hypothesis that GLP-1 acts as an incretin and suggest that the ability to increase carbohydrate oxidation in response to high-carbohydrate intake (i.e., diet-induced metabolic flexibility) may depend in part on the GLP-1 via its effect on insulin. Specifically, individuals who were able to increase GLP-1 following high-carbohydrate overfeeding also had greater increase in carbohydrate oxidation, presumably due to greater stimulation of insulin release by GLP-1 (incretin effect) as the increase in GLP-1 was positively correlated with the increase in plasma insulin concentration (Figure 2). The increase in PYY following high-carbohydrate overfeeding was also positively associated with diet-induced changes both in RQ and carbohydrate oxidation rate and negatively associated with lipid oxidation rate. However, our multivariate analysis including both GLP-1 and PYY indicated that the effect of PYY on metabolic flexibility measures was not independent from the effect of GLP-1. Thus, the PYY results by the univariate analysis may be due to a direct effect of GLP-1 on PYY secretion or due to the co-secretion of these hormones (Supporting Information Figure S1) making their physiologic roles difficult to disentangle.

Strengths and limitations

The strength of our study is the quantification of diet-induced metabolic flexibility via whole-room indirect calorimetry (44) to accurately assess energy metabolism for 24 hours while precisely controlling total energy intake and macronutrients content. Further, in addition to macronutrient imbalanced overfeeding diets, our study design also included a balanced overfeeding diet that: 1) had the same macronutrient composition of the energy balance diet, thus allowing the comparison between the two diets with the same macronutrient composition but different total caloric content; 2) allowed for comparison of macronutrient changes among the overfeeding diets.

Yet, we acknowledge that one of the limitations of current study was the lack of hormonal measurements in the post-prandial phase following meals ingestion, thus not allowing characterization of the short-term gut hormones post-prandial response (45, 46). This was due to the inability to draw blood during the 24 hours while volunteers resided inside the sealed environment of the metabolic chamber. Another limitation was the relatively high proportion of Native Americans (~32%) in our study cohort, which may not reflect that in the general population and may limit generalization of current findings. Although all our participants had normal glucose regulation and were likely more insulin sensitive, another limitation was the lack of direct measurements of insulin action as inter-individual variability in insulin sensitivity may explain in part differences in metabolic flexibility (6) independent from the insulinotropic effect of GLP-1 on insulin secretion. Further, insulin concentration was measured only in half the cohort although this subset was statistically adequate to detect the expected relationship between GLP-1 and insulin concentrations. Lastly, future studies should include assessment of mitochondrial function and substrate sensing to elucidate the cellular mechanisms underlying metabolic flexibility and fuel partitioning.

Conclusion

In the present study including healthy volunteers with normal glucose regulation, we evaluated the impact of gut hormones on diet-induced changes in substrate oxidation (i.e., metabolic flexibility) during 24-h fasting and varying overfeeding diets with different macronutrients composition. We found that during the high-carbohydrate overfeeding diet, but not after the other overfeeding diets or fasting, changes in plasma concentration of both GLP-1 and PYY were positively associated with changes in RQ and fuel selection, such that increased (decreased) gut hormone concentrations were associated with relatively greater (lower) carbohydrate oxidation rate and lower (greater) lipid oxidation rate during high-carbohydrate overfeeding. However, only GLP-1, but not PYY, was independently associated with quantitative measures of metabolic flexibility and plasma insulin concentration following this diet. These results suggest that the gut hormone GLP-1 may be implicated in the metabolic response to carbohydrate overload. A better understanding of the hormonal basis of diet-induced metabolic flexibility may allow the development of pharmacological therapies to prevent overfeeding-induced weight gain or to treat obesity and related metabolic diseases.

Supplementary Material

supinfo

Study Importance:

What is already known?

  • Metabolic flexibility represents the ability to switch the main substrate source for oxidation

  • Impaired metabolic flexibility (e.g., lower fat oxidation rate) to changes in dietary macronutrient content is associated with future weight gain.

  • Gut Hormones are secreted in response to nutrient ingestion, with GLP-1 and PYY influencing carbohydrate and lipid oxidation in different feeding conditions.

What does this study add?

  • Acute (200% energy requirements), short-term (24-h) overfeeding diets with different macronutrient content (high-carbohydrate vs. high-fat diets) induce changes both in 24-h respiratory quotient, substrate oxidation rates, as well as GLP-1 and PYY plasma concentrations.

  • Increased plasma GLP-1 concentration following 24-h high-carbohydrate overfeeding was associated with greater extent of fuel switching from lipids to carbohydrates, hence greater metabolic flexibility.

How might your results change the direction of research or the focus of clinical practice?

  • Clinical studies investigating diet-induced metabolic flexibility should consider including measurements of gut hormones as putative hormonal mediators of fuel switching

ACKNOWLEDGMENTS

The authors thank the volunteers who participated in the study. We also thank the nursing, clinical, dietary, and laboratory staff of the Phoenix Epidemiology and Clinical Research Branch for assistance conducting the study visits and for care of the volunteers. Data described in the manuscript will be made available upon request pending application and approval by the Institutional Review Board of the NIDDK.

Funding:

This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. P.P. was supported by the program “Rita Levi Montalcini for young researchers” from the Italian Minister of Education and Research (Ministero dell’Istruzione, dell’Università e della Ricerca).

Abbreviations

CARBOX

carbohydrate oxidation rate

EBL

standard eucaloric feeding

EE

energy expenditure

FFM

fat free mass

FM

fat mass

FST

fasting

GLP-1

Glucagon like peptide-1

ICC

intraclass correlation coefficient

LIPOX

lipid oxidation rate

NPY

Neuropeptide Y

PYY

Peptide YY

RQ

Respiratory quotient

Footnotes

Clinical Trial Registration Number (from clinicaltrials.gov): NCT00523627

Conflict of interest Statement: The authors have nothing to disclose.

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