Specific appetite, energetic and metabolomics responses to fat overfeeding in resistant-to-bodyweight-gain constitutional thinness

Abstract

Background: Contrasting with obesity, constitutional thinness (CT) is a rare condition of natural low bodyweight. CT exhibits preserved menstruation in females, no biological marker of undernutrition, no eating disorders but a bodyweight gain desire. Anorexigenic hormonal profile with high peptide tyrosine tyrosine (PYY) was shown in circadian profile. CT could be considered as the opposite of obesity, where some patients appear to resist diet-induced bodyweight loss.

Objective: The objective of this study was to evaluate appetite regulatory hormones in CTs in an inverse paradigm of diet-induced weight loss.

Methods: A 4-week fat overfeeding (2640 kJ excess) was performed to compare eight CT women (body mass index (BMI)<17.5 kg m(-)(2)) to eight female controls (BMI 18.5-25 kg m(-)(2)). Appetite regulatory hormones profile after test meal, food intake, bodyweight, body composition, energy expenditure and urine metabolomics profiles were monitored before and after overfeeding.

Results: After overfeeding, fasting total and acylated ghrelin were significantly lower in CTs than in controls (P=0.01 and 0.03, respectively). After overfeeding, peptide tyrosine tyrosine (PYY) and glucagon-like-peptide 1 both presented earlier (T15 min vs T30 min) and higher post-meal responses (incremental area under the curve) in CTs compared with controls. CTs failed to increase bodyweight (+0.22±0.18 kg, P=0.26 vs baseline), contrasting with controls (+0.72±0.26 kg, P=0.03 vs baseline, P=0.01 vs CTs). Resting energy expenditure increased in CTs only (P=0.031 vs baseline). After overfeeding, a significant negative difference between total energy expenditure and food intake was noticed in CTs only (-2754±720 kJ, P=0.01).

Conclusion: CTs showed specific adaptation to fat overfeeding: overall increase in anorexigenic hormonal profile, enhanced post prandial GLP-1 and PYY and inverse to controls changes in urine metabolomics. Overfeeding revealed a paradoxical positive energy balance contemporary to a lack of bodyweight gain, suggesting yet unknown specific energy expenditure pathways in CTs.

Figure 1

GLP-1 and PYY post-test meal kinetic changes. Post-test meal kinetic changes in anorexigenic gut hormones before overfeeding (day 5), at the end of the 2640 kJ (630 kcal) per day excess overfeeding period (day 34) and after ad libitum food intake period (day 62) in the CT group (n=8, dotted line) and the control group (controls, n=8, plain line). Standardized test meal (1373 kJ (328 kcal); 80% carbohydrates, 13% lipids and 7% proteins) was served and eaten between T0 min and 15 min. (a) iAUC for total GLP-1 expressed as pmol per l.90 min at each test meal (days 5, 34 and 62). (b) iAUC for PYY_3–36 expressed as pg ml⁻¹ per 90 min at each test meal. (c) Kinetic changes of total GLP-1 after test meal expressed as percentage change from baseline (T0) on days 5, (d) 34 and (e) 62. (f) Kinetic changes of PYY_3–36 after test meal on days 5, (g) 34 and (h) 62. Data are expressed as mean±s.e.m. Statistical analysis: *P<0.05 vs T0 min in each group; $P<0.05 between CTs and controls.

Figure 2

Ghrelin/obestatin post-test meal kinetic changes. Post-test meal kinetic changes in ghrelin/obestatin before overfeeding (day 5), at the end of the 2640 kJ (630 kcal) per day excess overfeeding period (day 34) and after ad libitum food intake period (day 62) in the CT group (n=8, dotted line) and the control group (controls, n=8, plain line). Standardized test meal (1373 kJ (328 kcal); 80% carbohydrates, 13% lipids and 7% proteins) was served and eaten between T0 min and 15 min. (a) iAUC for total ghrelin expressed as pg ml⁻¹ per 90 min at each test meal (days 5, 34 and 62). (b) iAUC for acylated ghrelin expressed as pg ml⁻¹ per 90 min at each test meal. (c) iAUC for obestatin expressed as mg ml⁻¹ per 90 min at each test meal. (d) Kinetic changes in total ghrelin after test meal expressed as percentage change from baseline (T0) on days 5, (e) 34 and (f) 62. (g) Kinetic changes in acylated ghrelin after test meal on days 5, (h) 34 and (i) 62. (j) Kinetic changes in obestatin after test meal on days 5, (k) 34 and (l) 62. Data are expressed as mean±s.e.m. Statistical analysis: *P<0.05 vs T0 min in each group; $P<0.05 between CTs and controls.

Figure 3

Energy balance. Energy balance before overfeeding (day 5), at the end of the 2640 kJ (630 kcal) per day excess overfeeding period (day 34) and after ad libitum food intake period (day 62) in the CT group (n=8) and the control group (controls, n=8). Total daily energy expenditure (grey bars) was calculated as follows: TEE=REE × physical activity level. The physical activity level was evaluated with an accelerometer. Food intake (white bars) was evaluated with a daily dietary record completed for 5 days. The energy gap (striped boxes) was calculated as follows: TEE−food intake. Data are expressed as mean±s.e.m. Statistical analysis: *P<0.05 between TEE and food intake. 1NS=non-significant. a indicates P<0.05 vs day 5.

Figure 4

Metabolomics urine analysis. Metabolomics urine analysis before overfeeding (day 5), at the end of the 2640 kJ (630 kcal) per day excess overfeeding period (day 34) and after ad libitum food intake period (day 62) in the CT group (n=8) and the control group (controls, n=8). (a) PLS analysis with orthogonal signal correction (OSC-PLS) score plots of component 1 vs component 2 showing the group × time effect (CT34 R2cum=0.62, CT34 Q2cum=0.62). Day 5 controls are in red, day 34 controls in green, day 62 controls in blue, day 5 CTs in black, day 34 CTs in pink and day 62 CTs in orange. (b) Heatmap representing a hierarchical clustering analysis of the samples (group × time) and significant ions for interaction. The blue color corresponds to the highest value and yellow color to the lowest ones.