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. 2023 Sep 22;26(11):107996.
doi: 10.1016/j.isci.2023.107996. eCollection 2023 Nov 17.

The role of dysregulated ghrelin/LEAP-2 balance in anorexia nervosa

Chloé Tezenas du Montcel  1   2 , Philibert Duriez  1   2 , Jingxian Cao  1 , Nicolas Lebrun  1 , Nicolas Ramoz  1 , Odile Viltart  1   3 , Philip Gorwood  1   2 , Virginie Tolle  1
Affiliations

The role of dysregulated ghrelin/LEAP-2 balance in anorexia nervosa

Chloé Tezenas du Montcel et al. iScience. .

Abstract

LEAP-2 is a ghrelin antagonist with an anorexigenic drive. This study investigates the evolution of plasma ghrelin and LEAP-2 concentrations in 29 patients with anorexia nervosa (AN) before and after refeeding and compares it to physiological adaptations during fasting in healthy controls or to mouse model of chronic food restriction and refeeding. Acute and chronic food restriction decrease LEAP-2 and increase ghrelin concentrations in both humans and mice, while patients with AN displayed higher ghrelin and LEAP-2 concentrations before than after refeeding (p = 0.043). After 6 months follow-up, patients with unstable weight gain (n = 17) had significantly decreased LEAP-2 concentrations after refeeding (p = 0.044), in contrast to patients with stable weight gain (n = 12). We provide evidence that the ghrelin/LEAP-2 system is not regulated according to the nutritional status in AN, in contrast to what is physiologically expected when coping with food restriction.

Keywords: Biological sciences; Endocrinology; Health sciences; Medicine; Natural sciences; Nutrition; Psychiatry.

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Conflict of interest statement

Philip Gorwood received during the last 5 years fees for presentations at congresses or participation in scientific boards from Angelini, EISI, Janssen, Lundbeck, Otsuka, Pileje and Merk. The other authors have no interest to declare.

Figures

None
Graphical abstract
Figure 1
Figure 1
AG/LEAP-2 ratio is a sensor of chronic food restriction and refeeding in female mice Food-restricted mice of both FR and FRW group exhibited significant weight loss compared to ad libitum fed controls (A) but progressive refeeding over 10 days restored their body weight. Chronic food restriction was associated with increased plasma levels of acyl-ghrelin (B) and decreased levels of LEAP-2 (C) independently of running wheel in home-cage. AG/LEAP-2 ratio was higher in FR and FRW mice compared to ad libitum fed controls with no effect of the running wheel. Progressive refeeding lead to a significant decrease in AG plasma levels (F) and increase in LEAP-2 levels (G) leading to decreased AG/LEAP-2 molar ratio in refed FR and FRW mice. n = 8 animals per group. After refeeding, blood samples of the FRW group were assayed for AG in 7 mice only because of insufficient blood volume extracted at sacrifice for one animal. Data are presented as mean ± SEM plus individual values and were analyzed using three-way ANOVA (A), two-way ANOVA (B–D) or RM ANOVA (E–G) as described in Table S1. ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0,0001. AG: Acyl-ghrelin. LEAP-2: Liver-expressing Antimicrobial Peptide.
Figure 2
Figure 2
Flow chart of the longitudinal study in patients suffering from AN 42 patients following the inclusion criteria were admitted in the inpatient program so far. Among them, 39 patients were initially included in the study and 3 patients had to be excluded because the delay between admission and inclusion exceeded 8 days. During hospitalization, 9 patients were excluded because they dropped out of the inpatient program, and one was excluded because of somatic complications. On the remaining patients, 29 out of 30 went through the follow-up visit 6 months after discharge.
Figure 3
Figure 3
Dysregulated AG/LEAP-2 balance in patients with AN BMI (A) increased with refeeding during hospitalization in 30 patients with AN. AG levels (expressed in pmol/L, B) were significantly decreased with refeeding. LEAP-2 levels were also significantly decreased with refeeding (C). AG/LEAP-2 molar ratio (D) decreased after refeeding compared to undernourished state. Data are expressed as mean ± SEM plus individual values and were analyzed using paired Student’s t test: ∗p < 0.05, ∗∗∗∗p < 0.0001. BMI: Body mass Index (kg/m2), AG: Acyl-ghrelin. LEAP-2: Liver-expressing Antimicrobial Peptide-2. V1: undernourished state at admission; V2: refed state at discharge.
Figure 4
Figure 4
Higher LEAP-2 levels at admission than after discharge is associated with unstable remission AG/LEAP-2 evolution with refeeding in patients with stable (n = 12, BMI>18.5 kg/m2, A–C) and unstable remission (n = 17, BMI<18.5 kg/m2, D–F) 6 months after discharge. AG levels decreased after refeeding in stable (A) and unstable (D) patients. LEAP-2 levels remained stable during refeeding in patients with stable remission at 6 months (B) but significantly decreased in patients with unstable remission (E). The AG/LEAP-2 molar ratio decreased with refeeding in patients with stable remission (C) but did not significantly differ between before and after refeeding in patients with unstable remission (F). Data are expressed as individual values and were analyzed using paired Student’s t test or Mann-Whitney: ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. AG: Acyl-ghrelin. LEAP-2: Liver-Expressing Antimicrobial Peptide-2.
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