LEAP2 changes with body mass and food intake in humans and mice
Bharath K. Mani, … , Anthony P. Goldstone, Jeffrey M. Zigman
Bharath K. Mani, … , Anthony P. Goldstone, Jeffrey M. Zigman
Published August 19, 2019
Citation Information: J Clin Invest. 2019;129(9):3909-3923. https://doi.org/10.1172/JCI125332.
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Research Article Endocrinology Metabolism

LEAP2 changes with body mass and food intake in humans and mice

Abstract

Acyl-ghrelin administration increases food intake, body weight, and blood glucose. In contrast, mice lacking ghrelin or ghrelin receptors (GHSRs) exhibit life-threatening hypoglycemia during starvation-like conditions, but do not consistently exhibit overt metabolic phenotypes when given ad libitum food access. These results, and findings of ghrelin resistance in obese states, imply nutritional state dependence of ghrelin’s metabolic actions. Here, we hypothesized that liver-enriched antimicrobial peptide-2 (LEAP2), a recently characterized endogenous GHSR antagonist, blunts ghrelin action during obese states and postprandially. To test this hypothesis, we determined changes in plasma LEAP2 and acyl-ghrelin due to fasting, eating, obesity, Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), oral glucose administration, and type 1 diabetes mellitus (T1DM) using humans and/or mice. Our results suggest that plasma LEAP2 is regulated by metabolic status: its levels increased with body mass and blood glucose and decreased with fasting, RYGB, and in postprandial states following VSG. These changes were mostly opposite of those of acyl-ghrelin. Furthermore, using electrophysiology, we showed that LEAP2 both hyperpolarizes and prevents acyl-ghrelin from activating arcuate NPY neurons. We predict that the plasma LEAP2/acyl-ghrelin molar ratio may be a key determinant modulating acyl-ghrelin activity in response to body mass, feeding status, and blood glucose.

Authors

Bharath K. Mani, Nancy Puzziferri, Zhenyan He, Juan A. Rodriguez, Sherri Osborne-Lawrence, Nathan P. Metzger, Navpreet Chhina, Bruce Gaylinn, Michael O. Thorner, E. Louise Thomas, Jimmy D. Bell, Kevin W. Williams, Anthony P. Goldstone, Jeffrey M. Zigman

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Figure 6

Effects of RYGB and VSG in humans with obesity.

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Effects of RYGB and VSG in humans with obesity. BMI (A) and fasted plasm...
BMI (A) and fasted plasma LEAP2 (B) at baseline and at approximately 3 months (n = 14) and 2 years (n = 8) following RYGB (cohort 3A). Relationships of fasted plasma LEAP2 with BMI (C) and plasma glucose (D) before and 2 years after RYGB surgery in cohort 3A. Plasma LEAP2 (E) in adults before (baseline) and approximately 3 months after RYGB surgery before (time 0 hours) and 2 hours after ingestion of a 600 kcal liquid meal in cohort 3B (n = 11). BMI (F) at before (baseline) and at approximately 12 to 18 months following VSG surgery (cohort 2A). Plasma LEAP2 (G), acyl-ghrelin (H) (Millipore assay), and LEAP2/acyl-ghrelin molar ratio (I) in women with obesity before (baseline) and approximately 12 to 18 months after VSG surgery before (time 0 hours) and 1.5 hours after the start of consuming a standard 337 kcal meal following an overnight fast (cohort 2A). n = 7 (F–I). Data were analyzed by mixed effects ANOVA, followed by Šidák’s post hoc tests (A and B), Spearman’s correlation (rs) (C and D), 2-way repeated measures ANOVA with Šidák’s post-hoc test (E and G–I), and Students paired t test (F). Data in graphs (A, B, and E–I) are represented as mean ± SEM. *P < 0.05; **P < 0.01; ****P < 0.0001.