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 September 3, 2019; First 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 5

Changes associated with food intake in humans.

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Changes associated with food intake in humans. Plasma LEAP2 (A) at 0 hou...
Plasma LEAP2 (A) at 0 hours (after an overnight fast) and 1.5 hours (light gray) after eating a 377 kcal standard meal in normal weight women (BMI < 25 kg/m2) and in women with obesity (BMI > 35 kg/m2) (cohort 2). (B) Relationship of fasted plasma LEAP2 (0 hours) with BMI in cohort 2. (C) Relationship of the postprandial change in plasma LEAP2 (from baseline to 1.5 hours after the start of feeding; ΔLEAP2 0 to 1.5 hours) with BMI in cohort 2. (D) Corresponding plasma acyl-ghrelin concentrations (Millipore assay) of cohort 2. (E) Relationship of fasted plasma acyl-ghrelin (0 hours) with BMI in cohort 2. (F) Changes to LEAP2/acyl-ghrelin molar ratio in cohort 2. (G) Plasma LEAP2 at 0 hours, 1 hour (light gray), and 2 hours (dark gray) after consuming a 600 kcal liquid meal in adults with obesity (BMI > 35 kg/m2) (cohort 3). (H) Relationship of the postprandial change in plasma LEAP2 (from baseline to 2 hours after food intake; ΔLEAP2 0 to 2 hours) with BMI in cohort 3. Corresponding serum insulin (I), and plasma glucose (J) concentrations of cohort 3. Relationships of plasma LEAP2 with serum insulin (K) and plasma glucose (L) at baseline (0 hours), 1 hour, and 2 hours after consumption of the diet in cohort 3. Data in panel I are represented in semi-logarithmic scale (log10 y axis). Data were analyzed by 2-way repeated measures ANOVA followed by Šidák’s post hoc test (A, D, and F), Pearson’s correlation (r) (B and E), Spearman’s correlation (rs) (C, H, K, and L), or 1-way repeated measures ANOVA on ranks with post hoc Dunn’s test (G, I, and J). n = 12 for normal weight women; n = 20 for women with obesity (A–F); n = 20 (G–L). Data in G, I, and J are represented as mean ± SEM. **P < 0.01; ***P < 0.001; ****P < 0.0001.