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 4

Changes associated with obesity in fasted humans.

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Changes associated with obesity in fasted humans. Fasted concentrations ...
Fasted concentrations of plasma LEAP2 (A), plasma acyl-ghrelin (B; as assessed using 2-site University of Virginia acy-ghrelin ELISA), and plasma LEAP2/acyl-ghrelin molar ratio (C) in a cohort of adults across BMI categories. Relationships of fasted plasma LEAP2 with BMI (D), percentage of body fat (E), plasma glucose (F), HOMA-IR (G), serum triglycerides (H), VAT (I), SCAT (J), VAT/SCAT ratio (K), and percentage of IHCL (L). All data in this figure are from cohort 1, except those depicted in A and D, which are from cohort 1Ex. Data in panel L are represented in semi-logarithmic scale (log10 x axis). Data were analyzed by 1-way ANOVA on ranks with post hoc Dunn’s test (A–C) or Spearman’s correlation coefficient (rS) (D–L). n = 21–33 (A–C); n = 105 (D); n = 90 (E and F); n = 84 (G and H); n = 41 (I–K); and n = 40 (L). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.