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 1

Responses to chronic HFD and weight loss in mice.

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Responses to chronic HFD and weight loss in mice. Body weight curves of ...
Body weight curves of mice fed chow (lean) or HFD (obese) for 16 weeks (A). Ad libitum–fed plasma LEAP2 (B), plasma acyl-ghrelin (C), and plasma LEAP2/acyl-ghrelin molar ratio (D). Relationships of plasma LEAP2 (E) and plasma acyl-ghrelin (F) with fat mass. Body weights measured at 8 and 12 weeks in a separate cohort fed chow for 12 weeks (lean), HFD for 12 weeks (obese), or HFD for 8 weeks to induce obesity followed by chow for 4 weeks to induce weight loss (G). Inset shows body weight curves of the 3 groups throughout the study period. Arrows in the inset indicate the 8- and 12-week time points for measuring the following: plasma LEAP2 (H), plasma acyl-ghrelin (I), and plasma LEAP2/acyl-ghrelin molar ratio (J). Relationship of plasma LEAP2 (K) and plasma acyl-ghrelin (L) with fat mass at 12 weeks. Plasma LEAP2 replotted from H to facilitate analyzing plasma LEAP2 changes over time within the lean and obese groups (M). Data were analyzed by 2-way repeated measures ANOVA followed by Šidák’s post hoc test (A), Student’s unpaired t test (B–D and M), Pearson’s correlation coefficient (r) (E, F, K, and L), 1-way ANOVA followed by Šidák’s post hoc test (G–I), or 1-way ANOVA on ranks with post-hoc Dunn’s test (J). n = 10–12 (A–F); n = 9–11 (G–M). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.