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

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

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3909-3923
Number of pages15
JournalJournal of Clinical Investigation
Volume129
Issue number9
DOIs
StatePublished - Sep 3 2019

ASJC Scopus subject areas

  • Medicine(all)

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    Mani, B. K., Puzziferri, N., He, Z., Rodriguez, J. A., Osborne-Lawrence, S., Metzger, N. P., Chhina, N., Gaylinn, B., Thorner, M. O., Louise Thomas, E., Bell, J. D., Williams, K. W., Goldstone, A. P., & Zigman, J. M. (2019). LEAP2 changes with body mass and food intake in humans and mice. Journal of Clinical Investigation, 129(9), 3909-3923. https://doi.org/10.1172/JCI125332