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 8

Model of the effect of LEAP2 on acyl-ghrelin–mediated GHSR action.

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Model of the effect of LEAP2 on acyl-ghrelin–mediated GHSR action. The h...
The hormones LEAP2 and acyl-ghrelin both bind to GHSR. Acyl-ghrelin stimulates GHSR activity, while LEAP2 acts as a GHSR inverse agonist that blocks constitutive and acyl-ghrelin–mediated GHSR activity. A fall in plasma LEAP2 during deficient nutritional states (e.g., energy restriction and fasting) is usually associated with a coordinate rise in plasma acyl-ghrelin; these together create a permissive environment in which elevated acyl-ghrelin can most effectively act, for instance, to induce feeding, raise body weight, and/or prevent potentially life-threatening falls in blood glucose. In contrast, in states of nutritional abundance (e.g., obesity and food intake), a usual coordinated rise in plasma LEAP2 and fall in plasma acyl-ghrelin limits acyl-ghrelin’s orexigenic and blood glucose–raising actions so as to minimize food intake and increases in blood glucose. A shift in the plasma LEAP2/acyl-ghrelin molar ratio to higher levels may be a key determinant of ghrelin resistance that helps limit the contribution of acyl-ghrelin to obesity-associated morbidity.