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

Bharath Kumar 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

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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

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Ghrelin
Eating
Peptides
Liver
Blood Glucose
Gastric Bypass
Gastrectomy
Fasting
Ghrelin Receptor
Electrophysiology
Starvation
Type 1 Diabetes Mellitus
Hypoglycemia
Oral Administration
Obesity
Body Weight
Phenotype
Neurons
Glucose
Food

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mani, B. K., Puzziferri, N., He, Z., Rodriguez, J. A., Osborne-Lawrence, S., Metzger, N. 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

LEAP2 changes with body mass and food intake in humans and mice. / Mani, Bharath Kumar; Puzziferri, Nancy; He, Zhenyan; Rodriguez, Juan A.; Osborne-Lawrence, Sherri; Metzger, Nathan P.; Chhina, Navpreet; Gaylinn, Bruce; Thorner, Michael O.; Louise Thomas, E.; Bell, Jimmy D.; Williams, Kevin W; Goldstone, Anthony P.; Zigman, Jeffrey M.

In: Journal of Clinical Investigation, Vol. 129, No. 9, 03.09.2019, p. 3909-3923.

Research output: Contribution to journalArticle

Mani, BK, Puzziferri, N, He, Z, Rodriguez, JA, Osborne-Lawrence, S, Metzger, NP, Chhina, N, Gaylinn, B, Thorner, MO, Louise Thomas, E, Bell, JD, Williams, KW, Goldstone, AP & Zigman, JM 2019, 'LEAP2 changes with body mass and food intake in humans and mice', Journal of Clinical Investigation, vol. 129, no. 9, pp. 3909-3923. https://doi.org/10.1172/JCI125332
Mani BK, Puzziferri N, He Z, Rodriguez JA, Osborne-Lawrence S, Metzger NP et al. LEAP2 changes with body mass and food intake in humans and mice. Journal of Clinical Investigation. 2019 Sep 3;129(9):3909-3923. https://doi.org/10.1172/JCI125332
Mani, Bharath Kumar ; Puzziferri, Nancy ; He, Zhenyan ; Rodriguez, Juan A. ; Osborne-Lawrence, Sherri ; Metzger, Nathan P. ; Chhina, Navpreet ; Gaylinn, Bruce ; Thorner, Michael O. ; Louise Thomas, E. ; Bell, Jimmy D. ; Williams, Kevin W ; Goldstone, Anthony P. ; Zigman, Jeffrey M. / LEAP2 changes with body mass and food intake in humans and mice. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 9. pp. 3909-3923.
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AU - Osborne-Lawrence, Sherri

AU - Metzger, Nathan P.

AU - Chhina, Navpreet

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AU - Thorner, Michael O.

AU - Louise Thomas, E.

AU - Bell, Jimmy D.

AU - Williams, Kevin W

AU - Goldstone, Anthony P.

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