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 7

LEAP2 effects on arcuate hypothalamic NPY neuronal activity in mice.

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LEAP2 effects on arcuate hypothalamic NPY neuronal activity in mice. (A)...
(A) Brightfield illumination of a glass pipette patched onto a representative arcuate NPY-hrGFP neuron in a coronal brain section from an NPY-hrGFP mouse. (B) hrGFP fluorescence of the same neuron. (C) Complete dialysis of the neuron with Alexa Fluor 350. (D) Merged image of the NPY neuron targeted for electrophysiological recording. Scale bar: 50 μm. Arrows in A–D indicate the targeted NPY neuron. (E) A representative current-clamp record depicting the characteristic depolarization of arcuate NPY neurons by ghrelin (100 nM). (F) A representative current-clamp record showing hyperpolarization of NPY neuron by LEAP2 (100 nM). (G) A representative current-clamp trace demonstrating that ghrelin (100 nM) fails to alter the membrane potential of a NPY neuron that had previously been inhibited by LEAP2 (100 nM). (H) Scatter plot with bar illustrates the acute effects of acyl-ghrelin (100 nM, blue) and LEAP2 (100 nM, red) on the membrane potential of arcuate NPY neurons and that of ghrelin (100 nM) on the membrane potential of arcuate NPY neurons pretreated with and in the continued presence of LEAP2 (100 nM, black). (I) Representative current-clamp trace demonstrates reversal of acyl-ghrelin–induced depolarization of arcuate NPY neurons with addition of LEAP2 (100 nM). (J) Line graph illustrates the acute effects of acyl-ghrelin (100 nM, black) and the effect of the subsequent addition of LEAP2 (100 nM, red) in the continued presence of acyl-ghrelin on the membrane potential of arcuate NPY neurons. ***P < 0.001. Numbers within brackets indicate n for each experiment. Data in H are represented as mean ± SEM.