LEAP2 changes with body mass and food intake in humans and mice
Authors: Nathan P Metzger
Jimmy D Bell
Kevin W Williams
Nancy Puzziferri
Navpreet Chhina
Bruce Gaylinn
Michael O Thorner
Juan A Rodriguez
Sherri Osborne-Lawrence
Anthony P Goldstone
Bharath K Mani
Jeffrey M Zigman
E Louise Thomas
Zhenyan He
Journal: Journal of Clinical Investigation (2019)
Discipline: CLINICAL MEDICINE
Keywords: Diabetes; Endocrinology; Metabolism; Neuroendocrine regulation; Obesity.
Affiliations: Division of Hypothalamic Research., Division of Endocrinology & Metabolism, Department of Internal Medicine., Department of Psychiatry, and., Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA., Department of Surgery, Veterans Administration North Texas Heath Care System, Dallas, Texas, USA., PsychoNeuroEndocrinology Research Group, Neuropsychopharmacology Unit, Centre for Psychiatry, and., Computational, Cognitive and Clinical Neuroimaging Laboratory, Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom., Department of Endocrinology, University of Virginia, Charlottesville, Virginia, USA., Research Centre for Optimal Health, University of Westminster, London, United Kingdom.

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. 

Retracted: No

PubPeer comments:
 The amount of data presented with statistically but not biologically significant results is scary and it is honestly weird for a Journal with an impact factor of more than 11. Figures 4A and 4E are obvious examples - the authors state that there is a positive correlation between LEAP2 and BMI and body fat %, however if you look carefully, there is no biologically significant differences for different BMI groups, and there is absolutely no correlation, regardless of what the r coefficient and the associated p-value is. ,