SPLTRAK Abstract Submission
The endogenous ghrelin receptor antagonist LEAP2 changes with body mass and feeding in humans and mice.
BHARATH K. MANI1, NANCY PUZZIFERRI2,3, JUAN RODRIGUEZ1, SHERRI OSBORNE-LAWRENCE1, NATHAN METZGER1, ANTHONY P. GOLDSTONE4,5,6, JEFFREY M. ZIGMAN1,7,8
1Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States/2Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, United States/3Department of Surgery, Veterans Administration North Texas Heath Care System, Dallas, TX, United States/4PsychoNeuroEndocrinology Research Group, Neuropsychopharmacology Unit, Centre for Psychiatry, Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom/5Computational, Cognitive, and Clinical Neuroimaging Laboratory, Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom/6Imperial Centre for Endocrinology, Imperial College Healthcare NHS Trust, St Mary’s and Charing Cross Hospitals, London, United Kingdom/7Division of Endocrinology & Metabolism, Department of Internal Medicine, Dallas, TX, United States/8Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, United States
   LEAP2 (Liver Enriched Antimicrobial Peptide-2) has been newly characterized as a ghrelin receptor antagonist and inverse agonist. Here, we hypothesize that changes in plasma LEAP2 enhance ghrelin’s metabolic actions during fasted conditions while facilitating ghrelin resistance in obese states. To test this hypothesis, we determined changes in plasma LEAP2 and acyl-ghrelin due to fasting, eating, obesity, bariatric surgery, glucose administration, and Type 1 diabetes mellitus, using human subjects and/or mice.  Plasma LEAP2 positively correlated with BMI in humans and fat mass content in mice. Fasting lowered LEAP2 in humans with obesity and in lean mice.  Oral glucose administration increased LEAP2 in fasted mice. These changes in LEAP2 were mostly opposite to those of acyl-ghrelin (except following bariatric surgery or in a Type 1 diabetes model), leading to robust increases in the plasma LEAP2:acyl-ghrelin ratio in conditions of obesity and robust falls in the LEAP2:acyl-ghrelin ratio during fasted states. These results suggest that plasma LEAP2 is physiologically regulated by metabolic status, with its levels increasing with body mass and blood glucose, and decreasing with fasting. These metabolically-regulated changes to plasma LEAP2 are opposite to those for acyl-ghrelin in lean subjects and subjects with obesity in both the fed and fasted states but not following bariatric surgery or in a mouse model of Type 1 diabetes.  We predict that the plasma LEAP2:acyl-ghrelin ratio may be a key determinant modulating acyl-ghrelin activity in response to changes in body mass, feeding status, or blood glucose. We also propose that elevated plasma LEAP2 may confer ghrelin resistance during obese states, as would also be indicated by a higher plasma LEAP2:acyl-ghrelin ratio. 

Supported By: NIH (R01DK103884, NCATS ULTR000451), the Diana and Richard C. Strauss Professorship in Biomedical Research, the Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine, the Kent and Jodi Foster Distinguished Chair in Endocrinology, in Honor of Daniel Foster, M.D., and institutional funds from the University of Texas Southwestern Medical Center