TY - JOUR
T1 - LEAP2 changes with body mass and food intake in humans and mice
AU - Mani, Bharath Kumar
AU - Puzziferri, Nancy
AU - He, Zhenyan
AU - Rodriguez, Juan A.
AU - Osborne-Lawrence, Sherri
AU - Metzger, Nathan P.
AU - Chhina, Navpreet
AU - Gaylinn, Bruce
AU - Thorner, Michael O.
AU - Louise Thomas, E.
AU - Bell, Jimmy D.
AU - Williams, Kevin W.
AU - Goldstone, Anthony P.
AU - Zigman, Jeffrey M.
N1 - Funding Information:
This work was supported by the NIH (R01DK103884 to JMZ, R01DK100699 and R01DK119169 to KWW, and NCATS ULTR000451 to NP), 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., a gift from the David and Teresa Disiere Foundation (to JMZ), and funds from UT Southwestern Medical Center Department of Surgery (to NP). In the United Kingdom, this work was supported by grants from the United Kingdom Medical Research Council, the Wellcome Trust, the Imperial College Healthcare Charity, the European Union Sixth Framework Marie-Curie Programme, and an Imperial Wellcome-GSK fellowship (to NC), and infrastructure support was provided by the National Institute of Health Research (NIHR) Imperial Biomedical Research Centre and the NIHR Imperial Clinical Research Facility, Imperial College Healthcare National Health Service (NHS) Trust, London, United Kingdom. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the United Kingdom Department of Health and Social Care. We thank Joel Elmquist (UT Southwestern Medical Center) for kindly providing the NPY-hrGFP mice. We thank the staff of the Metabolic and Molecular Imaging Group and the Robert Steiner MRI Unit, MRC Clinical Sciences Centre, Imperial College London; the Division of Diabetes, Endocrinology and Metabolism, Imperial College London; the NIHR Imperial Clinical Research Facility, Hammersmith Hospital; the Imperial Weight Centre, St. Mary’s Hospital, the Imperial College Healthcare NHS Trust, and the Bariatric Clinic, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom for assistance with the United Kingdom studies.
Funding Information:
This work was supported by the NIH (R01DK103884 to JMZ, R01DK100699 and R01DK119169 to KWW, and NCATS ULTR000451 to NP), 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., a gift from the David and Teresa Disiere Foundation (to JMZ), and funds from UT Southwestern Medical Center Department of Surgery (to NP). In the United Kingdom, this work was supported by grants from the United Kingdom Medical Research Council, the Wellcome Trust, the Imperial College Healthcare Charity, the European Union Sixth Framework Marie-Curie Programme, and an Imperial Wellcome-GSK fellowship (to NC), and infrastructure support was provided by the National Institute of Health Research (NIHR) Imperial Biomedical Research Centre and the NIHR Imperial Clinical Research Facility, Imperial College Healthcare National Health Service (NHS) Trust, London, United Kingdom. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the United Kingdom Department of Health and Social Care. We thank Joel Elmquist (UT Southwestern Medical Center) for kindly providing the NPY-hrGFP mice. We thank the staff of the Metabolic and Molecular Imaging Group and the Robert Steiner MRI Unit, MRC Clinical Sciences Centre, Imperial College London; the Division of Diabetes, Endocrinology and Metabolism, Imperial College London; the NIHR Imperial Clinical Research Facility, Hammersmith Hospital; the Imperial Weight Centre, St. Mary's Hospital, the Imperial College Healthcare NHS Trust, and the Bariatric Clinic, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom for assistance with the United Kingdom studies.
Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019/9/3
Y1 - 2019/9/3
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI125332
DO - 10.1172/JCI125332
M3 - Article
C2 - 31424424
AN - SCOPUS:85071788917
SN - 0021-9738
VL - 129
SP - 3909
EP - 3923
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -