Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2

Research output: Contribution to journalJournal articlepeer-review

Standard

Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2. / Holm, Stephanie; Husted, Anna S; Skov, Louise J; Morville, Thomas H; Hagemann, Christoffer A; Jorsal, Tina; Dall, Morten; Jakobsen, Alexander; Klein, Anders B; Treebak, Jonas T; Knop, Filip K; Schwartz, Thue W; Clemmensen, Christoffer; Holst, Birgitte.

In: Endocrinology, Vol. 163, No. 6, bqac038, 2022.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Holm, S, Husted, AS, Skov, LJ, Morville, TH, Hagemann, CA, Jorsal, T, Dall, M, Jakobsen, A, Klein, AB, Treebak, JT, Knop, FK, Schwartz, TW, Clemmensen, C & Holst, B 2022, 'Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2', Endocrinology, vol. 163, no. 6, bqac038. https://doi.org/10.1210/endocr/bqac038

APA

Holm, S., Husted, A. S., Skov, L. J., Morville, T. H., Hagemann, C. A., Jorsal, T., Dall, M., Jakobsen, A., Klein, A. B., Treebak, J. T., Knop, F. K., Schwartz, T. W., Clemmensen, C., & Holst, B. (2022). Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2. Endocrinology, 163(6), [bqac038]. https://doi.org/10.1210/endocr/bqac038

Vancouver

Holm S, Husted AS, Skov LJ, Morville TH, Hagemann CA, Jorsal T et al. Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2. Endocrinology. 2022;163(6). bqac038. https://doi.org/10.1210/endocr/bqac038

Author

Holm, Stephanie ; Husted, Anna S ; Skov, Louise J ; Morville, Thomas H ; Hagemann, Christoffer A ; Jorsal, Tina ; Dall, Morten ; Jakobsen, Alexander ; Klein, Anders B ; Treebak, Jonas T ; Knop, Filip K ; Schwartz, Thue W ; Clemmensen, Christoffer ; Holst, Birgitte. / Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2. In: Endocrinology. 2022 ; Vol. 163, No. 6.

Bibtex

@article{02b519c2ed19439b939471ef3bbdef5b,
title = "Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2",
abstract = "INTRODUCTION: Liver-expressed antimicrobial peptide-2 (LEAP2) is an endogenous ghrelin receptor antagonist, which is upregulated in the fed state and downregulated during fasting. We hypothesized that the ketone body beta-hydroxybutyrate (BHB) is involved in the downregulation of LEAP2 during conditions with high circulating levels of BHB.METHODS: Hepatic and intestinal Leap2 expression were determined in 3 groups of mice with increasing circulating levels of BHB: prolonged fasting, prolonged ketogenic diet, and oral BHB treatment. LEAP2 levels were measured in lean and obese individuals, in human individuals following endurance exercise, and in mice after BHB treatment. Lastly, we investigated Leap2 expression in isolated murine hepatocytes challenged with BHB.RESULTS: We confirmed increased circulating LEAP2 levels in individuals with obesity compared to lean individuals. The recovery period after endurance exercise was associated with increased plasma levels of BHB levels and decreased LEAP2 levels in humans. Leap2 expression was selectively decreased in the liver after fasting and after exposure to a ketogenic diet for 3 weeks. Importantly, we found that oral administration of BHB increased circulating levels of BHB in mice and decreased Leap2 expression levels and circulating LEAP2 plasma levels, as did Leap2 expression after direct exposure to BHB in isolated murine hepatocytes.CONCLUSION: From our data, we suggest that LEAP2 is downregulated during different states of energy deprivation in both humans and rodents. Furthermore, we here provide evidence that the ketone body, BHB, which is highly upregulated during fasting metabolism, directly downregulates LEAP2 levels. This may be relevant in ghrelin receptor-induced hunger signaling during energy deprivation.",
keywords = "3-Hydroxybutyric Acid/metabolism, Animals, Diet, Ketogenic, Ghrelin/metabolism, Liver/metabolism, Mice, Obesity/metabolism, Receptors, Ghrelin/metabolism",
author = "Stephanie Holm and Husted, {Anna S} and Skov, {Louise J} and Morville, {Thomas H} and Hagemann, {Christoffer A} and Tina Jorsal and Morten Dall and Alexander Jakobsen and Klein, {Anders B} and Treebak, {Jonas T} and Knop, {Filip K} and Schwartz, {Thue W} and Christoffer Clemmensen and Birgitte Holst",
note = "{\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.",
year = "2022",
doi = "10.1210/endocr/bqac038",
language = "English",
volume = "163",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0013-7227",
publisher = "Oxford University Press",
number = "6",

}

RIS

TY - JOUR

T1 - Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2

AU - Holm, Stephanie

AU - Husted, Anna S

AU - Skov, Louise J

AU - Morville, Thomas H

AU - Hagemann, Christoffer A

AU - Jorsal, Tina

AU - Dall, Morten

AU - Jakobsen, Alexander

AU - Klein, Anders B

AU - Treebak, Jonas T

AU - Knop, Filip K

AU - Schwartz, Thue W

AU - Clemmensen, Christoffer

AU - Holst, Birgitte

N1 - © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.

PY - 2022

Y1 - 2022

N2 - INTRODUCTION: Liver-expressed antimicrobial peptide-2 (LEAP2) is an endogenous ghrelin receptor antagonist, which is upregulated in the fed state and downregulated during fasting. We hypothesized that the ketone body beta-hydroxybutyrate (BHB) is involved in the downregulation of LEAP2 during conditions with high circulating levels of BHB.METHODS: Hepatic and intestinal Leap2 expression were determined in 3 groups of mice with increasing circulating levels of BHB: prolonged fasting, prolonged ketogenic diet, and oral BHB treatment. LEAP2 levels were measured in lean and obese individuals, in human individuals following endurance exercise, and in mice after BHB treatment. Lastly, we investigated Leap2 expression in isolated murine hepatocytes challenged with BHB.RESULTS: We confirmed increased circulating LEAP2 levels in individuals with obesity compared to lean individuals. The recovery period after endurance exercise was associated with increased plasma levels of BHB levels and decreased LEAP2 levels in humans. Leap2 expression was selectively decreased in the liver after fasting and after exposure to a ketogenic diet for 3 weeks. Importantly, we found that oral administration of BHB increased circulating levels of BHB in mice and decreased Leap2 expression levels and circulating LEAP2 plasma levels, as did Leap2 expression after direct exposure to BHB in isolated murine hepatocytes.CONCLUSION: From our data, we suggest that LEAP2 is downregulated during different states of energy deprivation in both humans and rodents. Furthermore, we here provide evidence that the ketone body, BHB, which is highly upregulated during fasting metabolism, directly downregulates LEAP2 levels. This may be relevant in ghrelin receptor-induced hunger signaling during energy deprivation.

AB - INTRODUCTION: Liver-expressed antimicrobial peptide-2 (LEAP2) is an endogenous ghrelin receptor antagonist, which is upregulated in the fed state and downregulated during fasting. We hypothesized that the ketone body beta-hydroxybutyrate (BHB) is involved in the downregulation of LEAP2 during conditions with high circulating levels of BHB.METHODS: Hepatic and intestinal Leap2 expression were determined in 3 groups of mice with increasing circulating levels of BHB: prolonged fasting, prolonged ketogenic diet, and oral BHB treatment. LEAP2 levels were measured in lean and obese individuals, in human individuals following endurance exercise, and in mice after BHB treatment. Lastly, we investigated Leap2 expression in isolated murine hepatocytes challenged with BHB.RESULTS: We confirmed increased circulating LEAP2 levels in individuals with obesity compared to lean individuals. The recovery period after endurance exercise was associated with increased plasma levels of BHB levels and decreased LEAP2 levels in humans. Leap2 expression was selectively decreased in the liver after fasting and after exposure to a ketogenic diet for 3 weeks. Importantly, we found that oral administration of BHB increased circulating levels of BHB in mice and decreased Leap2 expression levels and circulating LEAP2 plasma levels, as did Leap2 expression after direct exposure to BHB in isolated murine hepatocytes.CONCLUSION: From our data, we suggest that LEAP2 is downregulated during different states of energy deprivation in both humans and rodents. Furthermore, we here provide evidence that the ketone body, BHB, which is highly upregulated during fasting metabolism, directly downregulates LEAP2 levels. This may be relevant in ghrelin receptor-induced hunger signaling during energy deprivation.

KW - 3-Hydroxybutyric Acid/metabolism

KW - Animals

KW - Diet, Ketogenic

KW - Ghrelin/metabolism

KW - Liver/metabolism

KW - Mice

KW - Obesity/metabolism

KW - Receptors, Ghrelin/metabolism

U2 - 10.1210/endocr/bqac038

DO - 10.1210/endocr/bqac038

M3 - Journal article

C2 - 35352108

VL - 163

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0013-7227

IS - 6

M1 - bqac038

ER -

ID: 310838438