Regulation of LEAP2 by insulin and glucagon in mice and humans
Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous antagonist and inverse agonist of the ghrelin receptor, countering ghrelin's effects on cell signaling and feeding. However, despite an emerging interest in LEAP2's physiology and pharmacology, its endocrine regulation remains unclear. Here, we report that plasma LEAP2 levels decrease significantly upon glucagon infusions during somatostatin clamps in humans. This effect is preserved in patients with obesity and type 2 diabetes while diminished following a hypercaloric diet and a sedentary lifestyle for 2 weeks. Additionally, insulin receptor antagonism offsets the upregulation of LEAP2 during the postprandial state in mice. Finally, insulin and glucagon receptor-expressing hepatocytes are the primary source of hepatic LEAP2 expression, coinciding with a putative enhancer-like signature bound by insulin- and glucagon-regulated transcription factors at the LEAP2 locus. Collectively, our findings implicate insulin and glucagon in regulating LEAP2 and warrant further investigations into the exact mechanisms orchestrating this endocrine axis.
Authors
- Natalia Petersen (ORCID: https://orcid.org/0000-0001-9344-6041)
- Malte P. Suppli (ORCID: https://orcid.org/0000-0002-8816-6472)
- Birgitte Holst (ORCID: https://orcid.org/0000-0001-7432-097X)
- Anna Katrina Jógvansdóttir Gradel (ORCID: https://orcid.org/0000-0001-5982-8417)
- Wouter F. J. Hogendorf
- Magnus F.G. Grøndahl (ORCID: https://orcid.org/0000-0001-6475-765X)
- Cesar A. Prada‐Medina (ORCID: https://orcid.org/0000-0003-1939-2297)
- Jens Lykkesfeldt (ORCID: https://orcid.org/0000-0002-6514-8407)
- Myrte Merkestein
- Christoffer Merrild (ORCID: https://orcid.org/0009-0004-5076-1534)
- Valdemar Brimnes Ingemann Johansen (ORCID: https://orcid.org/0000-0002-8288-1459)
- Joyceline Cuenco (ORCID: https://orcid.org/0000-0002-7156-4976)
- Asger Lund (ORCID: https://orcid.org/0000-0003-1212-3764)
- Damien Demozay
- Bharath K. Mani (ORCID: https://orcid.org/0000-0002-6189-3696)
- Stephanie Kjærulff Holm
- Christoffer Clemmensen (ORCID: https://orcid.org/0000-0003-2456-9667)
- Kei Sakamoto (ORCID: https://orcid.org/0000-0001-6894-6175)
- Filip Krag Knop
Institutions
- University of Copenhagen (DK)
- Steno Diabetes Centers (DK)
- Novo Nordisk (Denmark) (DK)
- Novo Nordisk Foundation (DK)
- Gentofte Hospital (DK)
- Novo Nordisk (United States) (US)
- Novo Nordisk (United Kingdom) (GB)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.101996
- Citations
- 7
- Primary Topic
- Regulation of Appetite and Obesity
- Type
- article
- Field-Weighted Citation Impact
- 6.40
Funders
- Novo Nordisk
- Copenhagen Graduate School for Nanoscience and Nanotechnology
- Novo Nordisk Fonden
- Novo Nordisk Foundation Center for Basic Metabolic Research