title: Apelin-36 Modulates Blood Glucose and Body Weight Independently of Canonical APJ Receptor Signaling.
abstract: Apelin-36 was discovered as the endogenous ligand for the previously orphan receptor APJ. Apelin-36 has been linked to two major types of biological activities: cardiovascular (stimulation of cardiac contractility and suppression of blood pressure) and metabolic (improving glucose homeostasis and lowering body weight). It has been assumed that both of these activities are modulated through APJ. Here, we demonstrate that the metabolic activity of apelin-36 can be separated from canonical APJ activation. We developed a series of apelin-36 variants in which evolutionarily conserved residues were mutated, and evaluated their ability to modulate glucose homeostasis and body weight in chronic mouse models. We found that apelin-36(L28A) retains full metabolic activity, but is 100-fold impaired in its ability to activate APJ. In contrast to its full metabolic activity, apelin-36(L28A) lost the ability to suppress blood pressure in spontaneously hypertensive rats (SHR). We took advantage of these findings to develop a longer-acting variant of apelin-36 that could modulate glucose homeostasis without impacting blood pressure (or activating APJ). Apelin-36-[L28C(30kDa-PEG)] is 10,000-fold less potent than apelin-36 at activating the APJ receptor but retains its ability to significantly lower blood glucose and improve glucose tolerance in diet-induced obese mice. Apelin-36-[L28C(30kDa-PEG)] provides a starting point for the development of diabetes therapeutics that are devoid of the blood pressure effects associated with canonical APJ activation.
authors.affiliation: From NGM Biopharmaceuticals, South San Francisco, California 94080.
authors.forename: Hadas
authors.initials: H
authors.lastname: Galon-Tilleman
authors.affiliation: From NGM Biopharmaceuticals, South San Francisco, California 94080.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: the Department of Antibody Discovery and Protein Engineering, MedImmune Ltd., Cambridge CB21 6GH, United Kingdom.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Bednarek
authors.affiliation: From NGM Biopharmaceuticals, South San Francisco, California 94080.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Spurlock
authors.affiliation: From NGM Biopharmaceuticals, South San Francisco, California 94080.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Paavola
authors.affiliation: From NGM Biopharmaceuticals, South San Francisco, California 94080.
authors.forename: Brian
authors.initials: B
authors.lastname: Ko
authors.affiliation: From NGM Biopharmaceuticals, South San Francisco, California 94080.
authors.forename: Carmen
authors.initials: C
authors.lastname: To
authors.affiliation: From NGM Biopharmaceuticals, South San Francisco, California 94080.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.affiliation: From NGM Biopharmaceuticals, South San Francisco, California 94080.
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.affiliation: the Department of Antibody Discovery and Protein Engineering, MedImmune Ltd., Cambridge CB21 6GH, United Kingdom.
authors.forename: Lutz
authors.initials: L
authors.lastname: Jermutus
authors.affiliation: the Department of Cardiovascular and Metabolic Disease Research, MedImmune LLC, Gaithersburg, Maryland 20878.
authors.forename: Joseph
authors.initials: J
authors.lastname: Grimsby
authors.affiliation: the Department of Cardiovascular and Metabolic Disease Research, MedImmune LLC, Gaithersburg, Maryland 20878.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Rondinone
authors.affiliation: the Department of Cardiovascular and Metabolic Disease Research, MedImmune LLC, Gaithersburg, Maryland 20878.
authors.forename: Anish
authors.initials: A
authors.lastname: Konkar
authors.affiliation: From NGM Biopharmaceuticals, South San Francisco, California 94080. Electronic address: dkaplan@ngmbio.com.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Kaplan
mesh_terms: D054392:Adipokines / Q000494:pharmacology*; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D001786:Blood Glucose / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D051379:Mice; D051381:Rats; D011918:Rats, Inbred SHR; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D054392:Adipokines; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; C491284:Aplnr protein, rat; D001786:Blood Glucose; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled
keywords: APJ; G protein-coupled receptor (GPCR); apelin; cardiovascular; diabetes; ligand-receptor promiscuity; metabolic syndrome; obesity; signal transduction