Apelin-36 Modulates Blood Glucose and Body Weight Independently of Canonical APJ Receptor Signaling

Abstract

Edited by Jeffrey E. PessinApelin-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.The apelin gene encodes a pre-pro-protein that is processed into a number of regulatory hormones. The best characterized of these peptide hormones are apelin-13, apelin-17, and apelin-36 (1). The 13 C-terminal amino acids of these peptides (comprising apelin-13) are shared, with apelin-17 extending an additional 4 amino acids from the N terminus, and apelin-36 extending a further 19 amino acids beyond the N terminus of apelin-17 (see Table 1). Apelin was discovered as an endogenous agonist of the G protein-coupled receptor APJ (2). Specifically, apelin-36 was purified from bovine stomach tissue extract based on its ability to stimulate signaling through APJ.Through a combination of pharmacological and genetic approaches, apelin 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) (3, 4). Both of these activities have been assumed to be mediated solely through APJ, but there is substantial evidence to suggest that APJ may have apelin-independent activities (5, 6). Here, we provide evidence that this ligand-receptor promiscuity goes in both directions, and that apelin may have APJ-independent activities as well. Specifically, we demonstrate that the metabolic activity of apelin-36 can be dissociated from canonical APJ signaling. ResultsTo evaluate the chronic metabolic activity of apelin peptid...

Hepatic and cardiac beneficial effects of a long‐acting Fc‐apelin fusion protein in diet‐induced obese mice

“…As anticipated, we observed the beneficial effects of Fc‐apelin‐13 treatment in obese mice by improving glucose disposal. Interestingly, Fc‐apelin‐13 did not affect body weight, which is consistent with a recent report that AAV‐mediated apelin‐36 over‐expression does not modulate body weight gain in mice being fed with high fat diet . Obese mice fed with high‐fat‐diet develop steatosis and mild fibrosis in the liver .…”

“…Interestingly, Fc-apelin-13 did not affect body weight, which is consistent with a recent report that AAV-mediated apelin-36 over-expression does not modulate body weight gain in mice being fed with high fat diet. 42 Obese mice fed with high-fat-diet develop steatosis and mild fibrosis in the liver. [43][44][45] We have found that the Fc-apelin-13 treatment ameliorates hepatic steatosis by reducing triglyceride content and fibrosis.…”

Development and validation of an LC-MS/MS method for detection and quantification of in vivo derived metabolites of [Pyr1]apelin-13 in humans

“…reported in metabolic diseases where it decreased adiposity, serum insulin and increased insulin sensitivity 16,17 ; and in renal diseases where it decreased acute renal injury and fibrosis 18 . It has recently emerged that apelin has pro-tumorigenic effects in various cancer models possibly by promoting angiogenesis and that inhibition of the apelin pathway was protective against tumour growth 14,19 .…”

Remodeling adipose tissue inflammasome for type 2 diabetes mellitus treatment: Current perspective and translational strategies

“…A clinical trial on the influence of pyr1‐apelin‐13 (exopeptidase degradation resistant) on insulin sensitivity in healthy overweight men has been completed and shown to significantly improve insulin sensitivity in a hyperinsulinemic–euglycemic clamp study as well as cause no adverse effects due to apelin administration . A long circulating PEGylated variant of apelin‐36 was found to significantly lower blood glucose and improve glucose tolerance in diet‐induced obese mice …”