Apelin, a novel adipokine over-produced in obesity: friend or foe?
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Adipocytes↗
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Opposing cardiovascular roles for the angiotensin and apelin signaling pathways.
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Angiotensin II↗
The msr/apj gene encoding the apelin receptor is an early and specific marker of the venous phenotype in the retinal vasculature.
Expression of the new G protein-coupled msr/apj receptor in the mouse embryo is restricted to the endothelial layer of the primary blood vessels and the newly forming heart (Mech. Dev. 84 (1999) 199). During development of the retinal vasculature, the msr/apj gene is not expressed throughout the vascular network, indicating a possible relationship between the localization of expression and the acquisition of arterial or venous identity (Mech. Dev. 110 (2002) 183). Here we first established that retinal expression of ephrin-B2 and its putative receptor EphB4 correlates with arterial and venous phenotype, respectively. Then we analyzed the expression pattern of msr/apj in the retinal vessels at various stages of postnatal development by in situ hybridization. In contrast to the expression of ephrin-B2 or EphB4, msr/apj transcripts can be detected as early as postnatal day P3. From P3 to P12, msr/apj expression in the vascular network is restricted to the venules and the associated capillaries. The msr/apj gene is thus an early and specific marker of the venous phenotype in the retinal vasculature.
Animals↗
Cell-cell fusion and internalization of the CNS-based, HIV-1 co-receptor, APJ.
APJ, a member of the human G protein-coupled seven-transmembrane receptor family, has been shown to serve as a coreceptor for the entry of human immunodeficiency virus type I (HIV-1) and simian immunodeficiency virus (SIV), and it is dramatically expressed in central nervous system (CNS)-based cells. In this study, expression of APJ tagged with the green fluorescent protein (GFP) and a fluorescent peptide, 5-carboxyfluorescein (5-CF) conjugated Apelin-13, were utilized for studying receptor internalization and recycling, in stably expressing indicator cells, human neurons, primary CNS microvascular endothelial cells (MVECs), and astrocytes. Fusion of the C-terminus of APJ to the N-terminus of GFP did not alter receptor ligand binding and functions, including signaling and internalization. Using 293 cells stably expressing APJ-GFP, we demonstrated that rapid internalization of the APJ receptor was induced by stimulation with Apelin-36 and Apelin-13, in a dose-dependent manner. Furthermore, investigations showed that the internalized APJ was colocalized with transferrin receptors, suggesting that the internalization of APJ induced by Apelin is likely to be via clathrin-coated pits. Interestingly, we found that the internalized APJ molecules were recycled to the cell surface within 60 min after removal of Apelin-13, but most of the internalized APJ still remained in the cytoplasm, even 2 h after washout of Apelin-36. The intact cytoplasmic C-terminal domain was found to be required for ligand-induced APJ internalization. Human neurons were dramatically stained by the APJ-binding fluorescent peptides. Primary human fetal astrocytes were less strongly labeled with 5-CF-Apelin-13, and in primary human CNS MVECs only weak distribution of green fluorescence specific for APJ in the cytoplasm was observed. Apelin-36 blocked cell membrane fusion mostly due to steric interference, with only a very modest effect on receptor internalization. The CNS represents a unique reservoir site for HIV-1. As such, molecular therapeutics and small molecular inhibitors of HIV-1 entry via this unique CNS receptor are now able to be rationally designed.
Animals↗
G protein-coupled APJ receptor signaling induces focal adhesion formation and cell motility.
APJ, a G protein-coupled receptor, has an endogenous ligand called apelin. APJ and apelain are highly expressed in the cardiovascular system from embryo to adulthood. It has been shown that apelin elicited the migration of APJ-expressing cells, but details of the receptor signaling have not been identified. To address the signal transduction molecular mechanisms of the apelin/APJ-induced cell motility, we established human embryonic kidney 293T cells stably expressing the mouse APJ (APJ/293T). APJ/293T cells exhibited a specific [(Glp65, Nle75, Tyr77) [125I]]-Apelin13 binding activity (Kd = 4.45 nM). Apelin induced Akt/PKB phosphorylation in APJ/293T cells, but not in the intact 293T cells (-/293T cells). This APJ-dependent activation of Akt/PKB was significantly inhibited by the pretreatment of pertussis toxin (PTx) and a PI3K inhibitor, LY29004. In addition, apelin enhanced focal adhesion kinase (FAK) phosphorylation and increased focal adhesion formation with staining for F-actin in APJ/293T cells. PTx and LY29004 significantly suppressed these responses to apelin. Moreover, we examined the migration activity by using a scratch-test. Apelin strongly accelerated the cell motility in APJ/293T cells, and this activity was abolished by PTx and LY29004. These results indicated that the apelin/APJ signaling coupled with the PTx-sensitive G-protein activates Akt/PKB and FAK proteins through PI3K.
Animals↗
Effects of all-trans retinoic acid on orphan receptor APJ signaling in spontaneously hypertensive rats.
OBJECTIVE: Studies show general agreement that all-trans retinoic acid (atRA) has been linked to the regulation of G protein-coupled receptor (GPCRs) signaling. To further validate effects of atRA on the cardiovascular GPCRs, the present study was designed to assess whether atRA will modulate orphan receptor APJ, a homologue of angiotensin II type 1 (AT(1)) receptor. METHODS: Real-time polymerase chain reaction and Western blot methods were performed to examine the expression of APJ and its endogenous ligand apelin in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats after chronic atRA treatment. RESULTS: APJ and apelin expression were markedly depressed in placebo-treated SHR, compared with WKY rats (p<0.01). However, in atRA-treated SHR, a significant upregulation of APJ and apelin expression was observed in both heart and aorta (p<0.05), accompanied by a reduction of AT(1) expression, an elevation of serum nitric oxide levels and a subsequent decrease of blood pressure. CONCLUSIONS: Chronic atRA treatment activates gene and protein expression of APJ and apelin and reduces blood pressure in SHR, suggesting that atRA may regulate the balance between apelin-APJ and angiotensin II-AT(1) signaling and have potential clinical value in the prevention and treatment of human hypertension.
Animals↗
Regulation of rat APJ receptor messenger ribonucleic acid expression in magnocellular neurones of the paraventricular and supraopric nuclei by osmotic stimuli.
The novel apelin receptor (APJ receptor, APJR) has a restricted expression in the central nervous system suggestive of an involvement in the regulation of body fluid homeostasis. The endogenous ligand for APJR, apelin, is also highly concentrated in regions that are involved in the control of drinking behaviour. While the physiological roles of APJR and apelin are not fully known, apelin has been shown to stimulate drinking behaviour in rats and to have a regulatory effect on vasopressin release from magnocellular neurones of the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. To determine the role of APJR in the regulation of water balance, this study examined the effects of osmotic stimulation on the expression of APJR mRNA in the magnocellular PVN (mPVN) and SON of salt-loaded and water-deprived rats. Intake of 2% NaCl and water deprivation for 48 h induced expression of APJR mRNA in the mPVN and SON. Using dual-label in situ hybridization histochemistry, we also investigated whether APJR is colocalized within vasopressin neurones in control, salt-loaded and water-deprived rats. APJR mRNA was found to colocalize with a small population of vasopressin-containing magnocellular neurones in control and water-deprived rats. Salt-loading resulted in an increased colocalization of APJR and vasopressin mRNAs in the SON. These data verify a role for APJ receptors in body fluid regulation and suggest a role for apelin in the regulation of vasopressin-containing neurones via a local autocrine/paracrine action of the peptide.
Animals↗
Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo.
APJ is a G-protein-coupled receptor with seven transmembrane domains, and its endogenous ligand, apelin, was identified recently. They are highly expressed in the cardiovascular system, suggesting that APJ is important in the regulation of blood pressure. To investigate the physiological functions of APJ, we have generated mice lacking the gene encoding APJ. The base-line blood pressure of APJ-deficient mice is equivalent to that of wild-type mice in the steady state. The administration of apelin transiently decreased the blood pressure of wild-type mice and a hypertensive model animal, a spontaneously hypertensive rat. On the other hand, this hypotensive response to apelin was abolished in APJ-deficient mice. This apelin-induced response was inhibited by pretreatment with a nitric-oxide synthase inhibitor, and apelin-induced phosphorylation of endothelial nitric-oxide synthase in lung endothelial cells from APJ-deficient mice disappeared. In addition, APJ-deficient mice showed an increased vasopressor response to the most potent vasoconstrictor angiotensin II, and the base-line blood pressure of double mutant mice homozygous for both APJ and angiotensin-type 1a receptor was significantly elevated compared with that of angiotensin-type 1a receptor-deficient mice. These results demonstrate that APJ exerts the hypotensive effect in vivo and plays a counterregulatory role against the pressor action of angiotensin II.
Alleles↗
Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor.
In the search for an endogenous ligand of the orphan G protein-coupled receptor APJ, the presence of the ligand in various tissue extracts was examined by measuring the increase in extracellular acidification rate of the cells expressing the APJ receptor as a specific signal induced by the interaction of the receptor and ligand. By monitoring this activity, we isolated an APJ receptor ligand, designated apelin, from bovine stomach extracts. The structures of bovine and human apelin preproproteins were deduced from the sequences of the corresponding cDNAs. The preproproteins consisted of 77 amino acid residues, and the apelin sequence was encoded in the C-terminal regions. Synthetic peptides derived from the C-terminal amino acid sequence of bovine preproapelin were capable of specifically promoting the acidification rate in the cells expressing the APJ receptor in a range from 10(-7) to 10(-10) M, indicating that apelin is an endogenous ligand for the APJ receptor.
Amino Acid Sequence↗
The N-terminal domain of APJ, a CNS-based coreceptor for HIV-1, is essential for its receptor function and coreceptor activity.
The human APJ, a G protein-coupled seven-transmembrane receptor, has been found to be dramatically expressed in the human central nervous system (CNS) and also to serve as a coreceptor for the entry of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV). Studies with animal models suggested that APJ and its natural ligand, apelin, play an important role in the central control of body fluid homeostasis, and in regulation of blood pressure and cardiac contractility. In this study, we characterize the structural and functional determinants of the N-terminal domain of APJ in interactions with its natural ligand and HIV-1 envelope glycoprotein. We demonstrate that the second 10 residues of the N-terminal domain of APJ are critical for association with apelin, while the first 20 amino acids play an important role in supporting cell-cell fusion mediated by HIV-1 gp120. With site-directed mutagenesis, we have identified that the negatively charged amino acid residues Glu20 and Asp23 are involved in receptor and coreceptor functions, but residues Tyr10 and Tyr11 substantially contribute to coreceptor function for both T-tropic (CXCR4) and dual-tropic (CXCR4 and CCR5) HIV-1 isolates. Thus, this study provides potentially important information for further characterizing APJ-apelin functions in vitro and in vivo and designing small molecules for treatment of HIV-1 infection in the CNS.
Amino Acid Sequence↗
APJ receptor mRNA expression in the rat hypothalamic paraventricular nucleus: regulation by stress and glucocorticoids.
The apelin receptor (APJ receptor, APJR) has recently come to prominence following the isolation and identification of its endogenous ligand, apelin, from bovine stomach tissue extracts. Investigation of APJR mRNA expression has revealed a hypothalamic distribution similar to that of vasopressin suggesting that the apelin-APJR system may be involved in the regulation of the hypothalamic-adrenal-pituitary (HPA) stress axis. To investigate whether APJR is involved in the regulation of hypothalamic function during stress, APJR mRNA expression levels were measured by in situ hybridization in the hypothalamus of rats subjected to acute and repeated restraint stress. Acute stress caused an increase in APJR mRNA expression in the hypothalamic parvocellular paraventricular nucleus (pPVN) while repeated restraint stress induced a sustained up-regulation of pPVN APJR mRNA expression in intact rats. Removal of endogenous glucocorticoids by adrenalectomy also resulted in an increased expression of APJR mRNA in the PVN, suggesting a negative regulation of APJR mRNA expression by glucocorticoids. The role of glucocorticoids in mediating these stress-induced changes was investigated by analysing the effects of acute and repeated restraint stress on APJR mRNA levels in adrenalectomized rats. In these rats, APJR mRNA expression levels did not change above the already elevated levels of adrenalectomized-control rats. These data suggest that acute and repeated stress exert a stimulatory influence on APJR mRNA expression at the hypothalamic level that may be dependent on basal levels of circulating glucocorticoids, and further suggest a role for APJR in the regulation of hypothalamic function.
Adrenal Glands↗
Visualizing differences in ligand-induced beta-arrestin-GFP interactions and trafficking between three recently characterized G protein-coupled receptors.
beta-Arrestin 1-GFP or beta-arrestin 2-GFP were coexpressed transiently with G protein-coupled receptor kinase 2 within cells stably expressing the orexin-1, apelin or melanin-concentrating hormone (MCH), receptors. In response to agonist ligands both the orexin-1 and apelin receptors were able to rapidly translocate both beta-arrestin 1-GFP and beta-arrestin 2-GFP from cytoplasm to the plasma membrane. For the MCH receptor this was only observed for beta-arrestin 2-GFP. beta-Arrestin 1-GFP translocated by the apelin receptor remained at the plasma membrane during prolonged exposure to ligand even though the receptor became internalized. By contrast, for the orexin-1 receptor, internalization of beta-arrestin 1-GFP within punctate vesicles could be observed for over 60 min in the continued presence of agonist. Co-internalization of the orexin-1 receptor was observed by monitoring the binding and trafficking of TAMRA-(5- and 6-carboxytetramethylrhodamine) labelled orexin-A. Subsequent addition of an orexin-1 receptor antagonist resulted in cessation of incorporation of beta-arrestin 1-GFP into vesicles at the plasma membrane and a gradual clearance of beta-arrestin 1-GFP from intracellular vesicles. For the melanin-concentrating hormone receptor the bulk of translocated beta-arrestin 2-GFP was maintained at concentrated foci close to, or at, the plasma membrane. These results demonstrate very distinct features of beta-arrestin-GFP interactions and trafficking for three G protein-coupled receptors for which the natural ligands have only recently been identified and which were thus previously considered as orphan receptors.
Animals↗
A 3D in vitro co-culture model to investigate tumor-endothelial interactions in Neurofibromatosis type 2-associated meningiomas.
BACKGROUND: Neurofibromatosis type 2 (NF2)-associated meningiomas and schwannomas are vascular tumors, and while vascular endothelial growth factor (VEGF) inhibition with bevacizumab has benefited some NF2-related schwannomas, most NF2-associated meningiomas remain nonresponsive. METHODS: Leveraging our transcriptomic data, we performed Gene Ontology (GO) analysis comparing NF2-deficient meningioma cells with NF2-expressing arachnoid cells (ACs). We then established a 3D in vitro angiogenesis model by co-culturing NF2-null meningioma cells with human umbilical vein endothelial cells (HUVECs). Endothelial sprouting was assessed by CD31/PECAM immunostaining. Effects of third-generation mechanistic target of rapamycin complex 1 (mTORC1)-selective inhibitor RMC-6272 as well as APLN knock-out using CRISPR-Cas9 gene editing were also examined. RESULTS: GO analysis identified vascular development among the top significantly upregulated pathways in NF2-deficient cells. In 3D co-culture, ECs formed radially sprouting tube-like networks from the spheroid surface, and our data supports an angiogenesis phenotype driven by meningioma cells. Given these results along with hyperactivation of mTORC1 upon NF2-deficiency, we examined whether RMC-6272 disrupts meningioma-driven angiogenesis. RMC-6272 potently suppressed EC sprouting. Cross-referencing baseline transcriptomic data, we identified Apelin (APLN), the ligand for APLN receptor (APLNR), as a basally upregulated angiogenic factor in NF2-deficient meningiomas. Quantitative RT-PCR (qRT-PCR) confirmed increased APLN expression in NF2-null immortalized and patient-derived meningioma lines, with reduced expression upon mTORC1 inhibition. Apelin-13 stimulation enhanced sprouting, whereas APLN deletion reduced endothelial sprouting. CONCLUSIONS: Here we establish a 3D-tumoroid model and implicate tumor-derived Apelin as an important contributor to NF2-associated meningioma angiogenesis. Our data also suggest that APLN expression is regulated, at least in part, by mTORC1. Together, these results provide a preclinical platform for investigating angiogenic vulnerabilities beyond VEGF in NF2-deficient meningiomas.
3D tumoroid model↗
Adipocyte-specific IGF1R knockout activates the β-catenin/apelin axis to combat diet-induced obesity in male mice.
AIMS: Obesity, driven by complex genetic and environmental interactions, remains a global health crisis with limited therapeutic options. The insulin-like growth factor 1 receptor (IGF1R) plays dual roles in metabolism and growth, but its tissue-specific functions in adipose biology are controversial. This study investigates how adipose-specific IGF1R knockout impacts systemic metabolism under high-fat diet (HFD) stress and explores the underlying mechanisms. METHODS: Adipose-specific IGF1R knockout mice (AdIGF1RKO) were generated by crossing Igf1rfl/fl mice with Adipoq-Cre transgenics. Mice were fed a normal chow diet (NCD) or HFD for 20 weeks. Metabolic phenotyping included glucose/insulin tolerance tests, body composition analysis and serum profiling. RNA-seq, Western blot and quantitative real-time reverse transcriptase PCR were used to identify molecular pathways. In vitro studies with stromal vascular fraction (SVF) cells validated β-catenin/apelin interactions. RESULTS: AdIGF1RKO male mice exhibited reduced adipose mass under NCD and resisted HFD-induced obesity, showing attenuated hepatic lipid deposition and improved glucose metabolism. Mechanistically, IGF1R knockout enhanced INSR and Akt phosphorylation, driving GSK3β-β-catenin activation and apelin upregulation. Apelin activated AMPK, suppressing lipogenesis and enhancing fatty acid oxidation. Notably, β-catenin's role shifted from inhibiting adipogenesis in precursors to promoting metabolic adaptation in mature adipocytes. CONCLUSION: We unveil a β-catenin/apelin-driven endocrine axis that reprograms energy metabolism under obesogenic stress. Therapeutically, targeting adipose IGF1R or apelin signalling could combat obesity while avoiding systemic toxicity. Limitations include unresolved β-catenin/Apln transcriptional mechanisms, APJ function and tissue-specific AMPK effects. Our findings redefine IGF1R's metabolic role and propose novel strategies for obesity-related disorders.
Animals↗
Transcriptomes of purified gastric ECL and parietal cells: identification of a novel pathway regulating acid secretion.
The gastric entero-chromaffin-like (ECL) cell plays a key regulatory role in peripheral regulation of acid secretion due to the release of histamine that stimulates acid secretion by the parietal cell. Studies in intact animals, gastric glands, and isolated cells after short-term culture have shown expression of stimulatory CCK2 and PAC1 and inhibitory SST2 and Gal1 receptors as well as histidine decarboxylase. However, the pattern of its gene expression as a neuroendocrine cell has not been explored. Comparison of gene expression by 95% pure ECL cells obtained by density gradient, elutriation, and fluorescence-assisted cell sorting with isolates of the intact fundic gastric epithelium (i.e., "subtractive hybridization") identified a variety of additional expressed gene families characteristic of this neuroendocrine cell. These include genes 1) involved in neuropeptide synthesis and secretory vesicle exocytosis, 2) involved in control of inflammation, 3) implicated in healing of the epithelium, 4) encoding inhibitory Gi protein-coupled receptors, 5) playing a role in neuroendocrine regulation of food intake, and 6) encoding proteins likely involved in maintenance of circadian rhythm, in addition to the ECL cell-specific genes histidine decarboxylase and monoamine transporter. Particularly, the inhibitory apelin receptor gene, APJ, was highly expressed in the ECL cell preparation. Because parietal cells express apelin, immunohistochemical and functional studies showed that there is an inhibitory feed back loop between the parietal and ECL cell during gastrin stimulation, providing evidence for a novel pathway of downregulation of acid secretion due to interaction between these two cell types.
Animals↗
The quest for novel bioactive peptides utilizing orphan seven-transmembrane-domain receptors.
Various sorts of bioactive molecules including hormones, neurotransmitters, and chemokines transmit signals into cells by binding to so-called seven-transmembrane-domain receptors (7TMRs). The recent progress in cDNA and genome DNA analyses has brought the discovery of numerous genes encoding ligand-unknown "orphan" 7TMRs. We have developed a strategy to identify the ligands of orphan 7TMRs by monitoring specific signal transductions induced in cells expressing orphan 7TMRs. Employing this method, we succeeded in identifying the natural ligands of the orphan 7TMRs, hGR3, and APJ. The ligand peptide identified for hGR3 was found to show a specific prolactin release promoting activity in rat anterior pituitary cells in in vitro culture and was therefore named "prolactin-releasing peptide." We named another novel bioactive peptide "apelin," for "APJ endogenous ligand." Although the biological functions of apelin are still under investigation, APJ reportedly acts as a coreceptor in the process of human immunodeficiency virus infection. We believe that the identification of orphan 7TMR ligands will provide clues to reveal the unknown regulatory mechanisms of various physiological phenomena and opportunities for novel drug discovery in the future.
Animals↗
Xapelin and Xmsr are required for cardiovascular development in Xenopus laevis.
The cardiovascular development is the elaborate process, and despite the extensive studies, the mechanisms underlying endothelial, hematopoietic, and cardiac developments, as well as the interrelation between these processes, are not fully understood. In this study, we demonstrated that Xenopus apelin and Xmsr play pivotal roles in cardiovascular development. Apelin is a recently identified ligand for an orphan G-protein-coupled receptor APJ and is involved in fluid homeostasis in mammals. Xenopus preproapelin (Xpreproapelin) was isolated and its mRNA localized to the region around the presumptive blood vessels, which are overlapping or adjacent to those expressing Xmsr, the Xenopus homologue of APJ. Overexpression of Xpreproapelin disorganized the expression of the endothelial precursor cell marker XlFli and the hematopoietic precursor cell marker SCL at the neurula, whereas embryos injected with morpholino antisense oligonucleotides for Xapelin and Xmsr displayed attenuated expression of Tie2, alpha-globin, XPOX2, and cTnI, markers of endothelium, erythrocytes, myeloid cells, and cardiomyocytes, respectively. XlFli morpholino had similar effects to Xapelin and Xmsr morpholinos on cardiac differentiation, suggesting an unexpected potential relationship between the endothelium and cardiac differentiation. Forced expression of constitutive active G alpha i rescued the phenotypes of Xmsr morpholino-injected embryos, indicating that the i/o type of G protein alpha subunit acts downstream of Xmsr.
Animals↗
Validation and refinement of a biomarker panel for frailty assessment and prediction of muscle weakness in older adults.
Frailty is a complex geriatric syndrome characterized by age-related declines in physiological function and cognitive reserve. To promote early prevention and intervention, minimally invasive and objective biomarkers that can detect frailty progression are required. We aimed to identify biomarkers associated with frailty progression and to elucidate their relevance to the Japanese version of the Cardiovascular Health Study (J-CHS) criteria, consist of five components (unintentional weight loss, self-reported exhaustion, muscle weakness, slow walking speed, and low physical activity). A total of 168 individuals (61 robust, 25 pre-frail, and 82 frail) enrolled in the NCGG (National Center for Geriatrics and Gerontology) Biobank were analyzed. Clinical information, blood-test data, aging-related factors, and gene-expression data were integrated for the analysis. First, linear regression identified one clinical factor, five aging-related factors, and 251 gene-expression factors associated with frailty. Subsequent logistic regression analyses examining each J-CHS components highlighted six candidate biomarkers. Cross-validation further suggested that three of these biomarkers-SMI, apelin, and GDF15-may represent potential biomarkers. Finally, retrospective and prospective analyses further demonstrated that those biomarkers were predictive of future muscle weakness, yielding a concordance index of 0.70. In conclusion, we validated and refined a biomarker panel consisting of SMI, apelin, and GDF15 that is associated with frailty, particularly muscle weakness (a major J-CHS component). These biomarkers may be useful for frailty assessment. Longitudinal analyses further suggested that they may be associated with the future development of muscle weakness in initially robust older adults, although validation in larger prospective cohorts is warranted.
Journal Article↗