Adiponectin Receptors Form Homomers and Heteromers Exhibiting Distinct Ligand Binding and Intracellular Signaling Properties

Almabouada, Farid; Díaz‐Ruiz, Alberto; Rabanal-Ruíz, Yoana; Peinado, Juan R.; Vázquez-Martı́nez, Rafael; Malagón, Marı́a M.

doi:10.1074/jbc.m112.404624

Cited by 56 publications

(60 citation statements)

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“…While consistent with findings from a previous study of healthy adolescent girls (Riis et al, 2013), these findings are contrary to findings from in vitro studies of adiponectin's effect on oral epithelial cells, primary gingival fibroblasts, and periodontal ligament cells (Iwayama et al, 2012;Kraus et al, 2012). Together, the findings demonstrate the importance of assessing adiponectin's relations with inflammation and health using various approaches and populations; the function and proprieties of adiponectin may vary based on characteristics of the hormone, its receptors and the health of the individual (Almabouada et al, 2013;Li & Wu, 2012).…”

Section: Adiponectin and Inflammatory Activity And Oral Healthcontrasting

confidence: 83%

“…Moreover, while total adiponectin in the present study was associated with oral inflammatory activity, the actual function of adiponectin in the oral environment remains a matter of debate and likely depends on the roles of different isoforms and possibly different patterns of expression of adiponectin receptors (Almabouada et al, 2013). For example, a positive effect of total adiponectin on skin keratinocyte proliferation has been reported in mice where adiponectin was directly associated with cutaneous wound healing (Shibata et al, 2012), and this effect was confirmed in human periodontal ligament (PDL) cells (Nokhbehsaim et al, 2014).…”

Section: Strengths and Limitationsmentioning

confidence: 74%

“…While the anti-inflammatory effects of adiponectin are well-documented (Fasshauer & Bluher, 2015;Lihn et al, 2005;Robinson et al, 2011), the influence of adiponectin on the surrounding cells likely depends on the health of the individual, and on the availably of different isoforms and receptor types (Almabouada et al, 2013;Li & Wu, 2012;D. Liu, Luo, & Li, 2015).…”

Section: Adiponectin and Inflammatory Activity And Oral Healthmentioning

confidence: 99%

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Adiponectin: Serum-saliva associations and relations with oral and systemic markers of inflammation

Riis

Bryce

et al. 2017

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This study addresses gaps in our understanding about the validity and utility of using salivary adiponectin to index serum adiponectin levels. Matched blood and saliva samples were collected on a single occasion from healthy adults (n= 99; age 18-36 years, 53% male). Serum and saliva was assayed for adiponectin and inflammatory cytokines (IL-1β, IL-6, IL-8, TNFα), and saliva was also assayed for markers of blood contamination (transferrin), total protein (salivary flow rate) and matrix metalloproteinase-8 (MMP-8). We examined the extent to which salivary adiponectin was associated with serum adiponectin, and the influence of potential confounders on the serum-saliva correlation, including age, sex, body mass index, and markers of inflammation, oral health, salivary blood contamination, and flow rate. Findings revealed a modest serum-saliva association for adiponectin, and strong positive associations between salivary adiponectin and salivary levels of inflammatory cytokines, MMP-8, transferrin, and total protein. By contrast, salivary adiponectin was not related to serum levels of inflammatory activity. The magnitude of the serum-saliva association was strengthened when controlling for total protein in saliva, blood leakage into oral fluid, salivary inflammatory cytokines, and MMP-8. The pattern of findings extends our understanding of salivary adiponectin and its potential use as an index of circulating adiponectin levels.

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Section: Adiponectin and Inflammatory Activity And Oral Healthcontrasting

confidence: 83%

Section: Strengths and Limitationsmentioning

confidence: 74%

Section: Adiponectin and Inflammatory Activity And Oral Healthmentioning

confidence: 99%

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Adiponectin: Serum-saliva associations and relations with oral and systemic markers of inflammation

Riis

Bryce

et al. 2017

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“…3). Indeed, it was shown that the two adiponectin receptors, AdipoR1 and AdipoR2, are capable of homoand hetero-dimerization, and changes in their cellular ratio/amounts lead to alterations in AMPK phosphorylation (44). Activation of adiponectin signaling was also observed in C2C12 myotubes under depletion of adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 2 (APPL2), an AdipoR1-binding protein that acts as a negative regulator of adiponectin signaling (45).…”

Section: Discussionmentioning

confidence: 99%

RNA-Binding Protein PTB and MicroRNA-221 Coregulate AdipoR1 Translation and Adiponectin Signaling

et al. 2014

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Adiponectin receptor 1 (AdipoR1) mediates adiponectin's pleiotropic effects in muscle and liver and plays an important role in the regulation of insulin resistance and diabetes. Here, we demonstrate a pivotal role for microRNA-221 (miR-221) and the RNA-binding protein polypyrimidine tract-binding protein (PTB) in posttranscriptional regulation of AdipoR1 during muscle differentiation and in obesity. RNA-immunoprecipitation and luciferase reporter assays illustrated that both PTB and miR-221 bind AdipoR1-39UTR and cooperatively inhibit AdipoR1 translation. Depletion of PTB or miR-221 increased, while overexpression of these factors decreased, AdipoR1 protein synthesis in both muscle and liver cells. During myogenesis, downregulation of PTB and miR-221 robustly induced AdipoR1 translation, providing a mechanism for enhanced AdipoR1 protein expression and activation in differentiated muscle cells. In addition, since both PTB and miR-221 are upregulated in liver and muscle of genetic and dietary mouse models of obesity, this novel translational mechanism may be at least partly responsible for the reduction in AdipoR1 protein levels in obesity. These findings highlight the importance of translational control in regulating AdipoR1 protein expression and adiponectin signaling. Given that adiponectin is reduced in obesity, induction of AdipoR1 could potentially enhance adiponectin beneficial effects and ameliorate insulin resistance and diabetes. Adiponectin, an adipocyte-derived abundant plasma protein (1-4) with insulin-sensitizing and antiinflammatory properties, gained recognition as a potential mediator between obesity, insulin resistance, and diabetes (5): Adiponectin levels are reduced in obesity (1), and mice lacking adiponectin develop insulin resistance, glucose intolerance, hyperglycemia, and hypertension-all characteristics of the metabolic syndrome (5,6). Adiponectin's biological effects depend not only on the relative circulating concentrations of the hormone but also on the expression level and function of its receptors (5,7-9). To date, two receptors for adiponectin have been identified (AdipoR1 and AdipoR2), which mediate adiponectin pleoitropic effects (10). Downregulation of the receptors in obesity is involved in the development of insulin resistance and diabetes (11).Skeletal muscle and liver are important targets of adiponectin and its receptors in the regulation of energy metabolism (12). Adiponectin, through AdipoR1, METABOLISMactivates AMP-activated protein kinase (AMPK) in vivo and in vitro, which increases fatty acid oxidation and glucose utilization and leads to an improvement in insulin sensitivity (10,11,(13)(14)(15). Recently, overexpression of AdipoR1 in rat skeletal muscle was shown to enhance insulin sensitivity in vivo through phosphatidylinositol 3-kinase-and AMPK-signaling pathways (16). In addition, specific deletion of AdipoR1 in mouse skeletal muscle demonstrated that AdipoR1 is involved in the regulation of Ca 2+ signaling, peroxisome proliferator-activated receptor g coactivat...

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“…Serum withdrawal resulted in increased expression of both AdipoR1 and AdipoR2 although AdipoR2 still exhibited significantly lower cell-surface expression than AdipoR1. The addition of serum or gAd reduced cell-surface expression of both receptors and microscopy suggested that this decrease reflected classic liganddependent internalisation consistent with a previous report 152 . Our findings using serum from wildtype and adiponectin KO mice suggest that, at least under these experimental conditions, no other circulating factors, such as members of the CTRP family 204 , are able to promote internalisation of the adiponectin receptors.…”

Section: Discussionsupporting

confidence: 90%

Molecular characterisation of the adiponectin receptors, AdipoR1 and AdipoR2

Keshvari¹

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The increasing global prevalence of cardiovascular and metabolic diseases necessitates the development of more effective therapeutic strategies that, in turn, require a greater understanding of the regulatory networks involved. Research over the last decade has increased our appreciation of the key role of the adiponectin axis as a major regulator of metabolic, cardiovascular and inflammatory tone, thereby establishing it as a province of therapeutic opportunity. The receptors for adiponectin, AdipoR1 and AdipoR2, are distant relatives of the largest single class of drug targets, the G-protein coupled receptor (GPCR) family. However, unlike GPCRs they have intracellular N-termini and extracellular C-termini and signal via atypical pathways. Our current understanding of AdipoR1 and AdipoR2 is rudimentary, constraining our ability to target these receptors effectively. The aim of this thesis was to characterise molecular features of AdipoR1 and AdipoR2 that facilitate adiponectin signal transduction to advance our understanding and identify strategies to enhance adiponectin's beneficial effects.We have begun to characterise basic properties of AdipoR1 and AdipoR2, focusing on molecular factors that drive cell-surface expression (CSE) of the receptors using a range of C-terminal, epitope-tagged AdipoR1 and AdipoR2 constructs. Surprisingly, under steady-state conditions (no serum starvation) only AdipoR1 was readily detected on the cell-surface (cell-surface ratio of AdipoR1 vs AdipoR2 is 0.6±0.1 vs 0.15±0.1, p<0.05). Generation and characterisation of a series of chimeric and truncated constructs demonstrated that a non-conserved, intracellular, N-terminal region of AdipoR2 (R2 ) restricted its CSE whilst the same region in AdipoR1 (R1 (1-70) ) promoted its CSE. We also confirmed that AdipoR1 and AdipoR2 form heterodimer and that coexpression of these receptors increase the CSE of AdipoR2. Subsequently, we provided evidence that the subcellular localisation of AdipoR1 and AdipoR2 is governed by multiple motifs across their non-conserved and conserved cytoplasmic domains. For instance, two highly conserved motifs, an ER exit motif (FxxxFxxxF) and Di-Leucine motif (DxxxLL), in the conserved Nterminal domain are required for the proper CSE of both AdipoR1 and AdipoR2, whilst different parts of the non-conserved domain of AdipoR2 inhibits its CSE.Moreover, we demonstrated that in HEK-293 cells over-expressing AdipoR1 adiponectin activated downstream signalling networks (AMPK, AKT, ERK & P38MAPK) acutely (peaking at 15 min) whereas signal transduction via AdipoR2 was relatively chronic (peaking at 24 h). This difference was also underpinned by the non-conserved N-terminal domains of AdipoR1 and AdipoR2. We also demonstrated that a number of conserved and non-conserved cysteines in the N-terminal domain of iii AdipoR1 and AdipoR2 are subject to palmitoylation and that palmitoylation of a conserved cysteine, situated in the juxta-membrane region of the N-termini of AdipoR1 and AdipoR2 in a position analogous to t...

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Adiponectin Receptors Form Homomers and Heteromers Exhibiting Distinct Ligand Binding and Intracellular Signaling Properties

Cited by 56 publications

References 57 publications

Adiponectin: Serum-saliva associations and relations with oral and systemic markers of inflammation

Adiponectin: Serum-saliva associations and relations with oral and systemic markers of inflammation

RNA-Binding Protein PTB and MicroRNA-221 Coregulate AdipoR1 Translation and Adiponectin Signaling

Molecular characterisation of the adiponectin receptors, AdipoR1 and AdipoR2

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