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Screening for blood-borne biomarkers of adiponectin action using the receptor agonist ALY688

ABSTRACT: The employment of adiponectin-based therapeutic strategies emerges as a compelling approach in the management of diverse metabolic pathologies and the attenuation of inflammatory processes. This has precipitated the development of adiponectin receptor agonists. However, the effective surveillance of pharmacodynamic actions within the context of clinical applications remains challenging. Therefore, in this study we attempted to identify and translate peripheral biomarkers to monitor adiponectin actions in blood samples, by using a small, 10 amino acid peptide, adiponectin receptor agonist, ALY688. RNA-sequencing analysis of whole blood validated the anti-inflammatory effect of ALY688 in a sublethal LPS mouse model treated with or without ALY688. Furthermore, RNAseq analysis identified a cluster of genes, including Tgfb2, Rorc, and Il17rb, that was significantly increased in the group administered ALY688 in comparison to vehicle treated group. This cluster of differentially expressed genes was validated by real-time quantitative PCR and further verified in human peripheral blood mononuclear cells treated with ALY688 ex vivo. Collectively, these data established anti-inflammatory effects of ALY688 and identified a gene cluster signature that can be assessed in blood samples to rapidly and easily biomarker pharmacodynamic action of adiponectin or its mimetics.

ORGANISM(S): Mus musculus

PROVIDER: GSE275088 | GEO | 2024/10/30

REPOSITORIES: GEO

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Project description:Background: Extra-articular manifestations of rheumatoid arthritis (RA), potentially due to systemic inflammation, include cardiovascular disease and sarcopenic obesity. Adiponectin, an adipose-derived cytokine, has been implicated in inflammatory processes in RA, but little is known regarding its association with inflammation in a pre-clinical period. Therefore, we investigated whether adiponectin was associated with inflammatory markers in individuals at risk for RA, and whether RA-related autoimmunity modifies these associations. Methods: We analyzed samples from 144 first-degree relatives (FDRs) of RA probands, of whom 23 were positive for anti-cyclic citrullinated peptide antibody and/or ≥ 2 rheumatoid factor isotypes (IgM, IgG or IgA). We called this phenotype the ‘high risk autoantibody profile (HRP)’ as it has been shown in prior work to be >96% specific for future RA. We measured adiponectin, cytokines/chemokines, and high-sensitivity C-reactive protein (hsCRP). Using linear mixed effects models, we evaluated interaction between HRP positivity and adiponectin on inflammatory markers, adjusting for age, sex, ethnicity, body mass index, pack-years smoking, and use of cholesterol-lowering medications. Results: In everyone, adiponectin concentration was inversely associated with hsCRP and IL-1b in adjusted models, where a 1% higher adiponectin was associated with a 26% lower hsCRP (p=0.04) and a 26% lower IL-1b (p=0.04). Significant interactions between HRP and adiponectin for associations with GM-CSF, IL-6, and IL-9 were detected in fully adjusted models (p=0.0006, p=0.006, p=0.01, respectively). In HRP positive FDRs but not HRP negative FDRs, a 1% higher adiponectin was associated with 97% higher GM-CSF, 73% higher IL-6, and 54% higher IL-9 concentrations. Conclusions: Adiponectin associates with inflammatory markers, and these associations differ in individuals with a high-risk autoantibody profile compared with those without. The interaction between adiponectin and autoimmunity may occur systemically, rather than at the joint, which may provide insight into the systemic effects of RA-related autoantibodies and inflammation in the absence of clinically apparent RA.

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Screening for blood-borne biomarkers of adiponectin action using the receptor agonist ALY688

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