Abstract
Background
Adipokines are peptides secreted from white adipose tissue (WAT), which have been linked to WAT dysfunction and metabolic complications of obesity. We set out to identify novel adipokines in subcutaneous WAT (sWAT) linked to insulin resistance (IR).
Methods
Gene expression was determined by microarray and qPCR in obese and non-obese subjects with varying degree of IR. WAT-secreted and circulating protein levels were measured by ELISA.
Results
In sWAT of 80 obese women discordant for IR, 44 genes encoding potential adipose-secreted proteins were differentially expressed. Among these, merely two proteins, S100A4 and MXRA5 were released from sWAT in a time-dependent manner (criterion for true adipokines) but only the circulating levels of S100A4 were higher in IR. In two additional cohorts (n = 29 and n = 56), sWAT S100A4 secretion was positively and BMI-independently associated with IR (determined by clamp or HOMA-IR), ATP-III risk score and adipocyte size (hypertrophy). In non-obese (n = 20) and obese subjects before and after bariatric surgery (n = 21), circulating and sWAT-secreted levels were highest in the obese and normalized following weight loss. Serum S100A4 concentrations were higher in subjects with type 2 diabetes. S100A4 sWAT expression associated positively with genes involved in inflammation/extracellular matrix formation and inversely with genes in metabolic pathways. Although S100A4 was expressed in both stromal cells and adipocytes, only the expression in adipocytes associated with BMI.
Conclusions
S100A4 is a novel adipokine associated with IR and sWAT inflammation/adipocyte hypertrophy independently of BMI. Its value as a circulating marker for dysfunctional WAT and IR needs to be validated in larger cohorts.
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Acknowledgements
We would like to thank Ms Kerstin Wåhlén for skilled technical assistance and research nurses Katarina Hertel and Yvonne Widlund for excellent help with the clinical examinations. MR, ID, and PA conceived the study. MR and PA collected all the data, EN and AT recruited all subjects, MR wrote the first version of the manuscript and is the guarantor of the data. MR, PA, PP, DE, ID and AB generated data and prepared figures/tables. MR, ID, AE, DE, PP and PA analyzed data. All authors read and contributed to the final version of the manuscript.
Funding
This work was supported by grants from the EU Innovative Medicines Initiative EMIF, the Swedish Research Council, The Swedish Diabetes Foundation, CIMED, the Diabetes Theme Center at Karolinska Institutet, the Stockholm County Council, the Erling-Persson Family Foundation and the Novo Nordisk Foundation including the Tripartite Immuno-metabolism Consortium (TrIC), Grant Number NNF15CC0018486 and the MSAM Consortium NNF15SA0018346.
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Arner, P., Petrus, P., Esteve, D. et al. Screening of potential adipokines identifies S100A4 as a marker of pernicious adipose tissue and insulin resistance. Int J Obes 42, 2047–2056 (2018). https://doi.org/10.1038/s41366-018-0018-0
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DOI: https://doi.org/10.1038/s41366-018-0018-0
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