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Human adipocytes induce an ERK1/2 MAP kinases-mediated upregulation of steroidogenic acute regulatory protein (StAR) and an angiotensin II — sensitization in human adrenocortical cells

International Journal of Obesity volume 31, pages 1605–1616 (2007)Cite this article

Abstract

Objectives:

Hypertension is a major complication of overweight with frequently elevated aldosterone levels in obese patients. Our previous work suggests a direct stimulation of adrenal aldosterone secretion by adipocytes. Owing to aldosterone's important role in maintaining blood pressure homeostasis, its regulation in obesity is of major importance. One objective was to determine the signaling mechanisms involved in adipocyte-induced aldosterone secretion. In addition to a direct stimulation, a sensitization toward angiotensin II (AngII) might be involved. The second objective was to determine a possible adipokines-induced sensitization of human adrenocortical cells to AngII.

Design:

Human subcutaneous adipocytes and adrenocortical cells, and the adrenocortical cell line NCI-H295R were used. Adrenocortical cells were screened for signal transduction protein expression and phosphorylation. Subsequently, steroidogenic acute regulatory protein (StAR), cAMP response element-binding protein (CREB), cAMP and phosphorylated extracellular regulated kinase were analyzed by Western blot, enzyme-linked immunosorbent assay, quantitative PCR, reporter gene assay and confocal microscopy to investigate their role in adipocyte-mediated aldosterone secretion.

Results:

AngII-mediated aldosterone secretion was largely increased by preincubating H295R cells with adipocyte secretory products. StAR mRNA and StAR protein were upregulated in a time-dependent way. This steroidogenic effect was independent of the cAMP-protein kinase A (PKA) pathway as cellular cAMP was unaltered and inhibition of PKA by H89 failed to reduce aldosterone secretion. However, CREB reporter gene activity was moderately elevated. Upregulation of StAR was accompanied by ERK1/2 MAP kinase activation and nuclear translocation of the kinases. Inhibition of MAP kinase by UO126 abolished adipokine-stimulated aldosterone secretion from primary human adrenocortical and H295R cells, and inhibited StAR gene activity. Adipokines stimulated steroidogenesis also in primary human adrenocortical cells, supporting a role in human physiology and/or pathology.

Conclusions:

Adipokines induce aldosterone secretion from human adrenocortical cells and sensitization of the cells to stimulation by AngII, possibly mediated via ERK1/2-dependent upregulation of StAR activity. This stimulation of aldosterone secretion could be one link between overweight and inappropriately elevated aldosterone levels.

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Acknowledgements

We thank Dr Mechthild Weiße-Lögering, Department of Plastic Surgery, Klinikum Pirna GmbH, Pirna and her team for their support in obtaining adipose tissue samples, Uta Buro for excellent technical assistance with quantitative PCR, and Jan Peychl, Max Planck Institute of Molecular Cell Biology and Genetics Dresden for technical assistance with confocal microscopy. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG grant EH161/4–1 to MEB and SRB), a MedDrive grant (to AWK), and the Grimmke Foundation (to AWK).

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Authors and Affiliations

  1. Medical Clinic III, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany

    A W Krug, K Vleugels, V Lamounier-Zepter, C G Ziegler, S R Bornstein & M Ehrhart-Bornstein

  2. Department of Endocrinology, University Medical Center, Heinrich Heine University of Duesseldorf, Duesseldorf, Germany

    S Schinner

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  1. A W Krug
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Correspondence to A W Krug.

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Krug, A., Vleugels, K., Schinner, S. et al. Human adipocytes induce an ERK1/2 MAP kinases-mediated upregulation of steroidogenic acute regulatory protein (StAR) and an angiotensin II — sensitization in human adrenocortical cells. Int J Obes 31, 1605–1616 (2007). https://doi.org/10.1038/sj.ijo.0803642

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