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Integrative Biology

Alarmin high-mobility group B1 (HMGB1) is regulated in human adipocytes in insulin resistance and influences insulin secretion in β-cells

International Journal of Obesity volume 38, pages 1545–1554 (2014)Cite this article

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Abstract

Background:

The nuclear protein high-mobility group box 1 (HMGB1) can be passively released by necrotic cells or secreted actively by several cell types to regulate immune and inflammatory responses, as well as tissue remodeling. We herein aimed to characterize the effect of insulin resistance on HMGB1 in adipose tissue and to examine its potential role as a metabolic regulator in β-pancreatic cells.

Design:

Plasma HMGB1 concentration and adipose HMGB1 expression were assessed in relation to obesity and insulin resistance. Cultured adipocytes from lean and obese patients were used to investigate the intracellular distribution and factors regulating HMGB1 release, as well as to test its effects on adipogenesis and lipid metabolism. A regulatory role for HMGB1 in insulin secretion was also investigated.

Results:

Circulating HMGB1 was positively associated with body mass index, while adipose HMGB1 mRNA levels correlated with the expression of inflammatory markers. Insulin resistance modified the intracellular distribution of HMGB1 in human adipocytes, with HMGB1 being predominantly nuclear in lean and obese normoglycemic individuals while localized to the cytosol in obese patients with type 2 diabetes. Adipocytes from lean individuals exposed to conditioned media from lipopolysaccharide-stimulated macrophages induced HMGB1 redistribution to the cytoplasm and release. HMGB1 treatment had no effect on differentiation and lipid metabolism in adipocytes. However, HMGB1, whose circulating levels correlated with postload insulin concentration, increased both insulin release and intracellular Ca2+ concentration in INS-1 cells.

Conclusions:

These findings show, for the first time, that HMGB1 expression and release by human adipocytes is altered by inflammatory conditions as those imposed by obesity and insulin resistance. Our data reveal a novel role for HMGB1 as a stimulatory factor of insulin secretion of β-pancreatic cells.

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Acknowledgements

This work was funded by MINECO/FEDER (BFU2010–17116), J. Andalucia/FEDER (CTS-03039, CTS-6606) and CIBERobn (Instituto de Salud Carlos III), Spain. We are indebted to Dr Angel Nadal (University Miguel Hernández, Spain) for kindly providing rat insulinoma INS-1 (832/13) cells. We thank Laura Molero (Department. of Cell Biology, Physiology and Immunology; IMIBIC/Reina Sofia University Hospital/University of Cordoba, CIBERobn, Spain) and Esther Peralbo Santaella (IMIBIC Reina Sofia University Hospital/University of Cordoba) for their technical assistance with cell cultures and confocal microscopy, respectively.

Author information

Authors and Affiliations

  1. Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigaciones Biomédicas de Córdoba (IMIBIC)/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain,

    R Guzmán-Ruiz, R Vázquez-Martínez, A Díaz-Ruiz, S Garcia-Navarro & M M Malagón

  2. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain

    R Guzmán-Ruiz, R Vázquez-Martínez, A Díaz-Ruiz, S Garcia-Navarro & M M Malagón

  3. Department of Diabetes, Endocrinology and Nutrition, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona (IdIBGi), Girona, Spain,

    F Ortega & J M Fernández-Real

  4. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain

    F Ortega & J M Fernández-Real

  5. Metabolic Research Laboratory, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain,

    A Rodríguez & G Frühbeck

  6. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain

    A Rodríguez & G Frühbeck

  7. Department of Biochemistry and Molecular Biology, Institut de Biomedicina (IBUB), University of Barcelona, Barcelona, Spain,

    M Giralt & F Villarroya

  8. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain

    M Giralt & F Villarroya

  9. Lipids and Atherosclerosis Unit, IMIBIC/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain,

    A Garcia-Rios & J López-Miranda

  10. CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Spain

    A Garcia-Rios & J López-Miranda

  11. Bariatric Surgery Unit, Reina Sofia University Hospital, Córdoba, Spain

    D Cobo-Padilla

  12. Biomedical Research Laboratory, Endocrinology and Nutrition Department, Hospital Clinico Virgen de la Victoria, Málaga, Spain,

    F J Tinahones

  13. CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Spain

    F J Tinahones

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  1. R Guzmán-Ruiz
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Correspondence to J M Fernández-Real or M M Malagón.

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Guzmán-Ruiz, R., Ortega, F., Rodríguez, A. et al. Alarmin high-mobility group B1 (HMGB1) is regulated in human adipocytes in insulin resistance and influences insulin secretion in β-cells. Int J Obes 38, 1545–1554 (2014). https://doi.org/10.1038/ijo.2014.36

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