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Endogenous cortisol excess confers a unique lipid signature and metabolic network

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Abstract

Chronic cortisol excess induces several alterations on protein, lipid and carbohydrate metabolism resembling those found in the metabolic syndrome. However, patients exposed to prolonged high levels of cortisol in Cushing syndrome (CS) present exceeding cardiometabolic alterations not reflected by conventional biomarkers. Using 3 ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS) platforms, we aimed to characterise the serum metabolome of 25 patients with active endogenous CS and 25 control subjects matched by propensity score (sex, BMI, diabetes mellitus type 2 (T2D), high blood pressure (HBP) and dyslipidaemia) to search for potential disease-specific biomarkers and pathways associated to the clinical comorbidities. A total of 93 metabolites were significantly altered in patients with CS. Increased levels of sulfur amino acids (AA), triacylglycerols, glycerophospholipids, ceramides and cholesteryl esters were observed. Contrarily, concentrations of essential and non-essential AA, polyunsaturated fatty acids, conjugated bile acids and second messenger glycerolipids were decreased. Twenty-four-hour urinary free cortisol (24h-UFC) independently determined the concentration of 21 lipids and 4 AA. A metabolic signature composed by 10 AA and 10 lipid metabolites presented an AUC-ROC of 95% for the classification of CS patients. Through differential network analysis, 152 aberrant associations between metabolites involved in the Lands cycle and Kennedy pathway were identified. Our data indicates that chronic hypercortisolemia confers a unique lipidomic signature and several alterations in numerous AA even when compared to patients with similar metabolic comorbidities providing novel insights of the increased cardiometabolic burden of CS.

Key messages

• Cortisol excess induces metabolic alterations beyond conventional biomarkers.

• The hypercortisolism extent determines the concentration of 21 lipids and 5 aa.

• Cortisol excess confers a unique metabolic signature of 20 metabolites.

• Kennedy and Lands cycle are profoundly disturbed by cortisol excess.

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Data availability

All data, materials and software application or custom code support their published claims and comply with field standards. All metabolomic data generated and analysed during this study is included in the present manuscript and as supplementary spreadsheets material in the initial submission (Additional File 2). The clinical dataset of the participants included in the study is available from the corresponding author upon reasonable request. Codes employed in R (programming language) for the present study are available from the corresponding author upon reasonable request.

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Acknowledgements

Arturo Vega-Beyhart sincerely acknowledges the Mexican National Council of Science and Technology (CONACYT) for the scholarship granted to pursue his doctorate at the University of Barcelona.

Funding

This work was supported by 2 grants of the Carlos III Health Institute of MINECO, Spain (FIS PI1500859 and PIE14/00031).

Author information

Authors and Affiliations

  1. Group of Endocrine Disorders, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Carrer Rosselló, 149, 08036, Barcelona, Spain

    Arturo Vega-Beyhart, Guillermo García-Eguren, Oriol Giró, Laura Boswell, Gloria Aranda, Vanesa Flores, Mireia Mora, Irene Halperin & Felicia A Hanzu

  2. Endocrinology and Nutrition Department, Hospital Clínic, Barcelona, Spain

    Arturo Vega-Beyhart, Adriana Pané, Laura Boswell, Vanesa Flores, Mireia Mora, Irene Halperin, Ramon Gomis & Felicia A Hanzu

  3. OWL Metabolomics, Derio, Spain

    Marta Iruarrizaga & Cristina Alonso

  4. Biomedical diagnostics Centre, Hospital Clínic, Barcelona, Spain

    Gregori Casals

  5. Surgery Department, Hospital Clínic, Barcelona, Spain

    Francesc Carmona, Joaquim Enseñat & Oscar Vidal

  6. School of Computing, Queen’s University, Kingston, ON, Canada

    Ting Hu

  7. Endocrinology and Nutrition Clinical Management Unit. Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain

    Gemma Rojo

  8. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

    Gemma Rojo, Ramon Gomis & Felicia A Hanzu

  9. Laboratory of Diabetes and Obesity, IDIBAPS, Barcelona, Spain

    Ramon Gomis

  10. Department of Medicine, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain

    Ramon Gomis & Felicia A Hanzu

Authors
  1. Arturo Vega-Beyhart
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  2. Marta Iruarrizaga
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  4. Guillermo García-Eguren
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Contributions

Conceptualization: Felicia A Hanzu, Adriana Pané, Ramon Gomis, Gemma Rojo, Arturo Vega-Beyhart

Data: Felicia A Hanzu, Arturo Vega-Beyhart, Adriana Pané, Guillermo García-Eguren, Oriol Giró, Laura Boswell, Gloria Aranda, Vanesa Flores, Francesc Carmona, Joaquim Enseñat, Oscar Vidal, Mireia Mora, Irene Halperin, Gemma Rojo

Formal analysis: Felicia A Hanzu, Arturo Vega-Beyhart, Marta Iruarrizaga, Ting Hu, Guillermo García-Eguren, Oriol Giró, Gregori Casals

Funding acquisition: Felicia A Hanzu, Gemma Rojo, Ramon Gomis

Investigation: All authors participated

Supervision: Felicia A Hanzu

Writing, review and editing: All authors participated

Corresponding author

Correspondence to Felicia A Hanzu.

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Ethics approval

The present study followed international and national regulations including the Declaration of Helsinki and national notes for guidance on Good Clinical Practice CPMP/ICH/135/95. The Institutional Research and Ethics Committee at Hospital Clínic de Barcelona approved the present study (Comité de Ética de la Investigación con medicamentos del Hospital Clínic de Barcelona). The Institutional Research and Ethics Committee at Hospital Regional Universitario de Málaga approved the present study (Comité de Ética de la Investigación Provincial de Málaga).

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Written informed consent was obtained from all participants prior to study inclusion and are available under considerable request.

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Not applicable. No personal nor any clinical details of participants are presented.

Competing interests

The authors declare no competing interests.

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Vega-Beyhart, A., Iruarrizaga, M., Pané, A. et al. Endogenous cortisol excess confers a unique lipid signature and metabolic network. J Mol Med 99, 1085–1099 (2021). https://doi.org/10.1007/s00109-021-02076-0

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