University of Oulu

Auvinen, J., Tapio, J., Karhunen, V., Kettunen, J., Serpi, R., Dimova, E. Y., Gill, D., Soininen, P., Tammelin, T., Mykkänen, J., Puukka, K., Kähönen, M., Raitoharju, E., Lehtimäki, T., Ala-Korpela, M., Raitakari, O. T., Keinänen-Kiukaanniemi, S., Järvelin, M.-R., & Koivunen, P. (2021). Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia. In Science Advances (Vol. 7, Issue 29, p. eabi4822). American Association for the Advancement of Science (AAAS). https://doi.org/10.1126/sciadv.abi4822

Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia

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Author: Auvinen, Juha1,2; Tapio, Joona3,4; Karhunen, Ville1,5,6;
Organizations: 1Faculty of Medicine, Center for Life Course Health Research, University of Oulu, 90014 Oulu, Finland
2Medical Research Center, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland
3Biocenter Oulu, 90014 Oulu, Finland
4Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, 90014 Oulu, Finland
5Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, W2 1PG London, UK
6Research Unit of Mathematical Sciences, University of Oulu, 90014 Oulu, Finland
7Computational Medicine, Faculty of Medicine, University of Oulu, 90014 Oulu, Finland
8NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, 70210 Kuopio, Finland
9Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George’s, University of London, London, UK
10LIKES Research Center for Physical Activity and Health, 40700 Jyväskylä, Finland
11Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20520 Turku, Finland
12Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
13NordLab Oulu, Medical Research Center Oulu, Oulu University Hospital and Department of Clinical Chemistry, University of Oulu, 90014 Oulu, Finland
14Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
15Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center - Tampere, Tampere University, Tampere, Finland
16Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, 20520 Turku, Finland
17Unit of Primary Care, Oulu University Hospital, 90220 Oulu, Finland
18Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK
19Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, Middlesex UB8 3PH, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.6 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2021101551257
Language: English
Published: American Association for the Advancement of Science, 2021
Publish Date: 2021-10-15
Description:

Abstract

Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans (nn = 7175) and used Mendelian randomization (MR) to evaluate potential causality (n = 173,480). The results showed evidence for lower Hb levels being associated with lower body mass index, better glucose tolerance and other metabolic profiles, lower inflammatory load, and blood pressure. Expression of the key HIF target genes SLC2A4 and Slc2a1 in skeletal muscle and adipose tissue, respectively, associated with systolic blood pressure in MR analyses and body weight, liver weight, and adiposity in mice. Last, manipulation of murine Hb levels mediated changes to key metabolic parameters. In conclusion, low-end normal Hb levels may be favorable for metabolic health involving mild chronic activation of the HIF response.

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Series: Science advances
ISSN: 2375-2548
ISSN-E: 2375-2548
ISSN-L: 2375-2548
Volume: 7
Issue: 29
Article number: eabi4822
DOI: 10.1126/sciadv.abi4822
OADOI: https://oadoi.org/10.1126/sciadv.abi4822
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Subjects:
Funding: This study was supported by the Academy of Finland grants 266719 and 308009, the S. Jusélius Foundation, the Emil Aaltonen Foundation, and the Jane and Aatos Erkko Foundation to P.K. This work was also supported by the Academy of Finland Profi 5 funding for mathematics and AI: data insight for high-dimensional dynamics and the Academy of Finland Project 312123. D.G. was supported by the British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College London, and a National Institute for Health Research Clinical Lectureship (CL-2020-16-001) at St. George’s, University of London. NFBC1966 received financial support from University of Oulu grant nos. 65354 and 24000692; Oulu University Hospital grant nos. 2/97, 8/97, and 24301140; Ministry of Health and Social Affairs grant nos. 23/251/97, 160/97, and 190/97; National Institute for Health and Welfare, Helsinki grant no. 54121; Regional Institute of Occupational Health, Oulu, Finland grant nos. 50621 and 54231; ERDF European Regional Development Fund grant no. 539/2010 A31592; the European Union’s Horizon 2020 research and innovation programme grant agreement nos. 633595 (DynaHEALTH), 733206 (LifeCycle), 643774 (iHEALTH-T2D), 824989 (EUCAN Connect), and 721567 (EU H2020-MSCA-ITN-2016 CAPICE Marie Sklodowska-Curie), and grant nos. MR/M013138/1, MRC/BBSRC, and MR/S03658X/1 (the Medical Research Council, UK, JPI HDHL); and Academy of Finland, University Hospital Oulu, and NHLBI grant 5R01HL087679-02 through the STAMPEED program. The Young Finns Study has been financially supported by the Academy of Finland: grants 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere, and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; and Diabetes Research Foundation of Finnish Diabetes Association. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 848146 for T. Aition and grant agreement 755320 for TAXINOMISIS; European Research Council (grant 742927 for MULTIEPIGEN project); and Tampere University Hospital Supporting Foundation and Finnish Society of Clinical Chemistry.
EU Grant Number: (633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(733206) LIFECYCLE - Early-life stressors and LifeCycle health
(824989) EUCAN-Connect - A federated FAIR platform enabling large-scale analysis of high-value cohort data connecting Europe and Canada in personalized health
Academy of Finland Grant Number: 266719
308009
312123
Detailed Information: 266719 (Academy of Finland Funding decision)
308009 (Academy of Finland Funding decision)
312123 (Academy of Finland Funding decision)
Dataset Reference: Supplementary material:
  https://www.science.org/doi/suppl/10.1126/sciadv.abi4822/suppl_file/abi4822_sm.pdf
Copyright information: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
  https://creativecommons.org/licenses/by/4.0/