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

Abstract

Copyright © 2021 The Authors. 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 (n = 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.Academy of Finland grants 266719 and 308009; S. Jusélius Foundation; Emil Aaltonen Foundation; Jane and Aatos Erkko Foundation; Academy of Finland Profi 5 funding for mathematics and AI: data insight for high-dimensional dynamics and the Academy of Finland Project 312123; British Heart Foundation Centre of Research Excellence (RE/18/4/34215); National Institute for Health Research Clinical Lectureship (CL-2020-16-001) at St. George’s, University of London. NFBC1966; 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; European Union’s Horizon 2020 research and innovation programme under grant agreement no. 848146; 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