Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia
Auvinen, Juha; Tapio, Joona; Karhunen, Ville; Kettunen, Johannes; Serpi, Raisa; Dimova, Elitsa Y.; Gill, Dipender; Soininen, Pasi; Tammelin, Tuija; Mykkänen, Juha; Puukka, Katri; Kähönen, Mika; Raitoharju, Emma; Lehtimäki, Terho; Ala-Korpela, Mika; Raitakari, Olli T.; Keinänen-Kiukaanniemi, Sirkka; Järvelin, Marjo-Riitta; Koivunen, Peppi (2021-07-14)
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
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/
https://urn.fi/URN:NBN:fi-fe2021101551257
Tiivistelmä
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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