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

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 =...

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Bibliographic Details
Published in:Science Advances
Main Authors: Auvinen, J, Tapio, J, Karhunen, V, Kettunen, J, Serpi, R, Dimova, EY, Gill, D, Soininen, P, Tammelin, T, Mykkanen, J, Puukka, K, Kahonen, M, Raitoharju, E, Lehtimaki, T, Ala-Korpela, M, Raitakari, OT, Keinanen-Kiukaanniemi, S, Jarvelin, M-R, Koivunen, P
Format: Article in Journal/Newspaper
Language:English
Published: American Association for the Advancement of Science 2021
Subjects:
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MENDELIAN RANDOMIZATION ANALYSES
INSULIN-RESISTANCE
CARDIOVASCULAR RISK
NORTHERN FINLAND
BLOOD-PRESSURE
GLUCOSE
SERUM
HEMATOCRIT
OBESITY
HIF
Northern Finland
Online Access:http://hdl.handle.net/10044/1/94513
https://doi.org/10.1126/sciadv.abi4822
Description
Summary: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.

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