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, Kähonen Mika, Raitoharju Emma, Lehtimäki Terho, Ala-Korpela Mika, Raitakari Olli T, Keinänen-Kiukaanniemi Sirkka, Järvelin Marjo-Riitta, Koivunen Peppi
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
: 2021
: Science Advances
: SCIENCE ADVANCES
: SCI ADV
: ARTN eabi4822
: 7
: 29
: 12
: 2375-2548
DOI: https://doi.org/10.1126/sciadv.abi4822(external)
: https://research.utu.fi/converis/portal/detail/Publication/66661574(external)
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.