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Lower hemoglobin levels associate with lower body mass index and healthier metabolic profile

Hemoglobin (Hb) is the main carrier of oxygen. In general, high-end Hb levels within the normal range are considered beneficial for health1. However, activation of the hypoxia response has been shown to protect mice against metabolic dysfunction2-4. We used Hb levels as an indicator for oxygenation status and studied its association with >170 anthropometric or metabolic parameters in two Finnish birth cohorts (total n = 7,175) in a longitudinal design. Here we show a remarkable strong positive linear association between Hb levels and body mass index (BMI). Subjects with the lower Hb levels also had better glucose tolerance, lower cholesterol and blood pressure levels, less adverse metabolite profiles and lower inflammatory load. Notably, these associations were not only mediated by the lower BMI, and the effect size of many of them increased with age. Polygenic risk score analyses indicated shared genetic determinants between Hb levels and BMI and insulin, triglyceride and HDL cholesterol levels. Manipulation of Hb levels by venesection in mice confirmed causal effects on body weight and metabolic parameters. Our findings suggest that lower-end normal Hb levels are favorable for and maintenance of healthy metabolism involving mild chronic activation of the hypoxia response. Therefore modulation of Hb levels could serve as a novel strategy towards treatment of metabolic syndrome.