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. 2021 Jul 14;7(29):eabi4822.
doi: 10.1126/sciadv.abi4822. Print 2021 Jul.

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

Juha Auvinen  1   2 , Joona Tapio  3   4 , Ville Karhunen  1   5   6 , Johannes Kettunen  1   3   7   8 , Raisa Serpi  3   4 , Elitsa Y Dimova  3   4 , Dipender Gill  5   9 , Pasi Soininen  7   8 , Tuija Tammelin  10 , Juha Mykkänen  11   12 , Katri Puukka  13 , Mika Kähönen  14 , Emma Raitoharju  15 , Terho Lehtimäki  15 , Mika Ala-Korpela  1   3   7   8 , Olli T Raitakari  11   12   16 , Sirkka Keinänen-Kiukaanniemi  1   17 , Marjo-Riitta Järvelin  18   3   17   19   20 , Peppi Koivunen  21   4
Affiliations

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

Juha Auvinen et al. Sci Adv. .

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 (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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Figures

Fig. 1
Fig. 1. Study hypothesis associating lower Hb levels with better metabolic health.
HIF, hypoxia-inducible factor; HIF-P4H, HIF prolyl 4-hydroxylase; OXPHOS, oxidative phosphorylation.
Fig. 2
Fig. 2. Association of Hb levels with body weight, glucose tolerance, and insulin resistance in mice.
(A) Association of Hb levels with body weight in 1-year-old C57Bl/6 male mice (n = 29). (B and C) Association of the highest quartile (High Hb) and the lowest quartile (Low Hb) of Hb levels with GTT area under the curve (AUC) and HOMA-IR scores, respectively, in the 1-year-old C57Bl/6 male mice (C). The data in (B) and (C) are means ± SEM. *P < 0.05.
Fig. 3
Fig. 3. Association of Hb levels with key anthropometric measures and oxygen consumption in human cohorts.
(A) Association of Hb levels with BMI in NFBC1966 at 46 years. Unadjusted regression line (blue) with 95% CIs (gray) of blood Hb levels (g/liter) with BMI (kg/m2). (B) Forest plot representing the effect size estimates and their 95% CIs for 1 SD change in anthropometric measures per 1 SD change in Hb. Red, blue, and black lines indicate effect sizes for NFBC1966 at 46 years, YFS at 42 years, and meta-analysis, respectively. The effect sizes were adjusted for sex, smoking, physical activity, age, and height for parameters other than BMI. (C to E) Added variable plots for sex-adjusted partial associations of Hb levels with oxygen consumption at rest (C), oxygen consumption at rest with body fat percentage (D), and Hb levels with body fat percentage (E) in the NFBC1966 subpopulation (n = 123) at 31 years.
Fig. 4
Fig. 4. Association of Hb levels with key metabolic parameters.
Forest plot representing the effect size estimates and their 95% CIs of the association in SD units of Hb levels with log(fasting insulin) and fasting glucose levels, log(HOMA-IR) and log(HOMA-B) indexes, log(triglycerides), log(AUC of glucose in OGTT)*, log(AUC of insulin in OGTT)* and 2-hour glucose in levels in a 2-hour OGTT*, log(Matsuda Index)*, fasting serum total cholesterol, HDL cholesterol and LDL cholesterol levels, systolic and diastolic blood pressure, and log[high-sensitivity C-reactive protein (CRP)] levels in meta-analysis of NFBC1966 at the age of 46 and YFS at 42 years, respectively. * indicates the associations only analyzed in NFBC1966. The effect sizes were adjusted for sex, smoking, physical activity (blue), and, in addition, BMI (red). Values with ±3 SD exclusions are presented.
Fig. 5
Fig. 5. Positive association of Hb levels with most anthropometric and metabolic parameters strengthens with age.
Effect sizes of association in SD units of Hb levels with log(BMI), waist and hip circumference, waist-hip ratio, fasting glucose and log(fasting insulin) levels, HOMA-IR and HOMA-B indexes, systolic and diastolic blood pressure, fasting serum cholesterol, LDL cholesterol, HDL cholesterol and triglyceride levels, and log(high-sensitivity CRP) in NFBC1966 at the age of 31 (red) and 46 (blue) years, respectively. The P values for the difference in effect size between age 31 and 46 years are indicated. The effect sizes for the anthropometric parameters (above the black horizontal line) were adjusted for sex, smoking, physical activity, and height (excluding BMI), and the metabolic parameters were adjusted for sex, smoking, physical activity, and BMI.
Fig. 6
Fig. 6. Higher Hb levels associate with metabolic signatures of adiposity, insulin resistance, and cardiovascular risk.
Effect sizes in SD units of association of Hb levels with systemic metabolite levels in random-effects meta-analysis of NFBC1966 at 46 years and YFS at 42 years. The effect sizes were adjusted for BMI, sex, smoking, and physical activity.
Fig. 7
Fig. 7. Genetic analyses between Hb levels and HIF target genes and metabolic outcomes.
(A) GSEA of the YFS lowest Hb quartile (Hb < 132 g/liter, n = 392) versus YFS highest Hb quartile (Hb > 152 g/liter, n = 371) and selected hypoxia-induced HIF target genes. Cohort n = 1636. The analysis was adjusted for sex, age, numbers of thrombocytes and leukocytes, the first five principal components of the transcriptomics data, BMI, research center, and three technical microchip variables. (B) eQTL MR analyses of selected HIF target genes in the indicated tissues. The hollow point indicates P < 0.00125 (Bonferroni-corrected threshold of 0.05 for 40 exposures). ENO1, enolase 1; FLT1, VEGR receptor 1; LOX, lysyl oxidase; P4HA1, collagen prolyl 4-hydroxylase subunit alfa 1; PDK1, pyruvate dehydrogenase kinase 1; PFKL, phosphofructokinase liver; PFKM, PFK muscle; PFKP, PFK platelet; SLC2A1, glucose transporter 1; SPP1, secreted phosphoprotein 1; VEGFA, vascular endothelial growth factor A. (C) Association of WAT Slc2a1 mRNA levels with key anthropometric and metabolic markers and Hb levels in 1-year-old C57Bl/6 male mice (n = 14).
Fig. 8
Fig. 8. Manipulation of Hb levels by venesection in mice alters causally metabolic parameters.
Hb levels, body weight, fasting blood glucose, fasting serum insulin, HOMA-IR, 2-hour blood glucose levels in GTT, total cholesterol, HDL cholesterol, LDL + VLDL cholesterol, triglycerides, and lactate levels of 3-month-old C57Bl/6 male mice (n = 21) before (Baseline) and 2 weeks after venesection (Post venesection). Data are means ± SEM. *P < 0.05, **P < 0.01, and ****P < 0.0001.
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