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.

To evaluate the incidence and severity of knee magnetic resonance imaging (MRI) findings and their associated lifestyle and health factors in a relatively healthy subset of a general population-based birth cohort. The study population (n = 288, 61.1% females, mean age 33.7 years) is a subpopulation of the Northern Finland Birth Cohort 1986 (NFBC1986) on whom a thorough clinical evaluation, laboratory analyses and knee MRI were conducted at 33 years of age. Knee MRI data was graded using the MRI Osteoarthritis Knee Score (MOAKS) system. Descriptive statistics and multivariable regression models were used for data analysis. Subjects were mostly asymptomatic. Detected articular cartilage lesions were mostly small and identified in 56.2 % (n = 162) of patellofemoral and 25.3 % (n = 63) of tibiofemoral joints. Full thickness cartilage lesions and bone marrow lesions were mostly located in the patellofemoral joint. Osteophytes, mostly small or doubtful, were detected in 51.7 % (n = 146) of patellofemoral and 17.4 % (n = 41) of tibiofemoral joints. In finding-specific regression analyses, higher body mass index (BMI) was most frequently associated with knee MRI findings. In this relatively young and asymptomatic population, subtle knee MRI findings were already frequent, especially in the patellofemoral joint. Of analyzed background and clinical parameters, higher BMI was most frequently associated with MRI findings. Based on these results, longitudinal studies are warranted to further identify risk factors and proportions of progressing MRI findings.

Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases (HIF-P4Hs 1–3) are druggable targets in renal anemia, where pan-HIF-P4H inhibitors induce an erythropoietic response. Preclinical data suggest that HIF-P4Hs could also be therapeutic targets for treating metabolic dysfunction, although the contributions of HIF-P4H isoenzymes in various tissues to the metabolic phenotype are inadequately understood. Here, we used mouse lines that were gene-deficient for HIF-P4Hs 1 to 3 and two preclinical pan-HIF-P4H inhibitors to study the contributions of these isoenzymes to the anthropometric and metabolic outcome and HIF response. We show both inhibitors induced a HIF response in wildtype white adipose tissue (WAT), liver, and skeletal muscle and alleviated metabolic dysfunction during a 6-week treatment period, but they did not alter healthy metabolism. Our data indicate that HIF-P4H-1 contributed especially to skeletal muscle and WAT metabolism and that its loss lowered body weight and serum cholesterol levels upon aging. In addition, we found HIF-P4H-3 had effects on the liver and WAT and its loss increased body weight, adiposity, liver weight and triglyceride levels, WAT inflammation, and cholesterol levels and resulted in hyperglycemia and insulin resistance, especially during aging. Finally, we demonstrate HIF-P4H-2 affected all tissues studied; its inhibition lowered body and liver weight and serum cholesterol levels and improved glucose tolerance. We found very few HIF target metabolic mRNAs were regulated by the inhibition of three isoenzymes, thus suggesting a potential for selective therapeutic tractability. Altogether, these data provide specifications for the future development of HIF-P4H inhibitors for the treatment of metabolic diseases.

To investigate the associations between knee magnetic resonance imaging (MRI) findings, knee joint symptoms and related health factors in a random subpopulation of 33-year-olds from the Northern Finland 1986 Birth Cohort. Subjects with questionnaire, knee MRI, and clinical symptom data, were included in this study (n = 284, 60.9 % females, age 33.7 years). Knee MRI data was graded using the MRI Osteoarthritis Knee Score (MOAKS) system. Symptoms were evaluated using the Visual Analogue Scale (VAS) version of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and participants with VAS >3 in any WOMAC sub-question were considered symptomatic. 12.2 % (74.3 % females) of the study population were symptomatic, and were more likely to have a higher BMI, adverse lipid profile and a family history of knee OA. Advanced MRI findings were sparse. Most MRI findings, such as bone marrow lesions (BMLs) and osteophytes, were more prevalent and severe in symptomatic participants. In adjusted regression analyses, BMLs in the medial femoral compartment and osteophytes in the lateral tibial and medial femoral compartments, patellar tendon signal and joint effusion were associated with knee symptoms. Several MRI findings, most notably medial femoral BMLs, osteophytes, patellar tendinopathy and joint effusion were associated with knee symptoms. Of other factors, sex, family history and clinical factors such as body composition are associated with knee joint symptomatology from early adulthood.

Hb levels, one of the most commonly measured laboratory tests, could be used beyond anemia in assessment of cardiometabolic health already in adolescence; higher Hb levels within the reference interval are associated with an increased risk.

Heart rate variability (HRV) and baroreflex sensitivity (BRS), which can be measured noninvasively, can predict cardiac and metabolic diseases. Our findings show that within normal variation subjects with lower hemoglobin (Hb) levels have an overall healthier HRV profile and increased cardiac parasympathetic activity in middle age, independent of age, sex, smoking status, and key metabolic covariates. These findings support our previous findings that Hb levels can be used in assessing long-term risks for cardiometabolic diseases.