Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication

The role of xanthine oxidoreductase and uric acid in metabolic syndrome.

BACKGROUND Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the formation of uric acid from hypoxanthine and xanthine, leading to an increase in superoxide and reactive oxygen species. Activation of XOR promotes oxidative stress-related tissue injury. We investigated the associations between metabolic parameters and plasma XOR activity measured by a sensitive and accurate assay using a combination of liquid chromatography and triple quadrupole mass spectrometry to detect [13C2,15N2]-uric acid using [13C2,15N2]-xanthine as a substrate.Methods and Results:A total of 627 Japanese subjects (M/F, 292/335) from the Tanno-Sobetsu Study, a population-based cohort, were recruited. Plasma XOR activity was significantly higher in males than in females, and habitual smoking was associated with elevation of activity. Plasma XOR activity was positively correlated with body mass index (BMI; r=0.323, P<0.001), waist circumference, blood pressure, and levels of liver enzymes including alanine transaminase (r=0.694, P<0.001), uric acid (r=0.249, P<0.001), triglycerides (r=0.312, P<0.001), hemoglobin A1c, fasting glucose, insulin and HOMA-R (r=0.238, P<0.001) as a marker of insulin resistance and was negatively correlated with high-density lipoprotein cholesterol level. On stepwise and multivariate regression analyses, BMI, smoking and levels of alanine transaminase, uric acid, triglycerides and HOMA-R were independent predictors of plasma XOR activity after adjustment for age and gender. CONCLUSIONS Plasma XOR activity is a novel biomarker of metabolic disorders in a general population.

Plasma Xanthine Oxidoreductase Activity as a Novel Biomarker of Metabolic Disorders in a General Population.

Obesity and related pathologies such as diabetes and metabolic syndrome are associated with chronic inflammation and cancer. The serum level of xanthine oxidoreductase (XOR) is correlated to obesity-associated metabolic disorders. XOR can play a role in the pathogenesis of both metabolic syndrome and cancer through the inflammatory response and the oxidative stress elicited by the products of its activity. The reactive oxygen and nitrogen species and the uric acid derived from XOR concur to the development of hypertension, dyslipidemia and insulin resistance and participate in both cell transformation and proliferation, as well as in the progression and metastasis process. Despite the availability of different drugs to inhibit in vivo XOR activity, the complexity of XOR inhibition effects should be carefully considered before clinical application, save in the case of symptomatic hyperuricemia.

Metabolic syndrome and cancer risk: The role of xanthine oxidoreductase.

Uric Acid Is a Biomarker of Oxidative Stress in the Failing Heart: Lessons Learned from Trials With Allopurinol and SGLT2 Inhibitors.

Background and Aims The enzyme xanthine oxidoreductase (XOR) catalyzes the formation of uric acid (UA) from hypoxanthine and xanthine, which in turn are products of purine metabolism starting from ribose-5-phosphate. Besides the synthesis of UA, basic research has suggested that XOR is involved in the regulation of reactive oxygen species, adipogenesis, and peroxisome proliferator-activated receptor-γ (PPAR-γ). XOR activity has shown to be much lower in humans than in rodents, which makes its accurate measurement difficult. Recently, a novel human plasma XOR activity assay has been established using a combination of liquid chromatography (LC) and triple quadrupole mass spectrometry (TQMS) to detect [ 13 C 2 , 15 N 2 ]UA using [ 13 C 2 , 15 N 2 ]xanthine as a substrate. Using this novel assay, we for the first time determine plasma XOR activity in humans, and evaluate its association with insulin resistance, high-sensitivity C-reactive protein (hsCRP) levels, and other parameters. Methods Of the 29 volunteers who wished to participate in the study, 3 were excluded; of the remaining, 11 were female and 15 were male with a mean age of 25.9 ± 3.3 years. Blood samples were collected under fasting conditions in the early morning to measure XOR activity and other parameters. Results The natural logarithmic value of XOR activity (ln-XOR) in plasma was 3.4 ± 0.8 pmol/h/mL. Ln-XOR had a positive correlation with UA and body mass index (BMI) and a negative correlation with quantitative insulin sensitivity check index (QUICKI) and adiponectin. In addition, ln-XOR had a positive correlation with hsCRP levels, which serves as a marker of chronic inflammation. Conclusions The present study has shown that XOR activity is correlated with serum UA levels in humans. Furthermore, even in young subjects, XOR activity is correlated with insulin resistance, BMI, and subclinical inflammation. Thus, XOR activity may be potentially involved in adiposity and subclinical inflammation in humans.

Xanthine oxidoreductase activity is correlated with insulin resistance and subclinical inflammation in young humans.

Polymyalgia rheumatica (PMR) is a disease commonly seen in elderly individuals, however, the etiology has not been reported. Typical clinical features include bilateral shoulder pain and morning stiffness, while serologic autoantibody test findings are negative. Approximately 40%-50% of affected patients present with low-grade fever, fatigue, and appetite loss, which we often experience in the field of general medicine, and thus, the condition should not be given low priority. However, knowledge regarding such constitutional manifestations is also limited. We encountered an elderly woman with a fever of unknown origin that developed following a parathyroidectomy for a single parathyroid adenoma, after which severe shoulder pain and morning stiffness emerged, leading to a diagnosis of PMR. The fever developed several days prior to appearance of severe pain, which is an uncommon presentation in PMR cases. Our patient had low-grade inflammation without pyrexia prior to the surgery, which might have been an important reason for the accelerated immoderate immune activation leading to PMR induced by surgery in this case. Furthermore, she was infected with the influenza A virus 3 weeks before coming to us. Some reports have suggested a relationship between the influenza virus or vaccine and PMR. It is difficult to conclude regarding the definite trigger in our patient, though the details of this case should be helpful for a better understanding of the disease.

Tadahiko Sukenaga

Papers

Xanthine oxidoreductase activity is correlated with insulin resistance and subclinical inflammation in young humans.

Fever of unknown origin following parathyroidectomy prior to onset of typical polymyalgia rheumatica symptoms: a case report.