leptin and Hyperuricemia

Hyperuricaemia (HUA) significantly increases the risk of metabolic syndrome and is strongly associated with the increased prevalence of high serum free fatty acids (FFAs) and insulin resistance. However, the underlying mechanisms are not well established, especially the effect of uric acid (UA) on adipose tissue, a vital organ in regulating whole-body energy and FFA homeostasis. In the present study, we noticed that adipocytes from the white adipose tissue of patients with HUA were hypertrophied and had decreased UCP1 expression. To test the effects of UA on adipose tissue, we built both in vitro and in vivo HUA models and elucidated that a high level of UA could induce hypertrophy of adipocytes, inhibit their hyperplasia and reduce their beige-like characteristics. According to mRNA-sequencing analysis, UA significantly decreased the expression of leptin in adipocytes, which was closely related to fatty acid metabolism and the AMPK signalling pathway, as indicated by KEGG pathway analysis. Moreover, lowering UA using benzbromarone (a uricosuric agent) or metformin-induced activation of AMPK expression significantly attenuated UA-induced FFA metabolism impairment and adipose beiging suppression, which subsequently alleviated serum FFA elevation and insulin resistance in HUA mice. Taken together, these observations confirm that UA is involved in the aetiology of metabolic abnormalities in adipose tissue by regulating leptin-AMPK pathway, and metformin could lessen HUA-induced serum FFA elevation and insulin resistance by improving adipose tissue function via AMPK activation. Therefore, metformin could represent a novel treatment strategy for HUA-related metabolic disorders.

Topics: 3T3-L1 Cells; Adenylate Kinase; Adipocytes; Adipose Tissue, Beige; Adipose Tissue, White; Adult; Animals; Enzyme Activation; Fatty Acids, Nonesterified; Female; Humans; Hypertrophy; Hyperuricemia; Insulin Resistance; Leptin; Lipogenesis; Lipolysis; Male; Metformin; Mice; Mice, Inbred C57BL; Middle Aged; Signal Transduction; Triglycerides; Uric Acid

Vulnerability of the fetus upon maternal obesity can potentially occur during all developmental phases. We aimed at elaborating longer-term health outcomes of fetal overnutrition during the earliest stages of development. We utilized Naval Medical Research Institute (NMRI) mice to induce pre-conceptional and gestational obesity and followed offspring outcomes in the absence of any postnatal obesogenic influences. Male adult offspring developed overweight, insulin resistance, hyperleptinemia, hyperuricemia and hepatic steatosis; all these features were not observed in females. Instead, they showed impaired fasting glucose and a reduced fat mass and adipocyte size. Influences of the interaction of maternal diet∗sex concerned offspring genes involved in fatty liver disease, lipid droplet size regulation and fat mass expansion. These data suggest that a peri-conceptional obesogenic exposure is sufficient to shape offspring gene expression patterns and health outcomes in a sex- and organ-specific manner, indicating varying developmental vulnerabilities between sexes towards metabolic disease in response to maternal overnutrition.

Topics: Adipocytes; Animals; Body Weight; Cell Size; Diet, High-Fat; Disease Susceptibility; Fatty Liver; Female; Gene Expression Regulation, Developmental; Glucose Tolerance Test; Hyperuricemia; Insulin Resistance; Leptin; Male; Mice, Inbred Strains; Obesity; Overweight; Pregnancy; Prenatal Exposure Delayed Effects; Reverse Transcriptase Polymerase Chain Reaction; Sex Factors; Subcutaneous Fat; Time Factors

The polypeptide leptin exerts a multitude of regulatory functions. It has been implicated in the pathophysiology of inflammatory, metabolic and psychiatric disorders and has been found to be differentially expressed in men and women. Although a clear increase of leptin levels with age has been repeatedly observed in men, the association of leptin levels and age in women is an issue of scientific discussion. To investigate the association of age, gender, body mass index (BMI) and selected diseases with plasma levels of leptin in 551 adults randomly chosen from the Bavarian population, we assessed subjects' characteristics, lifestyle, and medical history including life time history of frequent diseases and performed blood sampling and standardized anthropometric measurements. Leptin plasma levels were measured using a Radioimmunoassay. Leptin levels were significantly higher in women as compared to men and this difference persisted even after controlling for differences in age or BMI. Leptin levels increased across the age groups in both men and women. Controlling for differences in BMI substantially attenuated the influence of age on leptin levels. In women, age was no longer significantly associated with leptin levels after controlling for BMI. With regard to medical history, hyperuricemia and gout were significantly associated with higher leptin levels, even after controlling for BMI, whereas subjects with high blood pressure or dyslipoproteinemia showed higher leptin levels only if the BMI was not considered as control variable. The BMI and its influence on the interrelations of gender, age and leptin should be considered when interpreting leptin levels.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Body Mass Index; Cross-Sectional Studies; Female; Gout; Humans; Hyperuricemia; Leptin; Male; Middle Aged; Sex Factors

Increased serum urate concentration is a frequent finding in patients with hypertension. Since hyperuricemia is associated with obesity, renal disease, hyperlipidemia, and atherosclerosis, whether or not serum urate is a cardiovascular risk factor per se has remained elusive. The subjects were 210 Turkish male and 210 female adults over 20 years of age. None had diabetes mellitus, endocrine diseases, or renal or hepatic disease, and those receiving antihypertensive drugs, systemic corticosteroids, or lipid-lowering drugs were excluded. Height, weight, blood pressure, serum glucose, lipid profiles, serum insulin, DHEA-SO4, and leptin were measured in the morning after an overnight fast. Women had significantly higher mean leptin (20.3 +/- 0.88 ng/mL vs 5.78 +/- 0.39 ng/mL, P < 0.001) and lower mean uric acid (248.03 +/- 4.76 micromol/L vs 311.6 +/- 5.35 micromol/L, P < 0.001), triglyceride (1.42 +/- 0.06 mmol/L vs 1.61 +/- 0.06 mmol/L, P < 0.001), and DHEA-SO4 (3.02 +/- 0.17 micromol/L vs 4.43 +/- 0.19 micromol/L, P < 0.001) concentrations than men, even when adjusted for BMI. On univariate correlation analysis, leptin showed the strongest association with BMI in both sexes and also correlated significantly with BMI, insulin, uric acid, glucose, total cholesterol, and triglycerides in males and BMI, insulin, uric acid, total cholesterol, apo B, and creatinine in females after adjustment for age and BMI. A statistical model containing creatinine, leptin, insulin, and triglycerides accounted for 34% of the variance in serum uric acid levels in men, whereas another consisting of creatinine, triglycerides, leptin, SBP, and insulin explained 42% of the variance in serum uric acid in women. The present study suggests that leptin could be one of the possible candidates for the missing link between obesity and hyperuricemia. Our study may also suggest that hyperuricemia is not only a metabolic end product but also a marker of a major pressor or pathogenic mechanism underlying the hypertension in obesity.

Topics: Adult; Body Mass Index; Cholesterol; Cross-Sectional Studies; Female; Humans; Hypertension; Hyperuricemia; Insulin; Leptin; Male; Obesity; Triglycerides; Uric Acid

The serum uric acid level has been said to be an independent predictor of cardiovascular disease death, mainly for women, and to be linked with the metabolic Syndrome X of insulin resistance, obesity, hypertension, and dyslipidemia. Recently, it has been suggested that the elevation of serum leptin, the ob gene product, may have a role in metabolic Syndrome X. Therefore, we studied the relationship of uric acid to leptin in 822 Japanese women in a cross-sectional manner. To estimate the effect of uric acid on the variables of metabolic Syndrome X, we calculated mean values of various components of the syndrome according to tertiles of uric acid (UA < 4.0 mg/dl, 4.0 < or = UA < 5.5, 5.5 < or = UA). Age, systolic and diastolic blood pressure (BP), body mass index (BMI), percent body fat mass (BFM), serum total cholesterol, triglyceride, atherogenic index, leptin, fasting immunoreactive insulin and homeostasis model assessment-ratio (HOMA-R: calculated insulin resistance) were significantly different across the uric acid tertiles with higher levels in the highest tertile in comparison to the first (ANOVA, p < 0.001, 0.001, 0.002, 0.001, 0.001, 0.025, 0.001, 0.001, 0.001, 0.001, 0.001, respectively), while high density lipoprotein cholesterol showed lower levels (p < 0.001). Serum leptin concentrations were also elevated in hyperuricemic women after adjusting for BMI or BFM (both p < 0.001), and were weakly correlated with serum uric acid concentrations (r = 0.22, p < 0.0001). BMI, HOMA-R, serum triglyceride, diastolic BP and age-adjusted serum leptin concentrations were calculated for each tertile of serum uric acid. Compared with the lowest tertile of uric acid level, BMI, HOMA-R, serum triglyceride, diastolic BP and age-adjusted leptin concentrations were higher in the highest tertile. In the stepwise regression analysis, serum leptin was the significant independent variable for uric acid values. These results indicate an independent relationship between leptin and uric acid, further supporting the involvement of leptin in metabolic Syndrome X.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arteriosclerosis; Blood Glucose; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Female; Humans; Hyperuricemia; Insulin; Leptin; Metabolic Syndrome; Middle Aged; Triglycerides; Uric Acid