Serum proteome signatures associated with liver steatosis in adolescents with obesity.

PURPOSE: Childhood obesity, a pressing global health issue, significantly increases the risk of metabolic complications, including metabolic dysfunction associated with steatotic liver disease (MASLD). Accurate non-invasive tests for early detection and screening of steatosis are crucial. In this study, we explored the serum proteome, identifying proteins as potential biomarkers for inclusion in non-invasive steatosis diagnosis tests. METHODS: Fifty-nine obese adolescents underwent ultrasonography to assess steatosis. Serum samples were collected and analyzed by targeted proteomics with the Proximity Extension Assay technology. Clinical and biochemical parameters were evaluated, and correlations among them, the individuated markers, and steatosis were performed. Receiver operating characteristic (ROC) curves were used to determine the steatosis diagnostic performance of the identified candidates, the fatty liver index (FLI), and their combination in a logistic regression model. RESULTS: Significant differences were observed between subjects with and without steatosis in various clinical and biochemical parameters. Gender-related differences in the serum proteome were also noted. Five circulating proteins, including Cathepsin O (CTSO), Cadherin 2 (CDH2), and Prolyl endopeptidase (FAP), were identified as biomarkers for steatosis. CDH2, CTSO, Leukocyte Immunoglobulin Like Receptor A5 (LILRA5), BMI, waist circumference, HOMA-IR, and FLI, among others, significantly correlated with the steatosis degree. CDH2, FAP, and LDL combined in a logit model achieved a diagnostic performance with an AUC of 0.91 (95% CI 0.75-0.97, 100% sensitivity, 84% specificity). CONCLUSIONS: CDH2 and FAP combined with other clinical parameters, represent useful tools for accurate diagnosis of fatty liver, emphasizing the importance of integrating novel markers into diagnostic algorithms for MASLD.

Sagittal abdominal diameter is more predictive of cardiovascular risk than abdominal fat compartments in severe obesity.

OBJECTIVE: To compare the predictive role of abdominal fat distribution by computed tomography (CT) with that of total abdominal fat by sagittal abdominal diameter (SAD) on cardiovascular risk in severe obesity. DESIGN: A cross-sectional, clinical study. SUBJECTS: 64 males and 64 females, aged 42+/-15 years (mean+/-s.d.; range 18-75 years), BMI (kg/m(2)) 41.7+/-5.3 (30.2-57.6). MEASUREMENTS: Blood glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides (TGLs), insulin (IRI), insulin resistance (HOMA-IR), slice areas (cm(2)) of total (tSAT), superficial (sSAT) and deep subcutaneous adipose tissue (dSAT), visceral adipose tissue (VAT) and SAD (mm) by CT. RESULTS: The sSAT depot was negatively associated with blood glucose, HOMA-IR, LDL cholesterol and TGLs, whereas dSAT was negatively associated with HDL cholesterol. VAT was associated with blood glucose and HOMA-IR, whereas SAD was associated with all variables evaluated. In males, VAT was associated with blood glucose (r(2)=0.12, P<0.01), SAD was associated with blood glucose (r(2)=0.67, P<0.01), IRI (r(2)=0.65, P<0.05), and HOMA-IR (r(2)=0.67, P<0.01). In females, sSAT was negatively associated with blood glucose (r(2)=0.63, P<0.05), whereas VAT was associated positively with blood glucose (r(2)=0.21, P< 0.001), total cholesterol (r(2)=0.16, P<0.01), LDL cholesterol (r(2)=0.20, P<0.001) and TGLs (r(2)=0.12, P<0.01). SAD was associated positively with IRI (r(2)=0.52, P<0.05), HOMA-IR (r(2)=0.53, P<0.05), total cholesterol (r(2)=0.52, P<0.05), LDL cholesterol (r(2)=0.54, P<0.01), TGLs (r(2)=0.52, P<0.05) and negatively to HDL cholesterol (r(2)=0.51, P<0.001). CONCLUSION: When compared with CT-based measures of abdominal fat compartments, SAD is a more predictive indicator of cardiovascular risk in severe obesity.

Abdominal fat index by ultrasound does not estimate the metabolic risk factors of cardiovascular disease better than waist circumference in severe obesity.

OBJECTIVE: To evaluate by ultrasound the ratio between preperitoneal (P) and subcutaneous (S) fat (AFI), in quantifying the cardiovascular risk in 258 obese patients (BMI 41.2+/-6.3 kg/m2; age 45.1 +/- 13.6 years). RESEARCH METHODS AND PROCEDURES: Glucose, insulin, lipid profile, uric acid and fibrinogen were measured. HOMA-IR, waist girth, AFI and quartiles of BMI were calculated. RESULTS: AFI lowered with increasing BMI and showed a positive correlation with TGL (r=0.37, P<0.01) and uric acid (r=0.40, P<0.001) in the 1st quartile of BMI (30.2-36.4) and a negative correlation with HDL (r=- 0.32, P<0.001) in the 3rd quartile (40.6-45.1). When BMI exceeded the value of 45.2 kg/m2 these correlations were no longer significant. In all subjects S correlated positively with uric acid (r=0.64, P<0.001), and negatively with HOMA-IR (r=- 0.41, P<0.001) and TGL (r=- 0.35, P=0.02); P correlated positively with CHOL (r=0.48, P=0.04) and TGL (r=0.33, P=0.03), and negatively with HDL (r=- 0.46, P=0.03). Waist girth showed more significant correlations than AFI in the lower quartiles of BMI, but not at the highest one. DISCUSSION: AFI, P and S, as waist girth do not seem to quantify the metabolic risk factors of cardiovascular disease in severe obese subjects, but AFI is probably useful in obese populations with BMI<45 kg/m2, even though not as strong as waist girth.

Subclinical hypothyroidism in obese patients: relation to resting energy expenditure, serum leptin, body composition, and lipid profile.

OBJECTIVE: To evaluate whether subclinical hypothyroidism (SH) affects resting energy expenditure (REE) as well as body composition, lipid profile, and serum leptin in obese patients. RESEARCH METHODS AND PROCEDURES: A total of 108 obese patients with SH defined as normal free thyroxine levels and thyroid-stimulating hormone (TSH) values of > 4.38 microU/ml (mean +/- 2 SD of the values of our reference group of obese patients with normal thyroid function) were compared with a group of 131 obese patients matched for age, sex, and body mass index (BMI) but with normal TSH levels. We assessed estimated daily caloric intake by 7-day recall, REE by indirect calorimetry, body composition by bioelectrical impedance analysis, serum leptin by radioimmunoassay, and lipid profile (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides). RESULTS: All of the variables measured were not different between the euthyroid obese patients and those with SH. In a multiple regression model with REE expressed for kilograms of fat free mass (REE/kgFFM) as a dependent variable and percentage of fat mass, BMI, waist-to-hip ratio, age, TSH, free thyroxine, serum leptin, and caloric intake as independent variables, only percentage of fat mass was significantly correlated with REE/kgFFM in both groups. In the SH group only, BMI, waist-to-hip ratio, age, and TSH were related to REE/kgFFM and explained 69.5% of its variability. After dividing the patients with SH using a cutoff TSH value of 5.7 microU/ml, which represents 3 SD above the mean of TSH levels of the group of obese patients with normal thyroid function, only REE/kgFFM was significantly different and lower in the group of more severely hypothyroid patients. DISCUSSION: In patients with obesity, SH affects energy expenditure only when TSH is clearly above the normal range; it does not change body composition and lipid profile. We suggest that, at least in obese patients, evaluation of TSH levels may be useful to rule out a possible impairment of resting energy expenditure due to a reduced peripheral effect of thyroid hormones.

The A19G polymorphism in the 5' untranslated region of the human obese gene does not affect leptin levels in severely obese patients.

Recently, the presence of different polymorphisms in the regulatory region of the ob gene has been associated with variations in leptin levels. However, the results of these studies are still contradictory. The aim of the present investigation was to evaluate the presence of the A19G polymorphism in an Italian population of obese patients and to verify its association with leptin levels and anthropometric, metabolic, and clinical parameters. Two hundred five obese patients [body mass index (BMI) > 36 kg/m2; 135 women and 70 men; mean age, 46.9+/-14.23 yr] were screened for presence of the polymorphism; 61 normal-weight controls (mean BMI, 21.05 kg/m2; 53 women, 8 men) were also screened to compare polymorphism frequency. For obese patients, BMI, waist-to-hip ratio, resting energy expenditure, body composition, fasting leptin, total cholesterol, high-density lipoproteins, triglycerides, and caloric intake were determined. Genotype frequencies in obese and control subjects were compared using the contingency table chi-square test; in obese subjects an ANOVA was performed to evaluate association between the polymorphism and several clinical parameters. No significant differences in genotype distribution between control and obese subjects were found. No significant correlations were found between this polymorphism and serum leptin levels and the other parameters considered. These findings confirm the results obtained in both a Finnish and a French population; taken together, these observations might rule out a significant role for the A19->G polymorphism in the regulation of leptin levels and other clinical, anthropometric, and metabolic parameters.

Leptin plasma concentrations are dependent on body fat distribution in obese patients.

AIM: To evaluate whether fat distribution plays a role in determining serum leptin concentrations. PATIENTS AND METHODS: One-hundred and forty-seven obese patients, 77 males and 70 females, aged 45.1 +/- 13.2 y (mean +/- s.d.; range 21-73 y), with body mass index (BMI) ranging from 30 to 55 kg/m2 (mean 42.3 +/- 5.9). Ultrasound assessment of the thickness of subcutaneous and preperitoneal fat was carried out and calculation of their ratio as abdominal fat index (AFI), waist-hip ratio (WHR), body composition by bioelectrical impedance to evaluate the percentage of fat mass (FM%) and total amount of fat (FMKg) were also determined. Plasma leptin was measured by radio immuno assay (RIA). RESULTS: In the whole group of patients, serum leptin concentrations were 37.2 +/- 18.4 ng/ml (range 6-101.3 ng/ml); in spite of BMI values not being significantly different, women had leptin values significantly higher (47.4 +/- 17.4 ng/ml) (P < 0.01) than males (28.1 +/- 15.1 ng/ml), also after correction for fat mass. The mean thickness of abdominal subcutaneous fat was 33.7 +/- 12.9 mm and it was significantly (P < 0.001) higher in female (40.9 +/- 10.6 mm) than in male (27.1 +/- 11.2 mm) patients; preperitoneal thickness was 22.9 +/- 7.1 mm, with significantly (P < 0.05) higher values in males (24.2 +/- 6.8 mm) than in females (21.7 +/- 7.3 mm). Accordingly, AFI (in all patients 0.84 +/- 0.6) was significantly higher in males (1.09 +/- 0.6) than in females (0.56 +/- 0.2). In the overall population, leptin concentrations were directly and significantly related to subcutaneous but not preperitoneal fat; they showed a strong inverse relationship with AFI and WHR. When the results were evaluated dividing the patients according to gender, subcutaneous fat thickness showed a stronger association with leptin levels in males than in females, whereas no association was found with preperitoneal fat thickness. Leptin and AFI values were significantly related only in men. WHR values were not correlated with leptin concentrations in either sex. When fat mass was added to the model, subcutaneous fat thickness, AFI and WHR remained independently associated with leptin concentrations. Age and diabetes did not influence these measures. CONCLUSIONS: Fat distribution contributes to the variability in serum leptin in obese patients. In particular, subcutaneous abdominal fat is a determinant of leptin concentration, also independently of the amount of fat mass, whereas the contribution of preperitoneal visceral fat is not significant.

Liver steatosis in juvenile obesity: correlations with lipid profile, hepatic biochemical parameters and glycemic and insulinemic responses to an oral glucose tolerance test.

OBJECTIVE: The aim of this study was to evaluate liver steatosis in prepubertal and pubertal obese and the correlations with the lipid profile, the serum levels of hepatic parameters and the glycemic and insulinemic responses to an oral glucose tolerance test. SUBJECTS: 375 obese, 205 males and 170 females, Tanner pubertal stage I (n=82), stages II-III (n=80) and stages IV-V (n=213). MEASUREMENTS: Body mass index (BMI), waist-hip ratio (WHR), total cholesterol and high density lipoprotein (HDL), cholesterol/HDL ratio, low density lipoprotein (LDL), very low density lipoprotein (VLDL), triglycerides (TGL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gGT, glycemia (G), insulinemia (IRI), fasting IRI/G ratio (FIGR), glycemic (mean blood glucose, MBG) and insulinemic (mean serum insulin, MSI) responses during a 120 min oral glucose tolerance test (OGTT), expressed as area under the curve (AUC)/120 min, pancreatic insulinemic response to glucose (IRG), and liver ultrasound scanning for assessing the degree of steatosis (moderate, severe). RESULTS: Liver steatosis was found in 33% of subjects in Tanner pubertal stage I, 36% in stage II-III and 47% in stages IV-V. BMI and transaminases were correlated with the degree of steatosis in all pubertal stages. AST, ALT and gGT were higher in the presence of steatosis, while elevated TGL was present in late puberty only; however the increase of ALT is specific for steatosis. CONCLUSION: Juvenile obesity involves a high risk of liver steatosis associated with alterations of transaminases and lipid but not glucose metabolism. These changes are apparent even to the prepubertal stage.

[Knemometry in the assessment of short term effects of growth hormone therapy in children with several growth disorders]. / Impiego della knemometria nella valutazione degli effetti a breve termine della terapia con GH in bambini con diversi disordini accrescitivi.

BACKGROUND: Knemometer is a non invasive device for measuring the leg length and evaluating statural variations otherwise not disclosed by means of Harpenden stadiometer. In several clinical conditions of short stature, knemometer allows to evaluate the short-term effect of growth promoting agents, as well as the role of infections on growth dynamics. METHODS: The short-term (37-56 days) variability of the leg length in subjects with isolated growth hormone deficiency (1 case), Turner syndrome (2 cases) and Silver-Russel syndrome (1 case) treated with rhGH have been evaluated. The measurements were performed weekly by the same operator, at the same weekday and daytime. RESULTS AND CONCLUSIONS: The results show a correlation between intercurrent illnesses and growth failure, as well as a growth resumption at the end of the former, despite the etiology of short stature. Growth hormone treatment seems to exert an influence on growth only in the subject with GH deficiency, whereas a similar short term effect is not found in the cases of Turner syndrome and Silver Russel syndrome. This fact suggests that, also by knemometry, a most prolonged follow-up is required to evaluate the effect of GH on short term growth.