Progranulin (PGRN), a novel peptide that has recently emerged as an important regulatory adipokine, is relevant to energy homeostasis and obesity in animals and adult humans. Little is known about its roles in children. The aim of the current study was to determine the potential role of PGRN and explore its relationship to various obesity-related markers in obese children. This was a cross-sectional study composed of 77 children (43 obese and 34 healthy, age 8.68 ± 0.28 and 8.46 ± 0.45 years, resp.). The PGRN levels were significantly higher in obese children (102.44 ± 4.18 ng/mL) comparing to controls (69.32 ± 5.49 ng/mL) (
Childhood obesity has become a global public health issue. The prevalence of obesity has tripled in the last three decades. Among Chinese children, the combined prevalence of overweight and obesity has increased rapidly over the past decades, from less than 3% in 1985 to 19.2% in 2010 [
As is well known, obesity is defined as excess fat mass accumulation. Adipose tissue, in addition to energy storage, has been found to have a variety of endocrine functions. It can secrete all kinds of adipokines [
Up to now, the clinical data have revealed a relationship between PGRN levels and obesity. However, few studies have explored the PGRN levels in obese children. Therefore, the purpose of the present study was to investigate possible correlations between PGRN levels and obesity in Chinese children, and to identify associations between PGRN levels and obesity-related disorders.
The study was initiated upon approval of the local ethics committee of the Faculty of Medicine of Soochow University, in light of the Helsinki Declaration. A written informed consent of the parent(s) of each subject was obtained before the study.
This study recruited 43 obese children, 13 girls and 30 boys, with BMI above the 95th percentile. Another 34 healthy subjects with BMI below the 85th percentile with similar age and gender distribution were enrolled as controls.
Before the outset of the study, all the patients and control subjects had under taken general physical examination and laboratory evaluation to exclude other illnesses. Those with chronic diseases (cardiovascular, gastrointestinal, or respiratory), history of drug use (steroids or antipsychotics), endocrine disorders (Cushing syndrome or hypothyroidism), or suspected syndromes associated with obesity (Prader-Willi or Laurence-Moon-Biedl syndromes) were excluded from the study. Pubertal development of subjects was evaluated according to Tanner staging [
Height was measured in the standing position, without shoes, using a stadiometer (sensitivity, 0.1 cm), and weight was measured using a portable scale (sensitivity, 0.1 kg) with the patients dressed in light clothing. BMI was calculated by dividing weight (kg) by squared height (m2).
Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured twice at the right arm after a 10 min rest in the supine position using a calibrated sphygmomanometer. For oral glucose tolerance test (OGTT), a 180 min OGTT (1.75 g/kg glucose, maximum 75 g) was performed in the morning after 10 to 12 hours overnight fasting. Blood samples were obtained by an antecubital venous catheter at 0, 30, 60, 120, and 180 min for determination of glucose, insulin, and C-peptide levels as described previously [
The homeostasis model assessment for insulin resistance (HOMA-IR) was calculated using the following formula: HOMA-IR = Insulin (mU/mL) × Glucose (mmol/L)/22.5, as previously described [
To assess the
Blood samples for glucose, insulin, lipid profiles, and PGRN levels were taken after 10–12 h night fasting. Blood was obtained from an antecubital venous catheter and placed on ice. Serum was separated within 20 min and stored at −80°C until analysis.
Fasting glucose was assayed by glucose oxidase method. HbAC1 was measured by isoelectric focusing. Serum insulin levels were measured by RIA using human insulin as standard (Millipore, Catalog number: EZHIASF-14K). Triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), liver function, and high-sensitive CRP concentrations were detected by autoanalyzer (Beckman CX-7 Biochemical Autoanalyser, Brea, CA, USA).
Serum PGRN, IL-6, and TNF
Statistical analyses of the data were conducted by SPSS 19.0.1 (SPSS Inc., Chicago, IL, USA). All values are presented as mean ± S.E.M. Distribution of data was evaluated with the Kolmogorov-Smirnov test. For numerical comparisons, Student’s
A total of 77 subjects were enrolled in this study, including 43 subjects (13 girls and 30 boys) in an obesity group and 34 subjects (12 girls and 22 boys) in a control group. Average age was 8.68 ± 0.28 years and 8.46 ± 0.45 years in the obesity group and control group, respectively. Table
The clinical and laboratory characteristics of obese and nonobese groups.
Variable | Obese subject | Nonobese subject | |
---|---|---|---|
Age(years) | 8.68 ± 0.28 | 8.46 ± 0.45 | N.S |
Boys/girls | 13/30 | 22/12 | N.S |
BMI (kg/m2) | 25.85 ± 0.38 | 15.40 ± 0.20 | <0.01 |
SBP (mmHg) | 111.63 ± 1.84 | 97.15 ± 0.81 | <0.01 |
DBP (mmHg) | 71.14 ± 1.48 | 65.76 ± 1.45 | <0.01 |
Glucose (mmol/L) | 4.39 ± 0.09 | 4.56 ± 0.13 | N.S |
HbAC1 (%) | 4.47 ± 0.07 | 4.32 ± 0.05 | <0.01 |
Insulin ( |
14.80 ± 1.28 | 4.31 ± 0.40 | <0.01 |
HOMA-IR | 2.86 ± 0.25 | 0.88 ± 0.09 | <0.01 |
HOMA- |
402.02 ± 53.61 | 83.12 ± 8.48 | <0.01 |
Insulinogenic index, ΔI30/ |
42.15 ± 4.56 | 62.13 ± 4.12 | <0.01 |
C-peptide index, ΔC30/ |
2.99 ± 1.09 | 4.05 ± 0.76 | <0.01 |
TG (mmol/L) | 1.57 ± 0.15 | 0.86 ± 0.08 | <0.01 |
TC (mmol/L) | 4.17 ± 0.10 | 4.12 ± 0.13 | N.S |
LDL (mmol/L) | 2.94 ± 0.10 | 2.70 ± 0.18 | <0.05 |
HDL (mmol/L) | 1.3 ± 0.03 | 1.56 ± 0.05 | <0.01 |
GPT (U/L) | 33.37 ± 5.18 | 17.17 ± 1.62 | <0.01 |
GOT (U/L) | 29.88 ± 2.11 | 26.89 ± 1.47 | N.S |
IL-6 (pg/mL) | 8.79 ± 0.21 | 7.38 ± 0.18 | <0.01 |
TNF- |
15.52 ± 0.56 | 11.34 ± 1.02 | <0.05 |
hsCRP (mg/dl) | 1.89 ± 0.30 | 0.38 ± 0.08 | <0.01 |
Data are presented as means ± S.E.M. BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; HOMA-IR: homeostasis model assessment of insulin resistance; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TC: total cholesterol; TG: triglycerides.
The clinical and laboratory characteristics of insulin resistant and nonresistant obese subjects.
Variable | IR ( |
Non-IR ( |
|
---|---|---|---|
Age (years) | 8.79 ± 0.45 | 8.57 ± 0.34 | N.S |
Boys/girls | 11/6 | 19/7 | N.S |
BMI (kg/m2) | 25.70 ± 0.05 | 25.94 ± 0.05 | N.S |
SBP (mmHg) | 111.65 ± 3.10 | 103.73 ± 4.48 | N.S |
DBP (mmHg) | 74.47 ± 2.48 | 68.96 ± 1.75 | N.S |
Glucose (mmol/L) | 4.39 ± 0.15 | 4.38 ± 0.12 | N.S |
HbAC1 (%) | 4.59 ± 0.09 | 4.35 ± 0.09 | N.S |
Insulin ( |
23.14 ± 1.48 | 9.35 ± 0.80 | <0.01 |
HOMA-IR | 4.48 ± 0.28 | 1.79 ± 0.14 | <0.01 |
HOMA- |
470.15 ± 70.15 | 367.95 ± 67.95 | <0.01 |
Insulinogenic index, ΔI30/ΔG30 ( |
51.74 ± 7.62 | 34.74 ± 5.15 | <0.05 |
C-peptide index, ΔC30/ |
2.36 ± 0.27 | 3.39 ± 1.81 | N.S |
TG (mmol/L) | 1.71 ± 0.27 | 1.59 ± 0.17 | N.S |
TC (mmol/L) | 4.09 ± 0.18 | 4.22 ± 0.11 | N.S |
LDL (mmol/L) | 2.82 ± 0.18 | 3.01 ± 0.11 | N.S |
HDL (mmol/L) | 1.31 ± 0.06 | 1.30 ± 0.04 | N.S |
GPT (U/L) | 42.89 ± 10.48 | 27.14 ± 4.98 | N.S |
GOT (U/L) | 34.90 ± 4.36 | 26.59 ± 1.81 | N.S |
IL-6 (pg/mL) | 8.32 ± 0.18 | 8.78 ± 0.22 | N.S |
TNF- |
62.82 ± 1.11 | 60.67 ± 0.05 | N.S |
hsCRP (mg/dl) | 1.82 ± 0.27 | 1.93 ± 0.48 | N.S |
Data are presented as means ± S.E.M. IR: insulin resistant; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; HOMA-IR: homeostasis model assessment of insulin resistance; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TC: total cholesterol; TG: triglycerides.
Compared to control group, obesity group displayed a significant increase in the PGRN concentrations (Figure
Serum PGRN levels and its correlation with clinical characteristics. (a) PGRN serum levels in nonobese and obese children, (b) PGRN serum levels between boys and girls in nonobese and obese group, (c) PGRN serum levels in noninsulin-resistant (non-IR) obese subject and insulin-resistant (IR) obese subject, and (d–h) scatter plots showing the correlation of serum PGRN levels with TG (d), TC (e), SBP (f), DBP (g), and IL-6 (h) in obese subjects. Data are expressed as mean ± SEM.
In obese subjects, the serum PGRN concentrations correlated positively and significantly with BMI, TG, TCs, SBP, DBP, and IL-6 (Table
Correlation of PGRN levels with clinical characteristics in obese groups.
Variable | ||
---|---|---|
BMI (kg·m2) | 0.742 | 0.001 |
Age (years) | −0.182 | 0.850 |
SBP (mmHg) | 0.670 | 0.003 |
DBP (mmHg) | 0.570 | 0.032 |
Insulin ( |
0.250 | 0.690 |
HbAC1 (%) | 0.219 | 0.832 |
Glucose (mmol/L) | 0.080 | 0.968 |
HOMA-IR | 0.260 | 0.668 |
HOMA- |
−0.222 | 0.750 |
Insulinogenic index, ΔI30/ΔG30 ( |
0.261 | 0.692 |
C-peptide index, ΔC30/ΔG30 (ng/mL per mmol/L) | 0.412 | 0.318 |
TGs (mmol/L) | 0.757 | 0.001 |
TCs (mmol/L) | 0.589 | 0.023 |
HDL (mmol/L) | 0.451 | 0.192 |
LDL (mmol/L) | 0.489 | 0.122 |
GPT (U/L) | 0.324 | 0.503 |
GOT (U/L) | 0.222 | 0.753 |
hsCRP (mg/dl) | 0.434 | 0.227 |
TNF (ng/L) | 0.258 | 0.672 |
IL6 (pg/mL) | 0.661 | 0.003 |
BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: fasting plasma glucose; HOMA-IR: homeostasis model assessment of insulin resistance; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TC: total cholesterol; TG: triglycerides.
Progranulin is a 68–88 kDa multifunctional protein, which was originally discovered by Anakwe and Gerton in 1990 [
To the best of our knowledge, this is the first study on PGRN and obesity-related markers in Chinese children. We found that serum PGRN concentrations were 1.5-fold higher in obese children, comparing to controls with normal weight. We also found that PGRN levels were positively correlated with BMI, TG, and TC in obese children. Our results were consistent with previous studies by Alissa and colleagues, who classified Saudi Arabia children into four groups based on quartiles of serum PGRN levels and found that children within the upper quartile of serum PGRN concentration were heavier and had higher concentrations of serum TC and TGs comparing to those in the lower quartile [
We also demonstrated that children presenting elevated levels of IL-6, TNF-
The present study showed that the HOMA-IR was higher in obese children comparing to nonobese children, suggesting that obese children had impaired insulin sensitivity, which is consistent with previous studies [
Few studies in the literature investigated the relationship between blood pressure and PGRN, especially in children. Qu et al. and Xu et al. have reported positive correlation between PGRN and blood pressure in adults [
One potential limitation of this study stems from a relatively small sample size. Furthermore, owing to lack of biological materials, we could not determine the expression of PGRN gene in adipose tissue of the study subjects.
In conclusion, this study showed that serum levels of PGRN were elevated in obese children, and may serve as a marker of ongoing obesity-related inflammation. Furthermore, our study also suggested that the elevation of PGRN levels in obese children may be an early marker and a potential therapeutic target for management of obesity-related disorders.
The authors declare that the data supporting the findings of this study are available within the article or are available from the corresponding author upon reasonable request.
The authors declare that they have no conflicts of interest.
Fengyun Wang and Ting Chen contributed equally to this study.
This study was supported by the National Natural Science Foundation of China (ID: 81300692 and 81700793) and Jiangsu Province Natural Science Foundation of China (17KJB320014).