The emerging role of leptin in humans

Leptin is an adipocyte-secreted hormone which plays a key role in energy homeostasis. Recent advances in leptin physiology have revealed that the main role of this hormone in humans is to signal energy availability in energy-deficient states. Interventional studies in leptin deficient children and observational studies in normal girls and boys support a role for leptin as a permissive factor for the initiation of puberty in children. Moreover, recent "proof of concept" studies involving leptin administration to humans further support its critical role in regulating energy homeostasis, neuroendocrine and immune function as well as insulin resistance in states of energy/caloric deprivation. Leptin's potential role in the therapy of several disease states, including hypothalamic amenorrhea, anorexia nervosa and syndromes of insulin resistance is under intensive investigation.     

单纯性肥胖儿童黑色棘皮症与胰岛素抵抗性及细胞因子的关系

目的 探讨单纯性肥胖儿童的黑色棘皮症(AN)和体质量指数、胰岛素抵抗性、瘦素、血浆酶原纤维蛋白溶解原活化抑制剂(PAI-1)的关系。方法 单纯性肥胖儿童38例,其中AN阳性17例,测量身高、体质量、腹围、臀围,同时测血胰岛素、瘦素、空腹血糖、PAI-1。结果 AN阳性者肥胖度、腹围、空腹胰岛素、自动动态平衡标准评价胰岛素抵抗指数(HOMA-R)关系有显著差异,AN与体脂肪率间无关。AN阳性肥胖儿中均升高,PAI-1 40μg／L以上,瘦素30 μg／L以上者均为AN阳性。结论　单纯性肥胖儿童,特别是伴AN阳性肥胖儿,要特别注意随访观察2型糖尿病和冠状动脉疾病的发生和发展。     

Relationship between plasma leptin, insulin and tumor necrosis factor alpha in obese children

OBJECTIVES: 1. To evaluate the relationship between plasma leptin and TNFalpha concentrations in obese children and to assess the differences between hyperinsulinemic and normoinsulinemic groups. 2. To evaluate the relationship between plasma leptin and insulin levels in obese children. 3. To investigate the TNFalpha G308A mutation in obese children. METHODS: Body mass index (BMI), fasting plasma glucose and insulin levels, oral glucose tolerance test results, homeostasis model assessment of insulin resistance (HOMA-IR) results, and plasma leptin and TNFalpha concentrations were evaluated in obese children (n = 45) and age- and gender-matched, lean healthy controls (n = 40). RESULTS: In obese children the fasting insulin, HOMA-IR results, plasma leptin and TNFalpha concentrations were significantly higher than in controls (p <0.05). Furthermore, obese females showed higher plasma leptin and insulin resistance compared to obese males. While plasma leptin, TNFalpha levels and HOMA-IR results were similar in the prepubertal and pubertal groups, insulin levels were significantly higher in the pubertal group. Plasma leptin and TNFalpha concentrations were similar in hyperinsulinemic and normoinsulinemic obese children. In control children, plasma leptin concentrations showed a positive correlation with BMI, age, fasting insulin and HOMA-IR results. In obese children, plasma leptin levels did not correlate with BMI, fasting insulin or TNFalpha. CONCLUSION: Plasma leptin concentrations did not show any correlation with TNFalpha levels in obese children. Furthermore, plasma leptin and TNFalpha concentrations were similar in hyperinsulinemic and normoinsulinemic obese children.     

Insulin and insulin resistance index are not independent determinants for the variation in leptin in obese children and adolescents

Recent findings have questioned the independent influence of insulin on leptin. We studied whether insulin contributes to leptin in obese children, independent of confounding parameters, such as total adiposity, fasting insulin resistance index, and fat free mass. In 100 obese boys and 103 obese girls, blood levels of leptin, insulin, glucose, and triglycerides were determined. The fasting insulin resistance index (FIRI) was calculated, and body composition was assessed by means of impedance. Leptin and glucose were higher in girls, and all estimates of adiposity were significantly associated with leptin. However, when adjusted for adiposity, the relationship between insulin and leptin, and also between FIRI and leptin, remained significant in boys and girls (p<0.05). Although several regression models were tested, neither insulin nor FIRI were found to contribute significantly and independently to leptin. BMI together with triglycerides and FFM were the main determinants for the variation in leptin in boys (adj. R2=0.46, p<0.0001). In girls, BMI explained a great magnitude of the variation in leptin (adj. R2=0.60, p<0.0001). These findings indicate that in the state of childhood and adolescent obesity, total adiposity but not insulin or insulin resistance index is the main determinant for leptin. In contrast to obese girls, the fat free mass and triglycerides contribute significantly to the variation in leptin in obese boys. The biological significance for these findings should be elucidated in longitudinal studies.     

Leptin and soluble leptin receptor levels in obese children in fasting and satiety states

AIM: To investigate the role of soluble leptin receptors in leptin resistance in obese children. METHODS: Thirty-one obese children (16 boys and 15 girls) with a median age of 12.1 years and 15 age- and sex-matched controls were included in the study. Leptin and soluble leptin receptor levels were measured in fasting and satiety states. RESULTS: Serum leptin levels were significantly higher and soluble leptin receptor levels were significantly lower in obese children compared to controls in fasting and satiety states. In obese children, there was a high and inverse correlation between leptin levels and soluble leptin receptor levels after fasting. Prepubertal obese children had lower leptin and higher soluble leptin, receptor levels compared to pubertal children in both states. CONCLUSION: In this study, being the first to consider both fasting and satiety states, obese children were found to have higher leptin, but lower soluble leptin receptor levels, compared to controls. With these findings, it can be postulated that leptin resistance in obese children originates from a defect of soluble leptin receptor production.     

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目的探讨丙戊酸治疗对癫癎患儿血浆胰岛素和瘦素水平的影响。方法测定2003-04—2004-02在山东大学齐鲁医院儿科癫癎治疗中心就诊且服用丙戊酸的32例癫癎患儿和33例对照组(儿外患儿)血浆胰岛素、瘦素水平并计算胰岛素抵抗值、体重指数,并对服用丙戊酸的癫癎患儿胰岛素抵抗值、瘦素与丙戊酸的剂量、疗程、体重指数进行相关分析。结果丙戊酸治疗组体重指数、胰岛素、胰岛素抵抗值、瘦素水平高于对照组;胰岛素抵抗值、瘦素水平与体重指数、丙戊酸疗程显著正相关,与剂量无相关性;偏相关分析示对照组胰岛素、胰岛素抵抗值与瘦素显著负相关,而丙戊酸治疗组胰岛素、胰岛素抵抗值与瘦素显著正相关。结论丙戊酸治疗可引起肥胖程度增加、胰岛素抵抗及瘦素抵抗;胰岛素抵抗、瘦素抵抗与肥胖程度增加有关,与丙戊酸疗程正相关;胰岛素抵抗与瘦素水平显著正相关。     

Adiponectin/Acrp30, an adipocyte-specific secretory factor: physiological relevance during development

Adiponectin/Acrp30 is a fat cell-specific secretory product. The convergence of results from epidemiological, pharmacological and genetic studies over the last 2 yr has highlighted the important role that this multimeric protein complex plays in the context of insulin sensitivity. While the exact mechanism of action has not been elucidated, it is clear that adiponectin has insulin-sensitizing effects on both liver and muscle. The important role that adipose tissue plays in energy homeostasis as a storage compartment for triglycerides has been appreciated for a long time. The identification of leptin as a key hormone involved in central control of energy metabolism suggested that adipocytes also use polypeptide hormones to influence metabolic processes at distant sites. The recent progress made towards the characterization of the physiological role of adiponectin highlights the important role of adipose tissue as an endocrine organ and its central role in the fine-tuning of hepatic and muscle insulin responsiveness.     

The role of leptin, soluble leptin receptor, resistin, and insulin secretory dynamics in the pathogenesis of hypothalamic obesity in children

Introduction  In this study, we have investigated the role of leptin, soluble leptin receptor(sOb-R), resistin, and insulin secretory dynamics in the development of hypothalamic obesity. Materials and methods  Children who had hypothalamo-pituitary tumor were divided into two groups. First group included obese-overweight (hypothalamic obese = HOB group, n = 23) and second group included non-obese children (hypothalamic non-obese = HNOB group, n = 16). Exogenously obese-overweight children (OB group, n = 22) were included as controls. Basal and second-hour serum glucose and insulin in oral glucose tolerance test (OGTT), basal serum leptin, sOb-R, resistin levels, and homeostasis model assessment (HOMA) indexes were compared between the groups. Results  Age, sex, and pubertal status were similar in study groups. Median and interquartile ranges of body mass index (BMI) z scores were similar in HOB and OB groups (2.0 (1.5–2.1) and 2.1 (1.8–2.3), respectively). Serum leptin levels corrected for BMI were highest and total leptin/sOb-R ratios (free leptin index (FLI)) tended to be higher in HOB than HNOB and OB groups, indicating leptin resistance (leptin/BMI, 4.0 (1.6–5.2), 1.5 (0.8–3.1), and 2.5 (1.8–3.5); FLI, 2.0 (0.8–3.5), 0.6 (0.3–1.2), and 1.5 (1–2.3) in HOB, HNOB, and OB groups; respectively). Serum resistin levels were similar in groups (2.6 (1.9–3.1), 2.8 (1.7–3.4), and 3.0 (2.2–3.5) ng/ml in HOB, HNOB, and OB groups, respectively). Basal serum glucose, basal and second-hour insulin levels in OGTT, and HOMA index were higher in OB group than the HOB and HNOB groups, indicating insulin resistance in simple obesity; however, increment of insulin to same glycemic load in OGTT was highest in the HOB group indicating insulin dysregulation (p < 0.05). Conclusion  Hypothalamic obesity seems to be related to both dysregulated afferent (leptin) and efferent (insulin) neural outputs through the autonomic nervous system resulting in energy storage as fat. This work has been presented in part in the free communication session of ESPE 2007 meeting (Helsinki-Finland, 2007).     

Nonalcoholic fatty liver disease and carotid atherosclerosis in children

Nonalcoholic fatty liver disease (NAFLD) is closely associated with several metabolic syndrome features, including obesity, dyslipidemia, insulin resistance, and increased cardiovascular risk. The present study was undertaken to assess whether NAFLD in children is associated with increased carotid artery intima-media thickness (IMT), a marker of early-generalized atherosclerosis. We analyzed carotid IMT along with serum triglycerides, total, low-density lipoprotein and high-density lipoprotein cholesterol, glucose, insulin, insulin resistance index (as homeostasis model assessment of insulin resistance), aminotransferases, leptin, and adiponectin in 29 obese children with NAFLD, 33 obese children without liver involvement, and 30 control children. The diagnosis and severity of NAFLD was based on ultrasound scan, after exclusion of infectious and metabolic disorders. Obese children with NAFLD had significantly increased carotid IMT [mean 0.58 (95% confidence intervals 0.54-0.62 mm)] than obese children without liver involvement [0.49 (0.46-0.52) mm; p = 0.001] and control children [0.40 (0.36-0.43) mm; p < 0.0005]. In a stepwise multiple regression model, after adjusting for age, gender, Tanner stage, and cardiovascular risk factors, the severity of fatty liver was significantly associated with maximum IMT (b = 0.08; p < 0.0005). Our results suggest that NAFLD is strongly associated with carotid atherosclerosis even in childhood.     

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目的观察单纯性肥胖儿童和健康正常体重儿童血清脑源性神经营养因子(BDNF)质量浓度的差异,探讨BDNF与儿童肥胖及瘦素抵抗、胰岛素抵抗的关系。方法南京军区福州总医院儿科等于2004年5月至2005年5月应用酶联免疫法检测单纯性肥胖儿童(37例)和健康儿童(31例)血清BDNF质量浓度与胰岛素(INS)浓度,应用放射免疫法检测血清瘦素(LEP)质量浓度。比较两组儿童血清BDNF、INS、LEP的差异,分析血清BDNF质量浓度与血清LEP质量浓度和INS浓度的关系。结果(1)两组儿童的体重指数(BMI)、BDNF、INS及LEP均差异显著(BMI:F=175·05,P<0·01;BDNF:F=12·35,P<0·01;INS:F=21·71,P<0·01;LEP:F=48·89,P<0·01),肥胖组BMI、INS及LEP均明显高于健康组,而肥胖组BDNF明显低于健康组。(2)影响LEP的因素依次为BMI、丙氨酸转氨酶(ALT)、BDNF(R2=0·5946,F=0·31,P<0·01);影响INS的因素依次为BMI、BDNF(R2=0·2647,F=11·34,P<0·01)。去除BMI、ALT影响后,BDNF与LEP、INS负相关(BDNF与LEP:r=-0·2455,P<0·05;BDNF与INS:r=-0·2878,P<0·05)。结论(1)肥胖儿童血清BDNF缺乏,未发现“BDNF抵抗”的特点。(2)学龄前儿童血清LEP、INS受BMI影响最大,还受血清BDNF影响。BDNF是二者独立的负相关因素。     

Insulin resistance and ferritin as major determinants of abnormal serum aminotransferase in severely obese children.

OBJECTIVES: Liver involvement is a common complication of obesity related in part to insulin resistance. The role of ferritin has not been investigated in children. The aim was to determine the prevalence of liver enzyme abnormalities in severely obese children and to look for relationships between fat mass distribution, insulin resistance, and plasma ferritin. METHODS: 197 children with severe obesity (defined as a body mass index Z-score (BMI-Z) > 3.0) were studied prospectively from 2001 to 2004. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values were measured, as well as anthropometric characteristics: blood pressure; body composition by dual energy X-ray absorptiometry, and plasma fasting glucose, insulin, leptin, lipid, and ferritin concentrations. RESULTS: Serum ALT and AST values were abnormal in 23 (11.7%) and 13 (6.6%) children, respectively. By univariate analysis, serum ALT and AST values were positively correlated with android fat mass distribution (P < 0.0001 and P = 0.005, respectively) after adjustment for age, sex, ethnicity, and Tanner stage. Using the same model, a positive correlation and a positive trend linked plasma ferritin to serum AST (P = 0.02) and serum ALT (P = 0.06), respectively. Serum ALTwas positively correlated to insulin resistance (P = 0.03). Using a multivariate model, with the android/gynoid fat mass ratio as an additional independent variable, ferritin remained correlated with serum AST and ALT (P = 0.001 and P = 0.008, respectively). CONCLUSIONS: Abnormal serum aminotransferase values are uncommon in severely obese children in France. Android fat mass distribution, insulin resistance, and higher ferritin concentrations are significantly associated with liver abnormalities in our cohort.     

Childhood craniopharyngioma: greater hypothalamic involvement before surgery is associated with higher homeostasis model insulin resistance index

Background  

Obesity seems to be linked to the hypothalamic involvement in craniopharyngioma. We evaluated the pre-surgery relationship between the degree of this involvement on magnetic resonance imaging and insulin resistance, as evaluated by the homeostasis model insulin resistance index (HOMA). As insulin-like growth factor 1, leptin, soluble leptin receptor (sOB-R) and ghrelin may also be involved, we compared their plasma concentrations and their link to weight change.     

Cardiac autonomic nervous system activity in obesity

The development of obesity is caused by a disturbance of energy balance, with energy intake exceeding energy expenditure. As the autonomic nervous system (ANS) has a role in the regulation of both these variables, it has become a major focus of investigation in the fields of obesity pathogenesis. The enhanced cardiac sympathetic drive shown in most of the studies in obese persons might be due to an increase in their levels of circulating insulin. The role of leptin needs further investigation with studies in humans. There is a blunted response of the cardiac sympathetic nervous system (SNS) activity in obese subjects after consumption of a carbohydrate-rich meal as well as after insulin administration. This might be due to insulin resistance. It is speculated that increased SNS activity in obesity may contribute to the development of hypertension in genetically susceptible individuals. It is also speculated that the increase in cardiac SNS activity under fasting conditions in obesity may be associated with high cardiovascular morbidity and mortality.     

Are C‐reactive protein and homocysteine cardiovascular risk factors in obese children and adolescents?

Background: Several prospective epidemiological studies have demonstrated that high-sensitivity C-reactive protein (hsCRP) and plasma homocysteine (hcy) are predictors of future coronary events among healthy men and women. The aim of the present study was therefore to investigate a possible relationship between hsCRP, hcy levels and body mass index (BMI), relative weight (RW), serum leptin levels, and cardiovascular risk factors in obese children and adolescents.
Methods: The study involved 28 obese children and adolescents (13 girls, 15 boys; BMI>95‰ for age and sex), 4.5–15 years of age (mean 10.7 ± 0.6 years), who attended hospital for a basic obesity check-up. The association between hsCRP, hcy levels and BMI, RW, serum leptin levels, and cardiovascular risk factors such as blood pressure (BP), lipid profile, serum fasting insulin levels, and insulin resistance indexes, was investigated.
Results: Serum hsCRP level was positively correlated with BMI ( r = 0.512, P  < 0.01), RW ( r = 0.438, P  < 0.05), systolic and diastolic BP ( r = 0.498, P  < 0.01), serum leptin levels ( r = 0.457, P  < 0.05), but not with serum lipid, glucose, fasting insulin, plasma hcy levels or insulin resistance indexes. For hcy level, in contrast, no correlation was found with BMI, RW, systolic and diastolic BP, serum lipid levels, leptin, hsCRP, glucose, fasting insulin levels, or insulin resistance indexes.
Conclusions: hsCRP is correlated with BMI, RW, BP and leptin, which are risk factors for coronary heart disease, which supports the relationship between obesity, inflammation and atherosclerosis. hsCRP in childhood obesity might be a useful index to predict possible atherosclerotic events.     

Insulin and Leptin Levels in Appropriate-for-Gestational-Age Infants of Diabetic Mother

Objective

Intensified management of gestational diabetes mellitus can normalize birth weight. However, it is still unknown whether intrauterine exposure to maternal diabetes is a risk factor for changing hormone levels involved in the development of insulin resistance in these infants. We compared insulin and leptin levels in appropriate for gestational age (AGA) infants of diabetic and non diabetic mothers.

Methods

We performed a cross-sectional study in the department of Neonatology of the Hospital of Gynecology-Pediatrics, in Leon, Mexico. We evaluated 182 full term AGA newborns (86 infants of diabetic and 96 of non-diabetic mothers). A venous blood sample was taken from cord blood immediately after the separation of the placenta and glucose, insulin and leptin levels were measured. In all diabetic mothers HbA1c was also evaluated immediately post-partum.

Findings

Leptin, insulin and insulin resistance index were significantly higher in infants of diabetic mothers. Leptin levels were positive correlated with insulin, parents‘ body mass index and age in the entire group. In infants of diabetic mothers only insulin levels showed a significantly correlation, whereas in those of non-diabetic mothers only mothers‘ age was significantly correlated with leptin levels.

Conclusion

AGA infants of diabetic mothers showed higher leptin, insulin levels and insulin resistance index than those of non-diabetic mothers.     

Relationship between insulin resistance and serum levels of adiponectin and resistin with childhood obesity

OBJECTIVE: The aim is to study the relationship between insulin resistance and serum adiponectin and resistin in obese children. METHODS: A total 113 obese and 37 nonobese children were enrolled and serum adiponectin and resistin were measured. RESULTS: Compared with controls, higher insulin resistance by homeostasis model (HOMA-IR) and lower whole body insulin resistance index (WBISI)were found in obese children (all P <0.05). The adiponectin levels in obese children and controls were 3.63 and 5.79 microg/L with a significant difference (P<0.001) while the difference of resistin levels was not significant (P = 0.948). Significant correlations between insulin resistance parameter and age,sexual development, BMI, serum triglyceride, ApoB, LDL-cholesterol, HDL-cholesterol, alanine aminotransferase, uric acid, or adiponectin levels (all P <0.05) were noted. Stepwise multiple regression analysis showed that BMI and adiponectin levels were independent determinants of WBISI. CONCLUSIONS: These results suggest that adiponectin may play a protective role in obese children through decreasing insulin resistance.     

Leptin in African-American children

Leptin, the protein product of the obesity gene, produced by adipose tissue, regulates body weight and energy expenditure through CNS feedback mechanisms. In obesity, leptin levels are elevated suggestive of leptin resistance. Because of increased prevalence of obesity in African-Americans, the aim of this study was to assess leptin and its relationship to adiposity in African-American children. We measured plasma leptin levels in 42 African-American children (23 M, 19 F), age 11.8 +/- 0.3 yr, and compared them with 30 American-White children matched for age, body composition and puberty. Body composition was assessed by bioelectrical impedance and plasma leptin by RIA. Data are presented as means +/- SEM and statistical significance is implied by p < 0.05. There was no racial difference in plasma leptin levels (Blacks: 9.8 +/- 1.6, Whites 9.8 +/- 1.9 ng/ml). Leptin correlated with %BF in Black (r = 0.75, p = 0.005) and White (r = 0.79, p = 0.005) children. There were no gender or puberty related differences in leptin levels in African-American children. We concluded that leptin levels are comparable between African-American and American White children of similar body composition. The major determinant of serum leptin levels in these children is degree of adiposity with no gender or puberty related differences. Longitudinal studies are needed to assess leptin's role during puberty in both genders.     

Changes in circulating levels of adiponectin and leptin in children during the first two years of life

AIM: Adiponectin, leptin and insulin play an important role in the control of growth and glyco-metabolic homeostasis both during pre- and post-natal life. In order to find out markers indicative of post-natal growth, we evaluated circulating levels of these growth factors in full term small for gestational age (SGA) children, during the first 2 years of life, correlating them with the auxological parameters. METHODS: Fourteen SGA (8 males and 6 females) and 16 AGA (appropriate for gestional age) infants (7 males and 9 females) have been included in this study, recording length, weight, body mass index (BMI), adiponectin, leptin and insulin levels at birth. In SGA subjects, these biochemical and clinical parameters have also been evaluated at the first and at the second year of age. RESULTS: AGA and SGA adiponectin and insulin levels at birth did not show statistically significant differences, while leptin concentrations were significantly (P=0.011) lower in SGA children (median 418.49, range 157.68-903.67 pg/mL) in comparison with AGA ones (median 811.71, range 312.50-3085.95 pg/mL). CONCLUSIONS: In conclusion, at birth adiponectin and insulin levels do not differ between AGA and SGA subjects while leptin concentrations are significantly lower in SGA infants and positively correlated to the birthweight.     

Metabolic syndrome,adipokines and ghrelin in overweight and obese schoolchildren: results of a 1-year lifestyle intervention programme

The aim of this study was to evaluate the effect of a lifestyle intervention programme (nutrition and exercise counselling) on metabolic syndrome (MS) components, adipokines (leptin, adiponectin) and ghrelin levels in overweight children. A total of 61 overweight children aged 7–9 years (≥85th body mass index (BMI) percentile; 27 boys/34 girls) were randomly assigned and completed a 1-year individual (IT) or group-based treatment (GT). Anthropometric and biochemical parameters were assessed at baseline, at 6 months and at 1 year. Twenty-two normal weight children (<85th BMI percentile; 7–9 years old; 13 boys/nine girls) were also evaluated at baseline. Insulin resistance (IR) was determined by the homeostasis model assessment of IR (HOMA-IR). Overweight children presented significantly higher blood pressure, triglycerides, apolipoprotein B, insulin, HOMA-IR, leptin, C-reactive protein and homocysteine levels, while apolipoprotein A-I was significantly lower. At baseline, MS was present in ten overweight children, of which only five maintained it at 1 year. Leptin and ghrelin levels were associated with IR and MS components. MS was predicted by apolipoprotein A-I, insulin and pre-puberty. The lifestyle intervention led to a significant improvement in standard deviation score of BMI, waist circumference/height ratio and lipid profile. Changes in insulin, HOMA-IR, leptin and adiponectin were not significant. Ghrelin behaved differently between IT and GT. The GT intervention seems to be more successful, with a decrease in BMI Z-score and an improvement of metabolic parameters. In conclusion, overweight children have multiple risk factors associated with MS. A lifestyle intervention programme seems to be an effective mean for reducing obesity and MS components and improving adipokines concentrations.