Ghrelin, Adipokines, Metabolic Factors in Relation With Weight Status in School-children and Results of a 1-year Lifestyle Intervention Program

Christine Rambhojan; Elodie Bouaziz-Amar; Laurent Larifla; Jacqueline Deloumeaux; Josiane Clepier; Jean Plumasseau; Jean-Marc Lacorte; Lydia Foucan

Disclosures

Nutr Metab. 2015;12(43) 

In This Article

Discussion

The current study is the first to evaluate the metabolic profile in overweight and obese Guadeloupean children. Obesity was associated with an adverse metabolic profile including, high frequencies of abdominal obesity (73 %) and of insulin resistance (89 %) highlighting the risk for development of type 2 diabetes and future cardiovascular complications in adulthood.[4,20] These obese children also exhibited, at baseline, the highest values for triglycerides and leptin levels and the lowest values for HDL-cholesterol, ghrelin and adiponectin levels. In addition, leptin levels appeared to have a stronger relationship with weight status and HOMA-IR than ghrelin and adiponectin at baseline which is in favor of a role of leptin in body weight regulation.[21] Our 1-year collaborative lifestyle intervention, led to improvements in BMI z-score and in most of the metabolic parameters particularly in the obese children. The results, after the intervention, also showed that changes in BMI z-score correlated with changes in leptin levels. Leptin levels decreased significantly only in the obese group whereas adiponectin concentrations increased in normal weight, overweight and obese children.

Anthropometric Parameters

All the anthropometric parameters (WC, WHtR and BMI Z-score) were significantly correlated with ghrelin, leptin and adiponectin except in girls in whom no correlation with ghrelin was observed. Abdominal obesity, defined in children as WHtR greater than 0.5,[18] has been associated in adulthood with cardio vascular complications[18] and was found in 2.3 % of normal weight, 28.2 % of overweight and 73 % of our obese children.

In a recent review, the authors recommended to pay more attention to abdominal obesity in children and adolescents because central body fat deposition increases the risk of cardio-metabolic risk factors, whatever the definition used for abdominal obesity and whatever the methods used for anthropometric measurements,.[22]

Metabolic Profile, Ghrelin and Cytokines

The lowest HDL-C concentrations, the highest triglycerides and FBG concentrations and the highest values for HOMA-IR index were observed in the obese children. It is well known that obesity is associated with comorbidities such as dyslipidemia, hypertension, insulin resistance[20,23] and with early indication of atherosclerosis.[24,25] We also observed high frequencies of insulin resistance (defined as HOMA-IR greater than 3.16) in obese (89 %), overweight (72 %) and normal weight children (39 %). Insulin sensitivity index was previously reported lower in black compared with white adolescents suggesting a more diabetic profile in the first group.[26] In our general population in which most people are of African ancestry and diabetes is highly prevalent (8 %), the results observed in children and adolescents highlight their high risk of metabolic complications. This risk is probably increased due to children family history showing 50 % of overweight and 7 % of diabetes in accompanying parents.

Despite ghrelin levels were not significantly associated with HOMA-IR in the linear regression (Table 3), the hormone has been recognized as an important regulator of energy metabolism and serves as a physiological regulator of insulinemia and glycemia.[3]

Adipose tissue is considered as an endocrine organ producing several proteins (including leptin and adiponectin) with important biological activity and, the adipocyte plays a central role in the balance, or imbalance, of metabolic homeostasis.[27] Adiponectin levels were the lowest and leptin levels the highest in the obese group. Numerous studies described significant negative correlations between adiponectin and the parameters of obesity. Low adiponectin concentrations which has been previously associated with coronary artery disease in the adult population of Guadeloupe[28] correlated with high plasma insulin levels and adverse blood lipid profile in the present study in children. Lower adiponectin levels in obesity were also associated with chronic inflammation, endothelial dysfunction, and insulin resistance.[29,30] The three multivariate linear regression models for ghrelin, adiponectin and leptin levels, as dependent variables (Table 3) and age, gender, weight status, tanner stage and HOMA-IR as independent variables, highlighted the strong associations of leptin and adiponectin levels with body weight and insulin resistance at baseline. The model accounted for 58 % of variability in leptin levels compared with 26 and 15 % of variability in adiponectin and in ghrelin levels respectively. Leptin levels increased significantly by 1.50 ng/ml for each unit of HOMA-IR. These strong relationships were also reported in a study on 321 children (109 normal, 212 obese) aged 6–12 years, analysing leptin, ghrelin, adiponectin levels.[10] In this study, leptin was found as the most sensitive adipokine marker for predicting the accumulation of cardiovascular risk factors and the presence of metabolic syndrome.[10] The gender difference for leptin levels, previously reported in children and adults,[7,21,31–33] was also found in our study with girls exhibiting higher values than boys. This difference might reflect the higher ratio of subcutaneous to visceral fat in women than in men since serum leptin is strongly related to subcutaneous fat mass.[21] But, other factors besides adiposity, such as sex steroids, might play a role in this gender difference.[21]

Leptin administration has been demonstrated to reduce obesity in leptin-deficient ob/ob mice[34] and, to decrease food intake, body weight, increase energy expenditure and improve metabolic status in leptin deficient subjects.[35,36] But, in most individuals, serum leptin levels are positively correlated with BMI and with indexes of obesity. Thus, the concept of leptin resistance has emerged to explain the paradoxical elevated leptin levels in obesity. Several mechanisms have been suggested to explain this leptin resistance, notably the impaired transport of leptin across blood brain barrier,[37] or decrease of hypothalamic leptin receptor expression[38] as well as attenuation of leptin signaling by protein tyrosine phosphatases.[39]

The mechanism by which increased body fat cause increased metabolic comorbidities is not really known. It was suggested that excess adipose tissue contribute to a state of chronic inflammation which promotes development of insulin resistance as well as other metabolic complications.[40] Leptin and adiponectin show opposite effects on inflammation and insulin resistance. While high leptin levels increase the expression of pro-inflammatory and pro-angiogenic factors[41] adiponectin, improves peripheral insulin sensitivity, and induces the production of anti-inflammatory cytokines.[42]

Changes in Anthropometric and Metabolic Parameters After 1 Year Follow-up

In this study population without significant differences between groups in age, sex and Tanner stage distributions, we observed after the 1-year lifestyle intervention, a reducing in BMI z-score in overweight and obese children and improvements in most of the metabolic parameters with greater benefits in the obese group. This group showed significant improvements in fasting insulin levels, HOMA-IR, leptin and adiponectin levels. These results are interesting since increase of insulin levels, HOMA-IR and leptin levels would be expected after one year with increasing age or puberty. In fact, in EarlyBird, a prospective cohort study of healthy children, insulin resistance started to rise in mid-childhood, and HOMA-IR rose, almost linearly, from age of 8.[43] Ballabriga A et al. reported that both prepubertal boys and girls showed a progressive increase of leptin levels during the years prior to the onset of puberty and until Tanner's stage 11.[44]

Serum leptin is believed to play a role in obesity but, although leptin levels were strongly associated with HOMA-IR and weight status at baseline, in the present study, significant decrease in leptin levels were noted only in obese children at one year follow-up. In other studies, after lifestyle intervention or after exercise training program, leptin levels decreased[45] or remained unchanged.[7,13,46] In addition, leptin levels increased in children without weight loss in one of these studies.[13]

At one year of follow-up, adiponectin levels increased significantly in the three groups although normal weight children showed no significant reduction of BMI z-score. Cambuli et al. evaluated adipokines levels but also fat-free mass and fat mass, before and after 1 year of lifestyle intervention in 104 overweight and obese children.[13] In this study, adiponectin in particular increased from baseline at the end of the study. In addition, the authors found that changes in adiponectin were significantly and independently associated with changes in percent fat mass and that, even those children who did not lose weight obtained a significant reduction in percent fat mass.[13] It was previously reported that high adiponectin concentrations predicted lower prevalence of type 2 diabetes in obese Mexican children[47] and that low adiponectin concentrations were associated with increased risk of type 2 diabetes in adults.[48,49] But, high leptin levels were not associated with risk of incident type 2 diabetes in an Aboriginal Canadian population.[48] In our population having a high prevalence of type 2 diabetes, adiponectin could be a tool for monitoring overweight or obese children having marked insulin-resistance.

Implications in Prevention of Overweight in Children

The efficiency of lifestyle intervention for childhood obesity has been previously reported with changes in body weight but also changes in metabolic parameters. Moreover, obesity treatment programs are more effective in reducing overweight in children if parents are involved. The positive effect of eating in school canteen should be highlighted. Our children with normal weight ate more frequently in school canteen than the other groups. In fact, it is a beneficial factor since the menus follow the recommendations designed to lower fat and sugar and increase vegetables and fruit in meals. In addition, the children can take advantage of the infrastructure for physical activity and sport activities proposed by the school.

Limitation and Strengths of the Study

The potential limitations of our study include i) the small sample size even if other lifestyle intervention studies were conducted on small sample sizes[7,12,13] and ii) the absence of controls groups (without lifestyle intervention) that did not let us draw any causality link between the lifestyle intervention and the improvement of the parameters studied.

Nevertheless, the present study has a number of strengths. i) the children were healthy, comparable between groups for age, sex and Tanner stage distributions and presented no associated diseases that could influence the metabolic profile, ii) the use of traditional markers for metabolic disease (ie, lipid profile, insulin levels, HOMA-IR) and the measurement for the first time of adiponectin, leptin and ghrelin concentrations in a sample of Guadeloupean children and iii) the providing of data on changes in metabolic parameters at the end of the lifestyle intervention.

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