Leptin is a mainly adipocyte-secreted protein that was discovered 5 years ago. Most of the research following this discovery focused on the role of leptin in body weight regulation, aiming to illuminate the pathophysiology of human obesity. However, more and more data are emerging that leptin is not only important in the regulation of food intake and energy balance, but that it also has a function as a metabolic and neuroendocrine hormone. It is now clear that it is especially involved in glucose metabolism, as well as in normal sexual maturation and reproduction. Besides this, interactions with the hypothalamic±pituitary±adrenal, thyroid and GH axes and even with haematopoiesis and the immune system have also been described. It has been shown that leptin secretion by the adipocyte is partly regulated by other hormones, such as insulin, cortisol, and sex steroids, mainly testosterone. Also, other hormones like thyroid hormone and GH are possibly involved in leptin synthesis. Leptin itself exerts effects on different endocrine axes, mainly on the hypothalamic±pituitary±gonadal axis and on insulin metabolism, but also on the hypothalamic±pituitary±adrenal, thyroid and GH axes.Leptin may thus be considered a new endocrine mediator, besides its obvious role in body weight regulation.

Overweight among 6-9-year-old children is a serious public health concern and its variation across the European Region highly depends on the country. Comparable monitoring of child growth is possible across Europe and should be emphasized in national policies and implemented as part of action plans.

OBJECTIVE:Leptin is an adipocyte-secreted hormone involved in body weight regulation, acting through the leptin receptor, localised centrally in the hypothalamus as well as peripherally, amongst others on adipose tissue. The aim of this study was to evaluate whether polymorphisms in the leptin receptor (LEPR) gene were related to obesity and body fat distribution phenotypes, such as waist and hip circumferences and the amount of visceral and subcutaneous fat. METHODS: Three known LEPR polymorphisms, Lys109Arg, Gln223Arg and Lys656Asn, were typed on genomic DNA of 280 overweight and obese women (body mass index (BMI) b 25), aged 18 ± 60 y. General linear model (GLM) analyses were performed in 198 pre-and 82 postmenopausal women, adjusting the data for age and menopausal state, plus fat mass for the fat distribution phenotypes. RESULTS: No associations were found between the LEPR polymorphisms and BMI or fat mass. In postmenopausal women, carriers of the Asn656 allele had increased hip circumference (P 0.03), total abdominal fat (P 0.03) and subcutaneous fat (P 0.04) measured by CT scan. Total abdominal fat was also higher in Gln223Gln homozygotes (P 0.04). Also in postmenopausal women, leptin levels were higher in Lys109Lys homozygotes (P 0.02). CONCLUSION: In conclusion, polymorphisms in the leptin receptor gene are associated with levels of abdominal fat in postmenopausal overweight women. Since body fat distribution variables were adjusted for fat mass, these results suggest that DNA sequence variations in the leptin receptor gene play a role in fat topography and may be involved in the predisposition to abdominal obesity.

Since the discovery of leptin, a boom of scienti®c knowledge became available about the OB-protein gene and its role and signi®cance in weight regulation. Both from animal and human research data, serum leptin can probably be considered as one of the best biological markers to re¯ect total body fat, and this ®nding is true over a wide range of body mass indexes (BMIs) and in different pathologies: in normal weight, anorexic and obese subjects; in non insulindependent diabetes mellitus (NIDDM) patients, PCO women, Prader-Willi children and subjects with hypogonadism and growth hormone de®ciency.Gender differences clearly exist, probably related to sex hormone differences, and from fat distribution studies it could be shown that subcutaneous fat is much more related to serum leptin concentrations than visceral fat: also leptin messenger-RNA (m-RNA) expression is signi®cantly higher in subcutaneous fat from human obese subjects.Leptin is not only correlated to a series of endocrine parameters such as insulin, insulin-like growth factor, (IGF) and SHBG, it seems involved as a mediator in some endocrine mechanisms (onset of puberty, insulin secretion, etc) as well.Weight loss will reduce human leptin concentrations, whereas the administration of human recombinant leptin seems to show only limited effects.Keywords: leptin; body fat distribution; endocrinology; hormones IntroductionObesity is becoming a major health problem in western countries, with an annual growing incidence and its association with increased morbidity and mortality. Furthermore, obesity is a very complex problem in its development, being a multifactorial disease, as well as in its treatment. Knowledge of the mechanisms by which obesity develops can help in prevention and better treatment. The discovery of leptin 1 and the subsequent wealth of research on the subject, has already led to more insight into these mechanisms. 2 Evidence from the research until now points out that leptin is likely to be a crucial hormone in the regulation of body weight, in humans as well as in animal models. 2 It is clear that leptin plays an important role in the regulation of body weight, more speci®cally of body fat stores. Almost all studies hitherto found a strong relationship between leptin and weight, expressed as body mass index (BMI) or percent body fat. 2 ± 4 But for a certain BMI, a large variability in leptin levels is found. 2,3,5 Also manifest differences in leptin concentration between men and women have been found by different authors. 6,7 Given the close interrelationships between body weight, body fat distribution and many hormonal functions, in energy balance regulation, leptin may play an important and triggering role as a hormonal determinant of energy balance in addition to the well-known role played by insulin, catecholamines, glucagon 8 and thyroid hormones. 9 As it is a fact that leptin and its receptor are two important components of a homeostatic system regulating body fat, it is likely that the process of leptin's signalling by the hypothalam...

The effect of one week of supplementation with a water-soluble fibre (guar gum) was studied in obese women who had lost weight. In study 1 (N=17; mean±SEM: age 38·5±2·3 yrs; weight 86·8±2·3 kg; BMI 32·2±0·9 kg.m ) energy intake and hunger and satiety scores were assessed under free-living conditions. In study 2 (N=14; age 44·5±1·8 yrs; weight 78·8±3·1 kg; BMI 29·0±0·9 kg.m −2 ) energy intake was fixed at 6 MJ.day −1 (their normal energy intake at that time) or 4 MJ.day −1 (low energy intake). In both studies, the effect of one week of fibre supplementation (40 g in study 1 and 20 g in study 2) was compared with no supplementation. In study 1, mean energy intake decreased significantly from 6·7±0·4 MJ to 5·4±0·2 MJ daily after fibre supplementation, while hunger and satiety scores did not change. At a low energy intake level of 4 MJ given in study 2, hunger scores were significantly decreased after fibre supplementation. No changes were seen in hunger and satiety scores during fibre supplementation at 6 MJ. The reduction in energy intake by soluble fibre under free living conditions and the hunger-reducing effect of fibre at the low energy intake level (4 MJ) suggests that fibre may be useful in the treatment of obesity, by facilitating compliance to low energy intake.

Interactions between leptin and insulin have been shown previously, in vitro and in vivo. In this study, we evaluate the associations of leptin levels with insulin secretion and insulin sensitivity in type 2 diabetes. Fasting leptin levels, HbA 1c, glucose, insulin, C-peptide, intact and des-31,32-proinsulin were measured in 100 non-insulin-treated type 2 diabetic patients. Glucose, insulin and C-peptide were measured 2 hours after an oral glucose load. Insulin resistance and beta-cell function were calculated using HOMA. Leptin levels were found to be associated with all measures of beta-cell secretion: with fasting and 2 hours insulin and C-peptide, with intact and des-31,32-proinsulin concentrations, and with beta-cell secretion estimated with HOMA. This association was independent of age and body fat in women, but in men, associations with insulin and C-peptide weakened after controlling for fat mass, whereas those with intact and des-31,32-proinsulin disappeared. Fasting insulin and C-peptide levels were also significant in multiple regression analyses, besides gender and fat mass. Insulin resistance, as assessed by HOMA, was strongly correlated with leptin, also after correction for age and fat mass in both genders. We conclude that, besides fat mass and gender - the main determinants for leptin levels in type 2 diabetic subjects as in healthy subjects - insulin secretion and the degree of insulin resistance also seem to contribute significantly to leptin levels.

WAUTERS, MACHTELD, ROBERT V. CONSIDINE, MONIQUE CHAGNON, ILSE MERTENS, TUOMO RANKINEN, CLAUDE BOUCHARD, AND LUC F. VAN GAAL. Leptin levels, leptin receptor gene polymorphisms, and energy metabolism in women. Obes Res. 2002;10: 394 -400. Objective: Resting metabolic rate (RMR) is mainly determined by fat-free mass and additionally by age, sex, hormones, and possibly genetic differences. We evaluated whether leptin levels and polymorphisms in the leptin receptor (LEPR) gene were associated with energy expenditure phenotypes. Methods: RMR, body composition, and leptin levels were measured in 125 overweight and obese women. Three LEPR polymorphisms, Lys109Arg, Gln223Arg, and Lys656Asn, were typed on genomic DNA of another group of 192 women in whom RMR was measured. Fat, protein, and carbohydrate oxidation were calculated for 103 of these subjects. In 38 subjects, glucose-induced thermogenesis was measured over 3 hours. Results: In the first study group, a negative correlation between RMR and leptin levels was found after controlling for fat and fat-free mass. In multiple regression analysis, leptin contributed significantly to RMR, independent of body composition. In the second study group, RMR was not associated with LEPR polymorphisms. Differences in substrate oxidation rates were found among genotypes at the Lys656Asn site. In fasting conditions, Lys656Lys showed a trend to oxidize more carbohydrates and less fat than Asn656 carriers, a trend which became significant after the glucose load when carbohydrate oxidation rate in Lys656Lys was 15% higher than in Asn656 carriers (p ϭ 0.04), and fat oxidation rate was 44% lower (p ϭ 0.02). Discussion: These results suggest that DNA sequence variations in the LEPR gene could affect substrate oxidation. We hypothesize that this might be caused by differences in glucose levels, leading to differences in glucose oxidation rates.

Plasminogen activator inhibitor type 1 (PAI-1), an inhibitor of fibrinolysis and an important and independent cardiovascular risk factor, has been shown to be elevated in obesity and type 2 diabetes. Recent study results have suggested that adipose tissue--visceral fat in particular--could play an important role in the fibrinolytic process.In order to assess the specific role of this fat distribution, we measured PAI-1 activity (AU/ml) and visceral fat (CT-scan at level L4-L5) in 2 groups of 30 overweight and obese diabetic and overweight and obese non-diabetic women. Subjects were matched for age, weight, body mass index, fat mass and total abdominal fat. Visceral adipose tissue and PAI-1 were significantly higher in diabetic women (p = 0.022 and p = 0.004 respectively) than in non-diabetic patients. Visceral fat correlated significantly with PAI-1 activity, even after correction for insulin and triglycerides (r = 0.28, p = 0.034). Stepwise regression analysis showed visceral fat as the most important determinant factor for PAI-1 in the whole group and in the non-diabetic group. In the diabetic group, fasting insulin was the most important determinant. These results show that visceral fat is more important than BMI or total body fat in the determination of PAI-1 levels. Furthermore, the increased amount of visceral fat in type 2 diabetics may contribute to the increase of PAI-1 activity levels and the subsequent increased risk for thrombovascular disease, regardless of BMI and total fatness.