Importance of plasma leptin in predicting future weight gain in obese children: a two-and-a-half-year longitudinal study

OBJECTIVE: To determine whether relatively low leptin levels predict changes in adiposity in prepubertal and pubertal obese children. RESEARCH METHODS AND PROCEDURES: In a biracial cohort of 68 obese children (33 male and 35 female; 46 Caucasians and 22 African-Americans, age range 7-18 y), we measured at baseline fasting insulin and leptin levels, height and weight and calculated body mass index (kg/m(2)) and expressed body mass index as (BMI) Z-score. After a 2.5-y follow-up, anthropometric measurements were repeated and changes in weight gain were calculated as changes in BMI Z-score. RESULTS: At baseline obese preadolescent boys and girls had similar age and BMI Z-score, fasting insulin and leptin levels. After an average follow-up of 2.5 y, mean weight change calculated by changes in BMI Z-score from baseline was similar in both groups. In obese adolescent boys and girls at baseline, no significant gender differences were observed for BMI Z-score and insulin levels. In contrast, plasma leptin levels were significantly higher in obese girls compared with obese adolescent boys. At follow-up, there was no significant difference in change in BMI Z-score between obese boys and girls. Multiple linear regression analysis revealed that high basal leptin levels were positively associated with greater changes in BMI Z-score only in girls (r(2)=0.18, P<0.02), after adjusting for basal BMI Z-score, Tanner stage, years of follow-up and basal insulin. High basal leptin levels in girls explained 18% of the weight gain. CONCLUSION: High leptin levels are associated with excessive future weight gain only in girls.     

Glycemic status and soluble tumor necrosis factor receptor levels in relation to plasma leptin concentrations among normal weight and overweight US men

OBJECTIVE: Leptin, an adipocyte-derived protein product of the obesity (ob) gene, is a multifunctional polypeptide associated with the development of obesity-related disorders in humans. There is considerable inter-individual variation in plasma leptin even among subjects with comparable obesity levels, which suggests that factors other than adipose mass may be involved in the regulation of leptin expression and/or production. The purpose of this study was to evaluate the potential role of glycemic status and adipose-derived cytokines in regulating plasma leptin levels among normal and overweight men. DESIGN: Cross-sectional study. SUBJECTS AND MEASUREMENTS: We measured plasma leptin, insulin, c-peptide and plasma soluble tumor necrosis factor receptor (sTNF-R) concentrations in 178 men. The subjects were selected from the Health Professionals Follow-up Study (HPFS), and aged 47-64 y in 1994, were free of cardiovascular disease, diabetes mellitus, malignant neoplasms, and had provided a fasting blood sample and a detailed lifestyle questionnaire. RESULTS: Men in the highest quintile of plasma leptin (mean = 12.7 ng/ml) weighed more, were less physically active and had higher circulating insulin, c-peptide, sTNF-R1 and sTNF-R2 concentrations than men in the lowest quintile (mean = 2.8 ng/ml). We found a significant correlation between plasma insulin, c-peptide, glycosylated hemoglobin (HbA1c), and sTNF-R1 on leptin concentrations (with Spearman correlation coefficients ranging from 0.17 to 0.48 and all P < 0.05). Only HbA1c and sTNF-R1 were independently and positively associated with plasma leptin after further adjusting for body mass index and other metabolic parameters of interest. Interestingly, these observed associations were limited to men with a BMI > or = 25 kg/m2. CONCLUSION: Our results suggest that glucose homeostasis and the activity of the TNF system may modulate leptin secretion and production among overweight men. Glucose homeostasis and TNF-alpha is important in metabolic disorders related to hyperleptinemia.     

Dietary and lifestyle factors in relation to plasma leptin concentrations among normal weight and overweight men

OBJECTIVE: Leptin, the product of the obesity (ob) gene, is a multi-functional polypeptide that is important in energy metabolism, which is strongly correlated with body fat mass and body mass index (BMI). In a recent prospective study, we found that leptin was positively associated with 4 y weight gain among overweight and obese men. This suggests that leptin resistance, marked by hyperleptinemia among obese subjects, may be an important marker for weight gain. The purpose of this study is to evaluate whether modifiable dietary and lifestyle factors are associated with plasma leptin concentrations among US men. METHODS: We included 268 men aged 47--83 y (who were free of cardiovascular disease, diabetes mellitus and cancer, except nonmelanoma skin cancer) from the ongoing Health Professionals Follow-up Study. These subjects completed a detailed dietary and lifestyle questionnaire (including cigarette smoking, alcohol drinking and physical activity) and provided a fasting venous blood sample in 1994. All blood samples were stored in a deep freeze (-70 degrees C) for 4--5 y before being analyzed. Plasma leptin concentrations were measured by radioimmunoassay. RESULTS: Men in the highest quintile of plasma leptin (mean=14.4 ng/ml) weighed more, were less physically active, and had higher total and saturated fat and cholesterol intake than men in the lowest quintile (mean=3.0 ng/ml). Physical activity and current smoking were inversely associated with plasma leptin concentrations (P<0.001). A 20 MET difference in physical activity per week (equivalent to approximately 3 h of jogging) was associated with 0.38--0.58 ng/ml lower plasma leptin concentrations for normal weight and overweight men after adjusting for total energy and fat intake, BMI and other confounding variables. Total fat and monounsaturated fat intakes were positively associated with plasma leptin concentrations even after adjusting for BMI and other confounding variables; however, this association was limited to men of normal weight (BMI<25 kg/m(2)). CONCLUSION: These data suggest that physical activity may be a significant determinant of plasma leptin concentrations in men. Increasing physical activity is associated with lower plasma leptin concentrations even after adjusting for BMI. Physical activity may lower leptin concentrations not only due to decreased body fat mass, but potentially through an increase in leptin sensitivity. International Journal of Obesity (2001) 25, 106-114     

Associations of leptin, insulin resistance and thyroid function with long-term weight loss in dieting obese men

OBJECTIVE: The aim of the present study was to identify predictors of weight loss in obese men participating in a 2-year behaviour modification programme. DESIGN: Longitudinal, clinical intervention study of a behaviour modifying weight loss program. SETTING: University Hospital, Stockholm, Sweden. SUBJECTS: Forty-four obese men (age, 42.7 +/- 1.1 years: BMI, 37.1 +/- 0.6 kg m(-2), mean +/- SEM) followed for 2 years. INTERVENTIONS: Behaviour modification weight loss programme. MAIN OUTCOME MEASURES: Associations between plasma leptin and thyroid function tests, insulin resistance by homeostatic model assessment (HOMA), dietary recall and anthropometrically determined body composition. RESULTS: At baseline, there were significant correlations between plasma leptin and body mass index (BMI), fat-free mass (FFM) and insulin resistance. Median weight loss over 2 years was 4.9 kg (range, -27.2 to +11.9). Baseline serum leptin concentrations adjusted for BMI (leptin/BMI ratio) were significantly correlated with 2-year weight change (r = 0.34, P = 0.04). A subset of seven of the 44 men gained weight over the 2 years. These 'gainers' differed significantly in initial leptin/BMI ratio (0.62 +/- 0.07) compared with the 37 'losers' (0.42 +/- 0.03, P < 0.05). In a multiple regression model, baseline leptin, insulin and age predicted 22% of the variance in weight change with no additional significant contribution from BMI, FFM, waist:hip ratio, thyroid function tests or energy intake. There was a strong correlation between the change in leptin concentrations and the change in insulin resistance from baseline to 2-year follow-up (r = 0.54; P < 0.001). CONCLUSION: Baseline plasma leptin concentrations predicted long-term weight loss. Inappropriate leptin secretion or disposal, corrected for BMI, was associated with failure to maintain weight loss in obese men in a behaviour modification weight loss programme.     

Effect of small doses of dexamethasone on plasma leptin levels in normal and obese subjects: a dose-response study

To further elucidate the role of glucocorticoids in the regulation of leptin secretion, we studied the effects of overnight small doses of dexamethasone on plasma leptin levels in normal weight controls and in obese patients and correlated the results with indexes of insulin sensitivity and body fat distribution. In 114 subjects (81 obese patients, 49 women and 32 men, BMI 37.4 +/- 0.77 kg/m2 and 33 normal-weight subjects, 17 women and 16 men, BMI 22.1 +/- 0.41 kg/m2) plasma F and leptin levels were measured at 08:00 h basally and after the administration of different doses of dexamethasone (a fixed dose of 1-mg and 0.0035, 0.007, 0.015-mg/kg bw, given po at 23:00 h the night before). Tests were performed one week apart with bw remaining stable over the study period. Basal leptin levels were significantly higher in obese than in normal subjects (31.9 +/- 2.41 vs 7.7 +/- 0.93 ng/ml, p<0.0001). In obese patients, leptin levels increased significantly by 1-mg (from 31.9 +/- 2.41 to 35.0 +/- 2.59 ng/ml, p<0.005) and the 0.015-mg/kg bw dose (from 31.5 +/- 2.34 to 33.7 +/- 2.44 ng/ml, p<0.05), while they were unaffected by each dose of dexamethasone in normal subjects. However, after splitting subjects by gender, mean leptin levels rose from 39.3 +/- 2.97 to 43.3 +/- 3.12 ng/ml after the 1-mg dose, p<0.005, from 39.1 +/- 2.87 to 43.6 +/- 2.91 ng/ml after the 0.015-mg/kg bw dose, p<0.005, from 39.3 +/- 2.90 to 42.2 +/- 2.90 ng/ml after the 0.007-mg/kg bw dose, p<0.05 and from 38.8 +/- 2.66 to 41.1 +/- 2.87 ng/ml after the 0.0035-mg/kg bw dose, p=0.055, only in obese women. Conversely, no leptin changes were seen in the other groups and no differences were observed in the leptin response between groups. After the 1-mg dose, in the whole group, the absolute leptin variation was weakly but significantly related to BMI values (r=0.231, p<0.02) while in all sessions the percent leptin changes over baseline were not significantly correlated with age, BMI, waist, WHR, insulin, HOMA index, a marker of insulin sensitivity, plasma dexamethasone concentrations and to the percent cortisol variation following dexamethasone. In conclusion, in obese women but not in obese men and in normal weight subjects, small overnight increases in plasma glucocorticoid concentrations induced gender-related plasma leptin elevations that were unrelated to body fat distribution and insulin sensitivity. A greater sensitivity of female adipose tissue to glucocorticoids probably underlies this sexually dimorphic pattern of leptin response. These findings provide an additional piece of information on the regulation of leptin secretion exerted by glucocorticoids.     

Effect of fish diets and weight loss on serum leptin concentration in overweight, treated-hypertensive subjects

BACKGROUND: Leptin, a circulating hormone secreted from adipocytes, is an index of adiposity and is reduced by caloric restriction and weight loss. A recent population study suggested that dietary-derived omega3 fatty acids lower leptin levels independent of body fat. OBJECTIVE: To examine whether dietary fish enhanced the effects of weight loss on serum leptin levels, in 69 overweight, treated hypertensive men and women. METHODS: Participants were randomized to a daily fish meal, a weight-reduction regimen, the two regimens combined or a control group for 16 weeks. RESULTS: A total of 63 individuals completed the study. Weight fell 5.6 +/- 0.8 kg with energy-restriction. Blood pressure (BP) reductions in the combined fish-weight loss group were twice that seen with either intervention alone. At baseline, in all groups combined, serum leptin levels correlated with serum insulin (r = 0.307, P = 0.014), but not with body weight. The greatest change in serum leptin occurred in the fish-weight loss group (control, 0.60 +/- 0.76 ng/ml; fish, 1.20 +/- 0.79 ng/ml; weight loss, -1.40 +/- 1.05 ng/ml; fish-weight loss, -5.08 +/- 1.64 ng/ml). In the fish-weight loss group, the change in serum leptin was predicted by changes in serum insulin (r = 0.488, P = 0.038), 24-h BP (systolic BP (SBP): r = 0.435, P = 0.060; diastolic BP (DBP): r = 0.563, P = 0.018) and 24-h heart rate (0.584, P = 0.028). Using general linear models, there was a significant fish x weight-loss interaction (P = 0.008) on post-intervention serum leptin after adjustment for baseline levels, independent of post-intervention insulin. CONCLUSION: A daily fish meal as part of a weight-reducing regimen was more effective than either measure alone at reducing leptin levels. Reductions in leptin may be related to the substantial fall in BP seen with the fish-weight loss program.     

Leptin and insulin responses to a four-day energy-deficient diet in men with different weight history

OBJECTIVE: To assess the leptin responses to a 4-day energy-restricted diet in men with different weight history; high retrospective weight gain was expected to be associated with a small decline in leptin. DESIGN: Changes in fasting leptin and insulin were measured during a 4-day controlled intervention, in which men with high retrospective weight gain and men who had stable weight consumed 35% of their estimated energy needs. SUBJECTS: A total of 44 healthy men (age: 31-52 y, BMI: 22.7-39.8 kg/m(2)) were recruited from a cohort study: 22 men who had gained weight (weight change >1 kg/y) and 22 men whose weight had remained stable (weight change +/-0.3 kg/y) between the first (1987-1991) and the second measurement (1993-1997) of the cohort study. The intervention study was carried out in 2001. RESULTS: After intervention, changes in fasting leptin levels were similar for both groups of retrospective weight gain: -2.2 microlU/ml (95% CI: -2.8; -1.7) and -2.4 microlU/ml (95% CI: -3.2; -1.7) respectively (P=0.69). Proportional changes in fasting leptin levels were different: -43.3% (95% CI: -47.8; -38.4) in the participants whose weight had remained stable (n=22) and -35.2% (95% CI: -42.4; -27.1) in those who had gained weight (n=22)(P<0.05). Analyses in a subgroup of men (n=18), in which the contrast in weight history was more pronounced than in the total group, did not show this difference. A higher proportional decrease in insulin levels was seen in men whose weight remained stable than in those who had gained weight: -35.4% (95% CI: -46.9; -21.3) and -12.8% (95% CI: -28.1; 5.7), respectively. The proportional decrease in leptin was positively associated with the proportional decrease in insulin (r=0.52; P<0.05). The decrease in leptin was positively associated with preintervention body weight (r=0.36; P<0.05), BMI (r=0.44; P<0.05), and waist-circumference (r=0.46; P<0.05). CONCLUSION: Although we found that the 4-day energy restriction had a smaller effect on the decrease in leptin in men with retrospective weight gain, our study does not show convincing evidence that men who gained weight are less leptin responsive to changes in energy balance than those who were weight stable.     

Relationships between physical activity and plasma leptin levels in healthy children: the Fleurbaix-Laventie Ville Santé II Study

OBJECTIVE: To study the relationships between physical activity and plasma leptin levels in children from a population-based study, taking into account puberty stages. DESIGN: Subjects were part of the Fleurbaix-Laventie Ville Santé (FLVS) II Study, a longitudinal study on the determinants of weight gain in children and their parents. At baseline examination, 253 girls and 257 boys aged 8-18 y were examined. MEASUREMENTS:: Height and weight were measured, adiposity was assessed by the sum of four skinfold thicknesses (SSK). Pubertal stage was assigned according to Tanner. Leisure-time physical activity (LTPA) was assessed by the Modifiable Activity Questionnaire and ambulatory activity by pedometer recording over a week. A fasting blood sample was obtained to determine plasma leptin and insulin levels. RESULTS: Plasma leptin was higher in girls compared to boys (8.3 (1.6-36.5) ng/ml vs 2.2 (0.1-15.3) ng/ml, P<0.001). Multivariate analyses were performed with leptin as dependent variable, and number of steps by day, Tanner stage, insulin and SSK as independent variables. In girls, leptin was negatively correlated to number of steps/day (P<0.001) and positively to SSK (P<0.001) and insulinemia (P<0.001). In boys, leptin was correlated to insulinemia (P<0.001), SSK (P<0.001), Tanner stage (P<.0001), but not to physical activity. CONCLUSION: Physical activity is negatively related to leptin levels in girls only and this association is independent of fasting plasma insulin. In children, fasting insulinemia remains associated with leptin levels after taking into account adiposity, physical activity and Tanner stage.     

Effect of orlistat on plasma leptin levels and risk factors for the metabolic syndrome

Background: The aim of this research was to assess the impact of treatment with Orlistat 120 mg three times daily on serum leptin levels, weight loss, glycemic control, and cardiovascular risk factors involved in the metabolic syndrome. Methods: A 3-month open-labeled prospective study was conducted on 40 patients with the clinical features of the metabolic syndrome divided into two groups-with and without type 2 diabetes mellitus. Twenty type 2 diabetic obese patients (group A) were studied, with BMI of 35.4 +/- 0.9 kg/m(2), as were 20 obese patients without diabetes (group B), with BMI of 36.2 +/- 0.7 kg/m(2). Weight, serum leptin levels, insulin resistance, and cardiovascular risk factors were measured at baseline and at the end of each month. Results: Patients reduced weight at 8.5 +/- 2.3 kg for men and 5.7 +/- 2.6 kg for women in group A against 7.9 +/- 1.9 kg for men and 5.6 +/- 2.0 kg for women in group B. Plasma leptin levels decreased at 4.5 +/- 1.9 ng/mL for men and 1.9 +/- 0.9 ng/mL for women in group A against 3.8 +/- 2.0 ng/mL for men and 2.8 +/- 1.4 ng/mL for women in group B. The level of insulin resistance measured with HOMA-IR decreased from 4.54 +/- 2.35 to 2.69 +/- 0.86 in group A against 3.98 +/- 1.89 to 2.87 +/- 0.93 in group B. In the lipid parameters, the highest decrease was found in triglycerides levels: 6.1 +/- 2.3 mmol/L for men and 3.5 +/- 2.6 mmol/L for women in group A against 2.1 +/- 1.9 mmol/L for men and 1.8 +/- 0.7 mmol/L for women in group B (all p < 0.05). Conclusions: Orlistat beneficially enhances weight loss, contributing to a decrease of serum leptin, insulin resistance level, and cardiovascular risk factors in both groups. An additional beneficial pleotropic effect of Orlistat could be proposed through a reduction of plasma leptin and lipid levels.     

Prospective cohort study of the relationship of markers of insulin resistance and secretion with weight gain and changes in regional adiposity

OBJECTIVE: To examine whether fasting insulin concentrations and markers of first-phase insulin secretion are associated with weight gain and changes in distribution of adiposity over 4.4y. DESIGN: Longitudinal prospective population-based cohort study of middle-aged Caucasians. SUBJECTS: 767 subjects (40-65y at baseline) were followed up for a mean of 4.4y. MEASUREMENTS: 75 g oral glucose tolerance test performed at baseline and follow-up. Insulin was measured at fasting, and 30 and 120 min post-glucose load using a highly specific assay. RESULTS: Fasting insulin levels were correlated with baseline weight (r = 0.32, P<0.001), as was the 30 min insulin incremental response (r = 0.17, P<0.001). Mean weight gain over the 4.4y of follow-up was 2.17 kg (range: -6.17-10.5 kg) for men and 2.49 kg (range: -7.41-12.39 kg) for women. In women, the 30 min insulin incremental response was negatively associated with percentage weight gain (P<0.001), but there was no relationship between fasting insulin levels and weight gain. The baseline fasting insulin was positively correlated with percentage increase in waist- hip ratio (r = 0.12, P = 0.01). In stratified analysis, this relationship was confined to women over the age of 50 y. However, in men, none of these relationships were demonstrable. CONCLUSION: In middle-aged women reduced first-phase insulin secretion was associated with an increased risk of future weight gain, whereas fasting hyperinsulinaemia was associated with an increase in waist-hip ratio over time.     

Obesity is associated with decreasing levels of the circulating soluble leptin receptor in humans

OBJECTIVE: Leptin plays a major role in the regulation of body weight. It circulates in both free and bound form. One of the leptin receptor isoforms exists in a circulating soluble form that can bind leptin. In the present study, we measured the soluble leptin receptor (SLR) levels in lean and obese humans. We investigated the relationship between plasma SLR levels, plasma leptin levels and the degree of obesity. We also examined whether SLR concentrations could be modulated by fat mass loss induced by a 3 month weight-reducing diet. SUBJECTS: A total of 112 obese (age 18-50 y; body mass index (BMI) 30-44 kg/m2; 23 men and 89 women), 38 overweight (age 19-48 y; BMI 25-29 kg/m2; 10 men and 28 women) and 63 lean (age 18-50 y; BMI 17-24 kg/m2; 16 men and 47 women) humans. MEASUREMENTS: A direct double monoclonal sandwich enzyme-linked immunosorbent assay (ELISA) was used for the quantitative measurement of the soluble human leptin receptor. Leptin was measured by radioimmunoassay (RIA). Body composition was assessed by biphotonic absorptiometry DEXA (dual energy X-ray absorptiometry). RESULTS: We observed that the SLR is present in human plasma (range 10-100 ng/ml). SLR levels were lower in obese and overweight than lean subjects (28.7+/-8.8, 40.2+/-14.9, 51.2+/-12.5 ng/ml, respectively) and were inversely correlated to leptin and percentage of body fat (r=-0.74 and r=-0.76; respectively; P<0.0001). The ratio of circulating leptin to SLR was strongly related to the percentage of body fat (r=0.91; P<0.0001). Interestingly a gender difference was observed in SLR levels, which were higher in obese and overweight men than in obese and overweight women. In obese subjects after a 3 month low-calorie diet, SLR levels increased in proportion to the decrease in fat mass. In the gel filtration profile, SLR coeluted exactly with the bound leptin fractions. CONCLUSION: Obesity, in humans is associated with decreasing levels of the circulating soluble leptin receptor (SLR). The relationship of SLR with the degree of adiposity suggests that high SLR levels may enhance leptin action in lean subjects more than in obese subjects.     

Plasma leptin levels are associated with abnormal fibrinolysis in men and postmenopausal women

BACKGROUND: Leptin is a crucial mediator of satiety signals and energy balance, and its circulating levels are increased in obesity. It has recently been shown that plasma leptin levels in humans correlate with circulating insulin and to insulin secretion. This indicates that leptin may be an important link in metabolic consequences of the insulin resistance syndrome. Whether this includes abnormalities in fibrinolysis has not been studied. METHODS AND RESULTS: Healthy subjects (n = 165; 85 men and 80 women) from the Northern Sweden MONICA population were investigated. Anthropometric measurements, oral glucose tolerance tests and sampling for plasma leptin, lipids, fibrinogen and fibrinolytic variables were made. Leptin levels were 342% higher in women than in men and were in both sexes strongly correlated to body mass index (BMI). After adjustments for age and BMI, leptin levels correlated significantly to pre/post glucoseload insulin levels in both sexes. After further adjustment for baseline insulin levels, leptin levels were in males significantly associated with increased waist circumference (P<0.001), low HDL cholesterol (P<0.05), low tPA activity (P<0.01) and high PAI-1 activity (P<0.001). In postmenopausal females, a significant association between leptin and low tPA activity/high PAI-1 activity was seen after adjustment for age and BMI (P<0.05). Conclusions. Circulating levels of leptin are associated with components of the insulin resistance syndrome, including defective fibrinolysis, in men and postmenopausal women. This suggests that leptin may be involved in the mediation of consequences of insulin resistance.     

Obesity, leptin and blood pressure among children in Taiwan: the Taipei Children's Heart Study

BACKGROUND: Obesity is associated with the occurrence of hypertension; however, the mechanisms of obesity-induced high blood pressure (BP) remain unclear. Leptin, the obese (ob) gene product, is associated with the occurrence of obesity and related disorders in humans. The purpose of this study was to evaluate the association between plasma leptin and BP among children. METHODS: After multistage sampling, we randomly selected 1265 children (618 boys and 647 girls) with a mean age of 13.3 years (12 to 16 years old) in this cross-sectional survey. Obesity measurements included body mass index (BMI) and waist-to-hip circumference ratio (WHR). Plasma leptin levels were measured by radioimmunoassay. RESULTS: The mean and median plasma leptin levels were 4.1 and 2.4 ng/mL among boys and 10.1 and 8.8 ng/mL among girls. Children in the highest quintile of leptin level (mean, 11.1 and 19.7 ng/mL for boys and girls, respectively) had higher body weight, BMI, WHR, BP, and insulin levels than children in the lowest quintile (mean, 1.1 and 3.9 ng/mL for boys and girls, respectively). Boys had a higher BMI, WHR, and BP levels, yet had lower leptin levels than girls. In both genders, BMI and plasma leptin levels were significantly positively correlated with BP. In multivariate regression analyses, plasma leptin levels were positively associated with BP; however, this association became insignificant among girls and even inversely associated with systolic BP among boys after adjusting for BMI. CONCLUSIONS: Obesity is positively associated with BP among school children in Taiwan; however, the role of plasma leptin on the development of obesity-related hypertension is still controversial among school children.     

Reproducibility of fasting plasma leptin concentration in lean and obese humans

We determined the reproducibility of plasma leptin levels in 20 healthy subjects (10 men, 10 women; 10 lean, 10 obese) at stable body weight. Blood samples were obtained, after an overnight fast, between 0700 and 0800 on days 1, 2, 3, 4, 5, 12, 19, and 26. Body weights were recorded on the same days. Plasma leptin was measured using a specific radioimmunoassay. The mean +/- SE baseline body weights (kg) were 65.8 +/- 3.6 (lean) and 96.4 +/- 7.1 (obese). The body mass indices (BMI) were 22.9 +/- 2.8 kg/m2 (lean) and 32.7 +/- 2.2 kg/m2 (obese). The mean daily fasting plasma glucose level was 98.7 +/- 3.7 mg/dl. Baseline plasma leptin levels (ng/ml) were 5.3 +/- 0.75 in lean men, 14.9 +/- 4.6 in obese men, 11.2 +/- 2.8 in lean women, and 27.1 +/- 8.4 in obese women. Fasting leptin levels on days 2 to 26 were highly correlated with the baseline levels on day 1 (r2 = 0.9, P<0.0001). Body weights remained within 98%-102% of baseline, whereas intra-individual leptin levels fluctuated between 80% and 120% of baseline values, throughout the 26 days of study. We conclude that fasting plasma leptin levels are reproducible, with a maximum day-to-day variation of approximately 20%, in healthy, free-living, lean and obese persons who maintain a stable body weight.     

Hormonal regulation of human leptin in vivo: effects of hydrocortisone and insulin

OBJECTIVE: To investigate the effects of continuous i.v. infusion of hydrocortisone or insulin on leptin secretion in humans. SUBJECTS: Six, nonfasting healthy adults (four women, two men), aged (mean +/- s.e.m.) 36.6 +/- 1.7 y; body mass index (BMI) 27.6 +/- 0.9 kg/m2. DESIGN: Randomized, placebo-controlled, cross-over study, with a 2-week 'wash-out' period. INTERVENTIONS: Intravenous infusion of hydrocortisone (3.3 microg/(kg min)), insulin (1 mU/(kg min)) or normal saline (placebo) for 24 h. MEASUREMENTS: Blood sampling every 1-2 h for measurement of glucose, insulin, cortisol and leptin; subcutaneous abdominal fat biopsy for determination of leptin mRNA expression. RESULTS: Plasma cortisol increased to 50.0 +/- 0.4 microg/dl during hydrocortisone infusion, but was unaltered during saline or insulin infusion. The plasma insulin levels were: 28.5 +/- 4.7 microU/ml (placebo), 40.8 +/- 9.2 microU/ml (hydrocortisone, P=0.214), and 243 +/- 23.0 microU/ml (insulin, P=0.0002). Peak hyperleptinemia occurred after 16h of insulin and 20h of hydrocortisone infusion; peak/baseline plasma leptin levels (ng/ml) were 18.2 +/- 4.2/15.1 +/- 3.3 (placebo, P=0.056), 42.1 +/- 7.0/16.0 +/- 3.8 (hydrocortisone, + 163%, P= 0.008) and 30.2 +/- 4.3/16.6 +/- 2.7 (insulin, +83%, P= 0.024). Adipocyte leptin mRNA increased by 350% after the hydrocortisone infusion. CONCLUSION: Hydrocortisone, a natural glucocorticoid, induces hyperleptinemia in vivo, with a potency greater than that of insulin. The interaction between glucocorticoids and leptin may be of metabolic significance in humans.     

Effects of weight gain on medical care costs

OBJECTIVE: To examine in middle-aged adults the effect of medical care costs of large, rapid weight gain compared to weight maintenance. DESIGN:: Retrospective cohort study for a 3-y time period. SETTING AND PARTICIPANTS: Population-based sample (N=15174) of men and women members of a large managed care organization, aged 35-65 y, with a body mass index (BMI) >25 kg/m(2) at baseline. Health-care utilization and costs were measured at baseline and over the 3-y follow-up period. RESULTS: Mean age at baseline was 49.7 y and mean BMI was 31.5 kg/m(2). During the 3-y follow-up period, 40.8% were classified as weight maintainers (+/-4 pounds), 45.3% gained 5-19 pounds, and 13.9% gained >/=20 pounds. A weight gain of >/=20 pounds was significantly associated with increased total medical care costs in all subgroups evaluated. Among all subjects, for those who gained >/=20 pounds compared to those who maintained weight, the adjusted 3-y increase in costs was 561 dollars. Among the subgroup with baseline comorbidities, the adjusted 3-y change in total medical care costs was 711 dollars. Multivariate analyses showed no significant differences between those who gained 5-19 pounds and those who maintained weight. Baseline BMI and comorbidities were also significant predictors of change in medical care costs, independent of weight gain. CONCLUSION: A large 3-y weight gain (>/=20 lb) in middle-aged overweight and obese adults is associated with a correspondingly larger increase in total medical care costs compared to weight maintainers. The prevention of large weight gains holds promise for significantly reducing future medical care costs. Future studies should examine the causes of rapid weight gain and evaluate approaches to prevent and reverse such weight gain.     

Size at birth and plasma leptin concentrations in adult life

OBJECTIVE: To determine whether low birthweight is associated with higher plasma leptin concentrations in adult life and whether leptin contributes to the metabolic alterations in adults that are associated with reduced foetal growth. DESIGN: Measurement of plasma leptin concentrations in a group of 502 men and women, aged 61-73, who were born in Hertfordshire and for whom records of birth and infant weight are available. Glucose tolerance was measured with a standard 75 g oral glucose tolerance test. MEASUREMENTS: Leptin concentrations were assayed in fasting plasma samples using a radioimmunoassay. RESULTS: Leptin concentrations ranged from 1.4 to 128.9 (mean 13.4) ng/ml and were higher in the 193 women than the 309 men (23.4 vs. 7.1 ng/ml). In both sexes leptin concentrations correlated positively with body mass index (r=0.65 in both men and women). Leptin concentration also correlated with fasting insulin (r=0.41) and with glucose and insulin concentrations 2 h after a glucose load (r=0.19 and 0.49). Adults with lower birth or infant weight had higher leptin concentrations than those of higher birthweight with similar degrees of obesity (P=0.02 and 0.06, respectively). Although both 2 h glucose and insulin concentrations negatively correlated with birthweight (r=-0.17, P<0.001 and r=-0.18, P<0.001, respectively), regression analysis suggested that the higher levels of leptin in adults who had low birthweight did not explain the association between low birthweight and glucose or insulin concentrations. CONCLUSION: These results suggest that adults who had had low birthweight had higher plasma concentrations of leptin than would be expected from their degree of obesity. The higher leptin concentrations, however, do not account for the association between birthsize and glucose tolerance. They may be a consequence of the altered body composition, hyperinsulinaemia, and other long-term endocrine changes associated with reduced foetal growth.     

High plasma leptin concentrations in hypertensive men but not in hypertensive women.

OBJECTIVE: Previous studies on humans have reported higher leptin levels in women than in men, independent of body fat, and leptin has been correlated with insulin resistance in men but not in women. Since insulin resistance is thought to play a role in raising blood pressure, we investigated sex differences in leptin concentrations between hypertensive and normotensive individuals. METHODS: Ninety-two nondiabetic hypertensive patients (48 men and 44 women) and 92 age, body mass index (BMI)-matched normotensive control individuals were studied. Fasting plasma glucose, insulin, leptin and lipoprotein concentrations, glucose and insulin responses to 75 g oral glucose tolerance test (OGTT) and insulin suppression tests were determined. RESULTS: Fasting plasma leptin concentrations were higher in hypertensive men than in normotensive men (5.1 +/- 0.5 versus 3.9 +/- 0.4 ng/ml, P = 0.015). However, fasting plasma leptin concentrations were not significantly different between hypertensive and normotensive women (11.8 +/- 1.0 versus 10.9 +/- 1.0 ng/ml, P = 0.440). Fasting plasma leptin concentrations showed good correlation with BMI, body fat, fasting plasma insulin concentrations, and insulin area to OGTT in both men and women (all P < 0.001). However, fasting plasma leptin concentrations were related to steady-state plasma glucose (SSPG) concentrations, a measure of insulin sensitivity by insulin suppression test, in men only (P < 0.001). After adjustment for body fat amount, age and duration of hypertension, fasting plasma leptin levels still correlated significantly with SSPG concentrations in men. These four variables together accounted for a 67.9% variation in fasting plasma leptin levels in men. In women, body fat amount was the only significant determinant for plasma leptin levels. These four variables accounted for a 78.2% variation in plasma leptin levels in women. CONCLUSIONS: Our study confirmed a sex difference in leptin levels both in hypertensive and normotensive subjects. Higher plasma leptin concentrations in hypertensive men but not in hypertensive women when compared with normotensive control individuals was also demonstrated. These observations are consistent with the findings that plasma leptin is correlated with insulin sensitivity in men but not in women. Further studies are needed to understand the causes and consequences of sex effects on leptin in blood pressure regulation.     

Partial reversal of cachexia by beta-adrenergic receptor blocker therapy in patients with chronic heart failure

BACKGROUND: Cachexia is a common problem in chronic heart failure (CHF) that may be partly mediated by activation of the sympathetic nervous system. The effects of beta-adrenergic receptor blocker (BB) therapy on body weight in cachectic and noncachectic subjects with CHF has not been previously reported. METHODS AND RESULTS: Body weight and plasma norepinephrine, leptin, and insulin levels were measured in 27 subjects with CHF before and after 6 months of beta-adrenergic receptor blockade with carvedilol or long-acting metoprolol. Before BB therapy, baseline weight, plasma leptin, and plasma insulin levels did not differ between cachectic and noncachectic subjects. Baseline plasma norepinephrine levels were increased in cachectic subjects when compared with noncachectic subjects (930+/-248 pg/mL versus 503+/-109 pg/mL, P=.063). After 6 months of BB therapy, subjects with baseline cachexia demonstrated significantly greater weight gain (+5.2+/-9.6 versus +0.8+/-5.0 kg, P=.027), greater increase in plasma leptin levels (+3.7+/-3.9 versus +1.2+/-4.3 ng/mL, P=.030), and greater decrease in plasma norepinephrine levels (-374+/-261 versus -41+/-122 pg/mL, P=.012) when compared with noncachectic subjects. CONCLUSIONS: Six months of BB therapy with carvedilol or long-acting metoprolol is associated with differential effects on body weight and hormonal levels in cachectic and noncachectic subjects with CHF. Further work is needed to determine the role the sympathetic nervous system in the pathogenesis of cachexia in patients with CHF.     

Work stress, weight gain and weight loss: evidence for bidirectional effects of job strain on body mass index in the Whitehall II study

OBJECTIVE: Previous research has focused on overall associations between work stress and body mass index (BMI) ignoring the possibility that stress may cause some people to eat less and lose weight and others to eat more. Using longitudinal data, we studied whether work stress induced weight loss in lean individuals and weight gain in overweight individuals. DESIGN: Prospective cohort study. SUBJECTS: A total of 7965 British civil servants (5547 men and 2418 women) aged 35-55 at study entry (The Whitehall II study). MEASUREMENTS: Work stress, indicated by the job strain model and measured as job control, job demands and job strain, was assessed at baseline and BMI at baseline and at 5-year follow-up. RESULTS: In men, the effect of job strain on weight gain and weight loss was dependent on baseline BMI (P27 kg/m(2)), these stress indicators were associated with subsequent weight gain. No corresponding interaction was seen among women. CONCLUSION: Inconsistent findings reported by previous studies of stress and BMI have generally been interpreted to indicate the absence of an association. In light of our results, the possibility of differential effects of work stress should also be taken into account.