Fasting Serum Leptin Concentrations Research Articles

Mutational analysis of the proopiomelanocortin gene in Caucasians with early onset obesity.

Mutations in the human gene encoding the polyhormone peptide proopiomelanocortin (POMC) are associated with obesity in rare cases and the gene co-localizes with a reported quantitative trait loci (QTL) for variations in circulating leptin levels and fat mass on human chromosome 2p21. In this study we have used polymerase chain reaction (PCR) and single strand conformation polymorphism (SSCP) analysis, to test whether variations in the human POMC gene are associated with human obesity. Primary mutational analysis was performed on the coding region of the POMC gene and 500 bp of the putative promoter region, by single strand conformational analysis and sequencing, in 56 subjects with juvenile onset obesity (body mass index (BMI) > or = 31 kg/m2 at the draft board examination). The prevalence of two polymorphisms were further studied in 156 obese and 205 control subjects, and in a population based cohort of 380 extensively characterized young healthy subjects. We have identified a total of six gene variants, five were silent nucleotide substitutions (No51(promoter) g-->c, No670(5'UTR)g-->a, No4512(codon6)c-->t Cys/Cys, No7726(codon116)c-->t Leu/Leu) of which one was prevalent (No8246(3'UTR)c-->t) and one variant changed an amino acid (No8086(codon236)g-->c Arg/Gln). The amino acid substitution was only seen in one subject. Comparing the prevalence of the frequent No8246 silent polymorphism, in an association study comprising 156 subjects with juvenile onset obesity and 205 randomly sampled control subjects (mean BMI 23.5+/-4.7 kg/m2), did not show any relationship to obesity. Also, comparing the prevalence of a known 9bp insertion/deletion variant in the coding region of the gene between obese and lean, showed no association to obesity. Furthermore, analyzing a population based cohort of 380 young healthy Caucasians for the prevalent 3'UTR polymorphism as well as the 9 bp insertion/deletion variant did not show any association to deviations in body fat contents or fasting serum leptin concentrations. In conclusion, it is unlikely that variations in the coding region and the putative promoter of the POMC gene are a major cause of juvenile onset human obesity.

Analysis of the relationship between fasting serum leptin levels and estimates of beta-cell function and insulin sensitivity in a population sample of 380 healthy young Caucasians.

Circulating leptin levels correlate positively with the degree of obesity and prolonged hyperinsulinaemia increases serum leptin levels. Moreover, insulin secreting beta-cells express functional leptin receptors indicating a functional relationship between leptin and insulin. The aim of this study was to examine the relationship between fasting serum leptin levels and measures of insulin sensitivity and beta-cell function in a population-based sample of 380 young healthy Caucasians. Multiple regression analysis was employed to analyse the relationship between fasting serum leptin levels and levels of fasting serum insulin, insulin sensitivity index and acute insulin response (AIR) in a population-based study of 380 young healthy Caucasians who underwent a combined intravenous glucose and tolbutamide tolerance test. Serum leptin levels were positively correlated to measures of adiposity and were 3.2 times higher in women than in men (P<0.00001). In multiple regression analyses adjusting for age, percentage body fat, waist circumference and maximal aerobic capacity, a significant positive correlation was observed between the fasting serum leptin concentrations and both fasting serum insulin levels (P<0.0001) and AIR (P = 0.014) for women. No significant interrelation of these variables was found in men. However, for both genders a significant negative correlation was observed between fasting serum leptin levels and measures of insulin sensitivity index (P = 0.007).

Serum leptin and longevity.

There are changes in the ability to regulate energy balance and caloric intake with aging. Consequently, we investigated whether human aging modifies the levels of serum leptin, a novel hormone implicated in the regulation of energy balance. We studied 268 Caucasian men and women aged 22-85 years, and divided them into groups with mean ages of 30, 40, 50, 65, 75, 80 and 85 years. Fasting serum leptin concentrations were determined by radioimmunoassay. Subjects aged 65 or older were followed for five years after the blood sampling. There were no statistically significant differences in fasting serum leptin concentrations across different age groups in females (p = 0.090). Fasting serum leptin concentrations were also similar in different age groups in males, except that males in the 30-year age group had lower serum leptin levels than males in the 75-year age group (p = 0.042). Leptin levels were 2-3 fold higher in females than in males in each age group (p < 0.005 except p = 0.063 in the 75-year age group). Elderly women, who lived longer, had 47% higher (p < 0.05) serum leptin concentrations, and 17% higher (p < 0.001) BMI than the women who died within five years of blood sampling. Leptin levels were not statistically different in these women after adjusting for BMI. Thus, aging has no apparent effect on serum leptin levels in women or men, and the gender differences in leptin is present also in the older age groups. Higher leptin concentrations in the females who live longer may reflect a better nutritional status, and a greater adipose tissue mass rather than a primary factor for survival.

Association of leptin and hunger-satiety ratings in obese women.

To measure leptin, insulin and cholecystokinin (CCK) concentrations in obese women on calorie restriction and to determine their correlation with hunger-satiety ratings. Although it has been proposed to play a role in appetite regulation, the effects of physiological concentrations of these hormones on hunger-satiety in humans have not yet been well established. Prospective metabolic study. A two week 'wash-in period' followed by a three-week observation period, during which each subject underwent six measurements of satiety, blood parameters and body weight. Energy Metabolism Research Unit, Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA. 22 moderately to severely overweight women (mean age: 45 +/- 8 y; body mass index (BMI): 33 +/- 6 kg/m2). Energy restriction, in the form of a 3.3 MJ (800 kcal) diet during five weeks. Fasting blood levels of leptin, insulin, glucose and CCK, fasting hunger-satiety scores and body weight. The mean (+/- s.d.) fasting serum leptin concentration at the beginning of the observation period was 26.1 +/- 15.9 ng/ml (range: 6.7-59.8 ng/ml). Leptin concentrations correlated positively with body weight (P < 0.0001). Furthermore, reductions in body weight were associated with decreases in fasting leptin levels (P = 0.002). Leptin concentrations correlated with serum levels of insulin (P = 0.0001) and CCK (P = 0.06), but in multivariate analysis including insulin, CCK and glucose, only leptin had a significant relationship with satiety (P = 0.04). This relationship was linear. These results confirm the association between leptin levels, body weight and serum insulin. We also showed that higher serum leptin levels correlated with greater feelings of fullness, a relationship which was not blunted in the more obese subjects. These findings suggest that leptin is a satiety hormone that reduces appetite, even in obese individuals, and that weight gain must be due to other factors, overriding this feed-back regulation.

Serum leptin, food intake and preferences for sugar and fat in obese women.

To examine the association of leptin with food intake and preferences for sugar and fat in obese humans. Food intake and preferences for sugar and fat were measured in 35 obese women by a four-day food record and three hedonic tests, respectively. High fasting serum leptin concentration adjusted for body fat mass and dietary underreporting was associated with low dietary energy and fat intakes. In addition, trends towards lower preference for chocolate as well as for the taste of high-fat, low-sugar mixture were observed in those with higher leptin concentration. High serum leptin concentration could be associated in obese women with lower dietary energy and fat intakes, and possibly with the lower preference for fat. These findings need to be verified in further human studies.

Is there a relationship between leptin and insulin sensitivity independent of obesity?A population-based study in the Indian Ocean nation of Mauritius

It has been shown previously in smaller studies that fasting serum leptin and insulin concentrations are highly correlated, and insulin sensitive men have lower leptin levels than insulin resistant men matched for fat mass. We have examined the association between insulin resistance (assessed by fasting insulin) and leptin after controlling for overall and central adiposity in a population-based cohort. Leptin levels were compared across insulin resistance quartiles within three categories of obesity (tertiles of body mass index (BMI)). Partial correlation coefficents and multiple linear regression models were used to assess the relationship between leptin and fasting insulin after adjusting for BMI and waist to hip ratio (WHR) or waist circumference. Subjects were normoglycemic participants of a 1987 non-communicable diseases survey conducted in the multiethnic population of Mauritius. 1227 men and 1310 women of Asian Indian, Creole and Chinese ethnicity had normal glucose tolerance and fasting serum leptin measurements. Mean serum leptin concentration increased across quartiles of fasting insulin in each BMI group and gender, after controlling for BMI, WHR and age. Furthermore, fasting insulin was a significant determinant of serum leptin concentration, independent of BMI and WHR, in both men and women. Similar results were found if waist circumference replaced BMI and WHR in the model. These results suggest that insulin resistance/concentration may contribute to the relatively wide variation in leptin levels seen at similar levels of body mass or alternatively, leptin may play a role in the etiology of insulin resistance. Further studies will be important to determine whether the hyperleptinemia/insulin resistance relationship has a role in the natural history of obesity, Type 2 diabetes mellitus and the other metabolic abnormalities associated with insulin resistance.

Serum Leptin and Energy Expenditure in Children1

Leptin has been hypothesized to play an important role in energy balance by affecting both energy intake and energy expenditure. The purpose of our study was to determine the relationship between fasting serum leptin concentrations and measures of energy expenditure in prepubertal children. We measured total energy expenditure (TEE; by the doubly labeled water technique), resting energy expenditure (REE; after an overnight fast), activity energy expenditure (AEE; TEE-REE), body composition (by dual energy x-ray absorptiometry), and fasting serum leptin concentration (by RIA) in 76 children. Simple correlations showed that all measures of energy expenditure (TEE, REE, and AEE) were positively related to the serum leptin concentration (r = 0.50, P < 0.001; r = 0.45, P < 0.001; and r = 0.30, P < 0.01, respectively). However, after adjusting for body composition (fat-free mass and fat mass), gender, and ethnicity, serum leptin concentrations were not related to any measure of energy expenditure (TEE, P = 0.61; REE, P = 0.97; AEE, P = 0.65). These latter findings were further confirmed using structural equation models with leptin and energy expenditure as dependent variables, and fat-free mass and fat mass as independent variables. Results from these models showed no direct effect of leptin and no indirect effect of fat mass (through leptin) on any measure of energy expenditure, when a path between fat mass and energy expenditure was present in the model. Thus, our data do not support the hypothesis that the serum leptin concentration (independent of fat mass) is related to measures of energy expenditure in children.

Effects of gender, ethnicity, body composition, and fat distribution on serum leptin concentrations in children.

The Ob protein leptin has been shown to be closely correlated with measures of body fat in humans and animals. Studies have suggested that there are both gender and ethnic differences in serum leptin concentrations, even after controlling for total and relative body fat and body mass index. We hypothesized that gender and ethnic differences in serum leptin concentrations are due to differences in both body composition and body fat distribution. We measured fasting serum leptin concentration, body composition (fat mass and fat-free mass by dual energy x-ray absorptiometry), and body fat distribution (intraabdominal and sc abdominal adipose tissue by computed tomography) in 74 prepubertal boys and girls (43 African-Americans and 31 Caucasians). Our results showed that gender differences in serum leptin concentrations could not be fully explained by differences in body mass index, total fat mass, or relative body composition. However, when serum leptin concentrations were adjusted for differences in relative body composition (fat mass and fat-free mass) and body fat distribution (sc and intraabdominal adipose tissue), gender no longer had an independent effect on the serum leptin concentration. Serum leptin concentrations were not influenced by ethnicity. Thus, when comparing group differences in serum leptin concentrations, it is necessary to adequately control for group differences in body composition and fat distribution.

Serum leptin concentrations in human immunodeficiency virus-infected men with low adiposity

The product of the obese gene ( ob) is the protein leptin, which is synthesized in and secreted from adipocytes. Fasting serum leptin concentrations are closely related to body fat content and are higher in obese than in normal-weight individuals. Leptin may contribute to body weight regulation. Overproduction of leptin in certain pathologic conditions such as acquired immunodeficiency syndrome (AIDS) might in principle contribute to the low body fat content associated with body wasting. We measured fasting serum leptin levels by radioimmunoassay in individuals infected with the human immunodeficiency virus (HIV) and in a group of healthy lean men to determine whether HIV infection increases leptin levels. Thirteen HIV-infected men aged 26 to 50 years with a body mass index (BMI) of 15 to 26 kg/m 2 and 4 to 24 kg body fat (7% to 29% body fat) had serum leptin levels (3.4 ± 1.6 ng/mL) that were not elevated compared with the levels in 17 healthy men (4.0 ± 1.4 ng/mL) matched for age (23 to 47 years), BMI (18 to 26 kg/m 2), and body fat (5 to 21 kg; 9% to 28%). In both groups of men, serum leptin concentrations were correlated with percent body fat and body fat content ( P < .001), and these relationships were not different between the two groups. In both groups, leptin concentrations were not correlated with lean body mass ( P ≥ .24). Energy intake in the HIV-infected men, assessed from 3-day intake records, was within the normal range. These findings extend the hypothesis that circulating leptin concentrations directly reflect adipose tissue mass, even in HIV-infected men with low body fat content. These findings do not support the hypothesis that HIV infection is associated with high circulating leptin concentrations, and suggest that low leptin levels do not stimulate food intake in HIV-infected individuals.

Circulating leptin concentrations in polycystic ovary syndrome: relation to anthropometric and metabolic parameters.

To determine the relation between metabolic and anthropometric parameters and circulating leptin concentrations in women with polycystic ovary syndrome (PCOS). Correlation of fasting serum leptin concentrations with anthropometric measures and multiple metabolic parameters including insulin and glucose responses to a 2-hour 75-g oral glucose tolerance test (OGTT) in 85 women with PCOS (17-36 years, body mass index (BMI) 29.9 +/- 0.9 kg/m2, mean +/- SD) and 18 control women (25-47 years, BMI 25 +/- 1.7 kg/m2). Diagnostic criteria for PCOS: characteristic ovarian morphology on ultrasound plus at least two of (1) elevated serum testosterone; (2) elevated serum androstenedione; and (3) reduced serum SHBG concentrations. Concentrations of androgens, lipids, PRL, gonadotrophins, and leptin were measured in the baseline fasting blood sample from an OGTT. Insulin and glucose were measured throughout OGTT. Serum leptin concentrations were measured by radioimmunoassay. Log leptin levels in the PCOS group correlated significantly with BMI (r = 0.85, P < 0.0001) and with 8 other parameters including waist/hip ratio (r = 0.51, P = 0.0005). By stepwise regression analysis, only BMI (P < 0.0001) and plasma high density lipoprotein concentration (P = 0.02) were independently correlated with log leptin levels, both positively. There was no effect of fat distribution, as measured by waist/ hip ratio, on leptin concentrations. Comparison of control subjects to a BMI-matched subgroup of 55 PCOS subjects revealed significantly higher circulating concentrations of LH, testosterone, DHEAS, progesterone and androstenedione, and higher glucose and insulin responses to OGTT in the PCOS group. Leptin levels were not different between the PCOS subgroup and control group (14.8 +/- 1.3 vs 12.1 +/- 2.3 micrograms/l, mean +/- SE, P = 0.26) and the relation of BMI to leptin levels determined by linear regression analysis also did not differ between the two groups. Our results indicate that circulating leptin concentrations in women with PCOS, a condition characterized by hyperandrogenaemia, increased LH concentrations and insulin resistance, are strongly related to BMI and not independently affected by circulating levels of insulin, gonadotrophins or sex hormones.

Gender Differences in Serum Leptin Levels in Humans

Leptin, the product of theobgene, is an adipose tissue-derived hormone that appears to regulate both satiety and thermogenesis. In the present report, we have reexamined the relationship between circulating leptin concentration and body fat in humans using a more valid measure of adiposity (hydrodensitometry) and have extended these observations to examine the influence of regional body fat distribution and cardiorespiratory fitness. Fasting serum leptin concentration was 6.9 ± 0.3 ng·ml−1in males (N= 333) and 15.2 ± 1.3 ng·ml−1in females (N= 63). Interestingly, total fat mass did not differ between groups (males 20.5 ± 0.5 kg; females 20.4 ± 1.5 kg), suggesting that females have higher leptin levels per unit fat mass. In a multiple regression model, fat mass was the best predictor of serum leptin concentration in males, accounting for 51% of the variance in leptin concentration. In females, percentage body fat was the best predictor of leptin, accounting for 49% of the variance. In both groups, the relationship between leptin and adiposity remained significant after adjusting for age, maximal treadmill time, waist circumference, and fasting insulin concentration. These observations support previous conclusions that circulating leptin is primarily a function of adiposity and demonstrate for the first time that this relationship is independent of fat distribution or cardiorespiratory fitness. The data also suggest that there is a gender dichotomy in the relationship between leptin and body fat mass in humans.