Collection and Interpretation of Plasma Leptin Concentration Data in Humans

JENSEN, MICHAEL D, DONALD HENSRUD, PETER C. O'BRIEN, AND SØREN NIELSEN. Collection and interpretation of plasma leptin concentration data in humans. Obes Res. Objective: To reassess the relationship between body fat and plasma leptin concentrations when a) replicate measures of leptin are made; b) energy intake is controlled at isoenergetic levels before the study; and c) body fat and percent body fat are measured with dual energy X-ray absorptiometry (DXA). Research Methods and Procedures: Two separate studies were conducted. In the first study, four plasma samples were collected for measurement of leptin over 30 minutes on a single day in 43 lean and obese men and women. For the second study, plasma samples were collected on four consecutive days from a group of 50 lean and obese men and women. Percent body fat (and body fat mass) was related to log-transformed mean plasma leptin concentrations using linear regression analysis; multiple linear regression analysis was used to determine whether there was an effect of gender on this relationship, and the analysis of Choi was used to examine whether percent body fat or body fat mass better predicts plasma leptin concentrations. Results: For the first study, percent body fat was highly correlated (r = 0. 96, p<O. OOOl) with log-transformed mean leptin concentrations. No difference in the relationship between leptin and percent body fat in men and women was detected. The second study confirmed this observation; the relationship between In leptin and percent body fat was virtually identical (r = 0. 93, p<0. 001). Analysis of the pooled data suggests that percent body fat is a better predictor of plasma leptin concentration than body fat mass. The use of multiple (as opposed to a single) leptin measurements did not significantly improve the leptinhody fat relationship. Discussion: When robust body composition techniques and diet control measures are taken into consideration, the relationship between In plasma leptin concentrations and percent body fat is not different in men and women.     

Serum Leptin Concentrations and Weight Gain in Postobese,Postmenopausal Women

Objective : This study was designed to determine if serum leptin concentrations (adjusted for fat mass) after weight loss on a low-calorie diet predict subsequent weight gain. Research Methods and Procedures : Body composition and serum leptin concentrations were determined on 14 moderately obese, postmenopausal, nondiabetic women with a familial predisposition to obesity. Assessments were obtained under tightly controlled metabolic ward conditions of macronutrient intake and weight maintenance both before (obese state) and after a mean weight loss of 12.0 kg to normal body weight (postobese state). Four years later, without intervention, body weight and body composition were reassessed. Results : Weight loss resulted in significant decreases in fat mass (29.7 ± 5.4 vs. 20.3 ± 4.7; kg), body mass index (27.7 ± 1.6 vs. 23.0 ± 1.5; kg/m2), percent body fat (40.7 ± 4.3 vs. 33.1 ± 5.0), and serum leptin concentrations (31.8 ± 16.0 vs. 11.5 ± 5.4; ng/mL). Serum leptin concentrations were positively correlated (p<<0.05) with fat mass in both the obese and postobese states (r = 0.67 and r = 0.56, respectively). However, residual serum leptin concentrations (adjusted for fat mass) in the obese and postobese states were not related to changes in body weight (p<= 0.61 and 0.52), fat mass (p = 0.72 and 0.42), body mass index (p = 0.59 and 0.33), or percent body fat (p = 0.84 and 0.46) over the follow-up period. Discussion : These finding do not support the hypothesis that relatively low concentrations of leptin predict weight regain after weight loss. However, because the number of subjects in this study was limited, further studies are warranted.     

BMI Is the Main Determinant of the Circulating Leptin in Women after Vertical Banded Gastroplasty

Objective: To assess the main determinant of serum leptin concentration changes in morbidly obese patients treated by banded vertical gastroplasty. Research Methods and Procedures: Serum leptin and insulin concentrations, insulin resistance, BMI, body weight, and body fat mass in 18 obese women and 8 obese men treated by vertical banded gastroplasty were studied. Lean women and men subjects were used as controls. Results: Before surgery, serum leptin and insulin concentrations and insulin resistance index were significantly higher in morbidly obese patients than in control subjects. BMI, body fat mass, and serum triacylglycerol concentrations were also significantly higher in obese than in lean subjects. All of these parameters gradually decreased during 50 weeks after surgery. Univariate regression analysis displayed significant correlations between the following: serum leptin concentration and BMI (and body fat mass), serum leptin concentration and serum insulin concentration, and serum leptin concentration and insulin resistance index. Multivariate regression analysis indicated that only BMI was independently correlated with the decrease in serum leptin concentration. Discussion: Obtained data suggest the following: 1) vertical banded gastroplasty causes reduction of body weight, serum leptin and insulin concentration, insulin resistance, and serum triacylglycerol concentration; and 2) BMI is the main determinant of the circulating leptin concentration in morbidly obese women after anti‐obesity surgery.     

Low Plasma Leptin Concentration and Low Rates of Fat Oxidation in Weight‐Stable Post‐Obese Subjects

Objective: A low resting metabolic rate for a given body size and composition, a low rate of fat oxidation, low levels of physical activity, and low plasma leptin concentrations are all risk factors for body weight gain. The aim of the present investigation was to compare resting metabolic rate (RMR), respiratory quotient (RQ), levels of physical activity, and plasma leptin concentrations in eight post‐obese adults (2 males and 6 females; 48.9 ± 12.2 years; body mass index [BMI]: 24.5 ± 1.0 kg/m²; body fat 33 ± 5%; mean ± SD) who lost 27.1 ± 21.3 kg (16 to 79 kg) and had maintained this weight loss for ≥2 months (2 to 9 months) to eight age‐ and BMI‐matched control never‐obese subjects (1 male and 7 females; 49.1 ± 5.2 years; BMI 24.4 ± 1.0 kg/m²; body fat 33 ± 7%). Research Methods and Procedures: Following 3 days of weight maintenance diet (50% carbohydrate and 30% fat), RMR and RQ were measured after a 10‐hour fast using indirect calorimetry and plasma leptin concentrations were measured using radioimmunoassay. Levels of physical activity were estimated using an accelerometer over a 48‐hour period in free living conditions. Results: After adjustment for fat mass and fat‐free mass, post‐obese subjects had, compared with controls, similar levels of physical activity (4185 ± 205 vs. 4295 ± 204 counts) and similar RMR (1383 ± 268 vs. 1430 ± 104 kcal/day) but higher RQ (0.86 ± 0.04 vs. 0.81 ± 0.03, p < 0.05). Leptin concentration correlated positively with percent body fat (r = 0.57, p < 0.05) and, after adjusting for fat mass and fat‐free mass, was lower in post‐obese than in control subjects (4.5 ± 2.1 vs. 11.6 ± 7.9 ng/mL, p < 0.05). Discussion: The low fat oxidation and low plasma leptin concentrations observed in post‐obese individuals may, in part, explain their propensity to relapse.     

Relationship of Leptin Concentration to Gender,Menopause, Age,Diabetes, and Fat Mass in African Americans

This investigation was designed to determine the relationship of leptin concentration to gender, sex hormones, menopause, age, diabetes, and fat mass in African Americans. Participants included 101 African Americans, 38 men (mean age, 34. 2 ± 7. 4 years), 29 age-matched premenopausal women (mean age, 32. 6 ± 3. 7 years), and 36 postmenopausal women (mean age, 57. 8 ± 5. 9 years). The women were not taking exogenous sex hormones, and 12 subjects were diabetic. Percent body fat was calculated with the Siri formula, fat mass (FM) was calculated as weight x percent body fat, and Fat-free mass (FFM) was calculated as weight minus FM. Fasting plasma was assayed for leptin, estradiol, free testosterone, glucose, and insulin concentrations. The nondiabetics had an oral glucose tolerance test (OGTT). The diabetics compared with the non-diabetics had a higher central fat index (^P=0. 04) but otherwise were similar to nondiabetics in all parameters measured. Body mass index, percent body fat, and FM were greater in women than men (p<0. 001). Leptin concentrations in men, premenopausal, and postmenopausal women were: 7. 51 ± 8. 5, 33. 9 ± 17. 3, 31. 4 ± 22. 3 ng/mL. Leptin/FM x 100 in the three groups were: 28. 9 ± 16. 1, 98. 65 ± 44. 9, 77. 1 ± 44. 5 ng/mL/kg. The gender difference in leptin concentration and leptin/FM was significant (p<0. 001), but the difference between premenopausal and postmenopausal women was not. In each group, weight, percent body fat, and FM were highly correlated with leptin concentration. Multiple regression analyses with leptin concentration as the dependent variable and age, diabetic status, percent body fat, weight, FM, FFM, estradiol, and free testosterone concentrations as independent variables demonstrated that the determinants of leptin concentration in men was weight only (R=0. 83,p<0. 001), in premenopausal women it was FM only (R=0. 57,P<0. 001), and in postmenopausal women it was weight only (R=0. 67, p<0. 001). With diabetics excluded, the multiple regression analysis was repeated with fasting insulin concentration and the area under the insulin curve during the OGTT included as independent variables. The results for this multiple regression analyses were the same as the first. Therefore, leptin concentration in African Americans is determined by gender and fat mass. Menopause, age, and diabetes do not affect leptin concentration.     

Anthropometry Versus Imaging for Prediction of Inflammation Among Hispanic Girls

Objective: This study aimed to compare total and regional estimates of body composition, by direct and indirect techniques, for the optimal prediction of C‐reactive protein (CRP) among young (aged 9‐12 years) Hispanic girls (N = 232). Methods: Standard anthropometric techniques were used to measure height, weight, and waist circumference. Dual‐energy X‐ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) assessed body composition. Fasting serum CRP was measured by the AU5812 Clinical Chemistry Analyzer (Beckman Coulter, Brea, California). Associations between each total and regional body composition parameter and CRP were tested using linear regression (log‐transformed, continuous CRP) and ordinal logistic regression (CRP < 1.0, ≥ 1.0‐2.9, and ≥ 3.0 mg/L), controlling for maturation, dietary energy, physical activity, and medications. Results: All measures of total and regional body fat were positively associated with CRP (P < 0.0001) except for intermuscular fat by pQCT. There were no clinically relevant differences in their association with CRP between anthropometric (BMI; waist circumference) and DXA‐derived (total fat and regional fat: trunk, gynoid, android fat, leg) measures of fat. Conclusions: Measurement of body habitus in Hispanic girls, by multiple commonly available means, predicts CRP equally well.     

The effect of pioglitazone and resistance training on body composition in older men and women undergoing hypocaloric weight loss

Age‐related increases in ectopic fat accumulation are associated with greater risk for metabolic and cardiovascular diseases, and physical disability. Reducing skeletal muscle fat and preserving lean tissue are associated with improved physical function in older adults. PPARγ‐agonist treatment decreases abdominal visceral adipose tissue (VAT) and resistance training preserves lean tissue, but their effect on ectopic fat depots in nondiabetic overweight adults is unclear. We examined the influence of pioglitazone and resistance training on body composition in older (65–79 years) nondiabetic overweight/obese men (n = 48, BMI = 32.3 ± 3.8 kg/m²) and women (n = 40, BMI = 33.3 ± 4.9 kg/m²) during weight loss. All participants underwent a 16‐week hypocaloric weight‐loss program and were randomized to receive pioglitazone (30 mg/day) or no pioglitazone with or without resistance training, following a 2 × 2 factorial design. Regional body composition was measured at baseline and follow‐up using computed tomography (CT). Lean mass was measured using dual X‐ray absorptiometry. Men lost 6.6% and women lost 6.5% of initial body mass. The percent of fat loss varied across individual compartments. Men who were given pioglitazone lost more visceral abdominal fat than men who were not given pioglitazone (?1,160 vs. ?647 cm³, P = 0.007). Women who were given pioglitazone lost less thigh subcutaneous fat (?104 vs. ?298 cm³, P = 0.002). Pioglitazone did not affect any other outcomes. Resistance training diminished thigh muscle loss in men and women (resistance training vs. no resistance training men: ?43 vs. ?88 cm³, P = 0.005; women: ?34 vs. ?59 cm³, P = 0.04). In overweight/obese older men undergoing weight loss, pioglitazone increased visceral fat loss and resistance training reduced skeletal muscle loss. Additional studies are needed to clarify the observed gender differences and evaluate how these changes in body composition influence functional status.     

Associations of leg fat accumulation with adiposity‐related biological factors and risk of metabolic syndrome

Objective:

To examine associations between regional fat mass (FM) distribution and cardiometabolic risk factors among ethnic minority groups, such as non‐Hispanic blacks and Hispanics.

Design and Methods:

The associations among 8,802 US residents who participated in the 1999‐2004 US National Health and Nutrition Examination Survey were examined. Body composition was measured using dual‐energy X‐ray absorptiometry. Leg fat indices included leg FM, leg FM percent (FM%), leg to whole body FM ratio (leg/whole), and leg to trunk FM ratio (leg/trunk). The correlation between leg fat indices and adiposity‐related risk factors, as well as the association of these indices with metabolic syndrome (MetS) was evaluated.

Results:

After adjusting for covariates including age, gender, and trunk FM or trunk FM%, higher leg FM and leg FM% were, in general, correlated favorably with adiposity‐related risk factors and associated with lower odds of MetS in all ethnicities, including non‐Hispanic whites and blacks and Hispanic groups. In addition, in all multivariate‐adjusted models, leg/whole and leg/trunk ratios were strongly associated with lower levels of most risk factors and decreased odds of MetS in these ethnicities (all odds ratios comparing extreme quintiles < 0.1).

Conclusions:

Results show that leg fat accumulation is inversely associated with adiposity‐related biological factors and risk of MetS in both whites and ethnic groups, suggesting that regional fat distribution plays an important role in the etiology of adiposity‐related diseases in these populations.     

Hispanic and Asian pubertal girls have higher android/gynoid fat ratio than whites

Objective: To examine differences in body size, composition, and distribution of body fat among Hispanic, white, and Asian adolescents. Research Methods and Procedures: This included cross‐sectional data from the baseline sample of the Adequate Calcium Today trial. Participants included 180 Asian, 234 Hispanic, and 325 white girls 11.8 ± 0.05 years of age from Arizona, California, Hawaii, Indiana, Ohio, and Nevada. Anthropometric and DXA measurements (Lunar Prodigy) were standardized across sites. Tanner pubertal stage was self‐selected from line drawings. Physical activity was assessed by a validated questionnaire. Comparisons between ethnic groups were examined using contrasts in the context of a general linear model. Results: Controlling for pubertal stage and study site only, Asians weighed less than Hispanics and were shorter than Hispanics and whites. Controlling for pubertal stage, height, weight, and study site, Asians had shorter leg lengths, smaller waist circumference, longer trunk lengths, more lean mass, less total fat mass, and less gynoid fat mass than Hispanics and whites; Asians had larger bitrochanteric width than whites; Asians had smaller DXA‐derived android fat mass than Hispanics; and whites had smaller mean android/gynoid fat ratio than Hispanics. However, whites had a smaller android/gynoid fat ratio than both Asians and Hispanics in a model that adjusted for ethnicity, pubertal stage, bitrochanteric width, waist circumference, trunk length, log of physical activity, and study site, which explained 77% of the variation. Discussion: Ethnic differences in fat distribution are partially explained by differences in skeletal dimensions.     

Leptin responses to glucose infusions in obesity-prone rats

The secretion of leptin is dually regulated. In fasting animals, plasma leptin concentrations reflect body fat stores, whereas the incremental leptin response to fasting or refeeding most likely reflects insulin-mediated energy flux and metabolism within adipocytes. Impaired secretion of leptin in either pathway could result in obesity. We therefore measured plasma leptin concentrations in fasted animals and plasma leptin concentrations after an intravenous glucose infusion in a rat model of obesity. Young Sprague-Dawley (S-D) and Fischer 344 (F344) rats had similar percent body fat and fasting glucose and fasting leptin concentrations. However, F344 animals had higher insulin concentrations and leptin responses to intravenous glucose than did the S-D animals. The animals were then fed a control or high-fat diet for 6 wk. High-fat fed animals gained more weight and body fat than did the control fed animals. Control and high-fat fed F344 animals gained approximately 40% (P < 0.0001) more weight and >100% (P < 0.01) more body fat than did the S-D animals. Fasting leptin concentrations and leptin concentrations after intravenous glucose infusions and feeding were more than double (P < 0.05) in F344 animals compared with S-D animals. Whether an animal is fed a control or high-fat diet had little effect on the leptin response to intravenous glucose. In conclusion, young, lean F344 animals, before the onset of obesity, demonstrated a greater acute leptin response to intravenous glucose than similarly lean S-D animals. After a 6-wk diet, F344 animals had a greater percent increase in body weight and insulin resistance and exhibited higher fasting leptin concentrations and a greater absolute leptin response to intravenous glucose compared with the S-D animals. The chronic diet (control or high fat) had little impact on the acute leptin response to intravenous glucose. F344 animals exhibit leptin resistance in young, lean animals and after aging and fat accumulation.     

Relation of Leptin to Insulin Resistance Syndrome in Children

Objectives: To examine the relation of leptin to insulin resistance, as measured by euglycemic insulin clamp, and insulin resistance syndrome factors in thin and heavy children. Research Methods and Procedures: Anthropometrics, insulin, blood pressure, and leptin were measured in 342 11‐ to 14‐year‐old children (189 boys, 153 girls, 272 white, 70 black). Insulin sensitivity (M) was determined by milligrams glucose uptake per kilogram per minute and expressed as M/lean body mass (M_lbm). Children were divided by median BMI (boys = 20.5 kg/m²; girls = 21.4 kg/m²) into below‐median (thin) and above‐median (heavy) groups. Correlation coefficients between log‐leptin and components of insulin resistance syndrome were adjusted for Tanner stage, gender, and race. Results: BMI was related to leptin in boys (r = 0.70, p < 0.001) and girls (r = 0.75, p < 0.001). Leptin was higher in girls than boys (32.6 vs. 12.3 ng/mL, p = 0.0001). Leptin levels increased in girls and decreased in boys during puberty, paralleling the changes in body fat. Leptin was significantly correlated with insulin, M_lbm, triglycerides, and blood pressure in heavy children and only with insulin in thin children. After adjustment for body fat, the correlations remained significant for insulin and M_lbm in heavy children and with insulin in thin children. Discussion: Significant associations were found between leptin and insulin resistance in children, and these associations were attenuated by adjustment for adiposity. These findings at age 13 likely have long‐term consequences in the development of the obesity‐insulin resistance‐related cardiovascular risk profile.     

Genetic Variation and Obesity in Australian Women: A Prospective Study

Objective: A number of candidate genes have been implicated in the pathogenesis of obesity in humans. This study examines associations between longitudinal changes in body mass and composition and the presence of polymorphisms in the β‐3 adrenergic receptor, tumor necrosis factor‐α, leptin, and leptin receptor (Lepr) in a cohort of Australian women. Research Methods and Procedures: Healthy white Australian women (n = 335) were randomly selected from the Barwon region of Victoria and underwent baseline anthropometry and double‐energy X‐ray absorptiometry for assessment of body mass and adiposity. These measurements were repeated again at 2‐year follow‐up. Genomic DNA was extracted and used for polymerase chain reaction‐based genotyping of all polymorphisms. Results: The Pro1019Pro Lepr polymorphism was associated with longitudinal increases in body weight (p = 0.02), fat mass (p = 0.05), and body mass index (p = 0.01) in this study, and individuals homozygous for the A allele at this locus had a greater propensity to gain body fat over time. The largest effects on body composition seemed to be in individuals already obese at baseline. Changes in body weight, fat mass, percent body fat, and body mass index over a 2‐year period were not associated with genetic variation in the β‐3 adrenergic receptor (Trp64Arg), tumor necrosis factor‐α promoter, or leptin genes in non‐obese or obese women. Discussion: These results suggest that a Lepr polymorphism is involved in the regulation of body mass and adiposity in obese Australian white women, which may have implications for the treatment of obesity in this population.     

Exercise Improves Body Fat,Lean Mass,and Bone Mass in Breast Cancer Survivors

Given the negative effects of a breast cancer diagnosis and its treatments on body weight and bone mass, we investigated the effects of a 6‐month randomized controlled aerobic exercise intervention vs. usual care on body composition in breast cancer survivors. Secondary aims were to examine the effects stratified by important prognostic and physiologic variables. Seventy‐five physically inactive postmenopausal breast cancer survivors were recruited through the Yale–New Haven Hospital Tumor Registry and randomly assigned to an exercise (n = 37) or usual care (n = 38) group. The exercise group participated in 150 min/week of supervised gym‐ and home‐based moderate‐intensity aerobic exercise. The usual care group was instructed to maintain their current physical activity level. Body composition was assessed at baseline and 6‐months through dual‐energy X‐ray absorptiometry (DXA) by one radiologist blinded to the intervention group of the participants. On an average, exercisers increased moderate‐intensity aerobic exercise by 129 min/week over and above baseline levels compared with 45 min/week among usual care participants (P < 0.001). Exercisers experienced decreases in percent body fat (P = 0.0022) and increases in lean mass (P = 0.047) compared with increases in body fat and decreases in lean mass in usual care participants. Bone mineral density (BMD) was also maintained among exercisers compared with a loss among usual care participants (P = 0.043). In summary, moderate‐intensity aerobic exercise, such as brisk walking, produces favorable changes in body composition that may improve breast cancer prognosis.     

Relationship of Serum Adiponectin and Leptin Concentrations with Body Fat Distribution in Humans

Objective: We investigated whether serum concentrations of adiponectin are determined by body fat distribution and compared the findings with leptin. Research Methods and Procedures: Serum concentrations of adiponectin and leptin were measured by radioimmunoassay (n = 394) and analyzed for correlation with sex, age, and body fat distribution, i.e., waist‐to‐hip ratio, waist and hip circumference, and subcutaneous adipose tissue area of the lower leg as assessed by magnetic resonance imaging. Results: After adjusting for sex and percentage of body fat, adiponectin was negatively (r = ?0.17, p < 0.001) and leptin was positively (r = 0.22, p < 0.001) correlated with waist‐to‐hip ratio. Leptin, but not adiponectin, correlated with both waist (r = 0.49, p < 0.001) and hip circumference (r = 0.46, p < 0.001). Furthermore, leptin, but not adiponectin, correlated with the proportion of subcutaneous fat of the lower leg cross‐sectional area (r = 0.37, p < 0.001). Discussion: These data suggest that both adipocytokines are associated with central body fat distribution, and serum adiponectin concentrations are determined predominantly by the visceral fat compartment.     

Body Composition Measured by Dual‐energy X‐ray Absorptiometry Half‐body Scans in Obese Adults

Dual‐energy X‐ray absorptiometry (DXA) has become a common measurement of human body composition. However, obese subjects have been understudied largely due to weight and scan area restrictions. Newer DXA instruments allow for heavier subjects to be supported by the DXA scanner, but the imaging area is still smaller than the body size of some obese subjects. In this study, we determined the validity of an automated half‐scan methodology by comparing to the standard whole‐body scans in a cohort of obese volunteers. Fifty‐two subjects whose BMI >30 kg/m² completed whole‐body iDXA (GE Lunar) scans. The resulting scans were analyzed in three ways: the standard whole‐body scan, total body estimated from the left side, and from the right side. Fat mass, nonbone lean mass, bone mineral content (BMC), and percent fat derived from each half scan were compared to the whole‐body scans. Total fat mass, nonbone lean mass, or percent fat was comparable for the whole‐body scans, left, and right side scans (>97% within individuals and >99.9% for the group). The BMC estimate using the right side scan was slightly but statistically higher than the whole‐body BMC (～30 g or 1%, P < 0.001), while the left side scan BMC estimate was lower than the whole‐body BMC by the same magnitude. No significant magnitude bias was found for any of the composition variables. We conclude that the new iDXA half‐body analysis in obese subjects appears to be closely comparable to whole‐body analysis for fat mass, nonbone lean mass, and percent fat.     

Serum Leptin in Elderly People: Associations with Sex Hormones,Insulin, and Adipose Tissue Volumes

BAUMGARTNER, RICHARD N., ROBERT R. ROSS, DEBRA L. WATERS, WILLIAM M. BROOKS, JOHN E. MORLEY, GEORGE D. MONTOYA, AND PHILIP J. GARRY. Serum leptin in elderly people: associations with sex hormones, insulin, and adipose tissue volumes. Obes Res. Objective There are few data for associations of serum leptin with body fat, fat distribution, sex hormones, or fasting insulin in elderly adults. We hypothesized that the sex difference in serum leptin concentrations would disappear after adjustment for subcutaneous, but not visceral body fat. Serum leptin would not be associated with sex hormone concentrations or serum fasting insulin after adjusting for body fat and fat distribution. Research Methods and Procedures Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were measured using magnetic resonance imaging in a cross-sectional sample of 56 nondiabetic, elderly men and women aged 64 years to 94 years. Serum leptin, sex hormones (testosterone and estrone), sex hormone-binding globulin, and fasting insulin were also measured. Nine women were taking hormone replacement, and five men were clinically hypogonadal. Results Leptin was significantly associated with both SAT and VAT in each sex. Adjustment for SAT reduced the sex difference in leptin by 56%, but adjustment for VAT increased the difference by 25%. Leptin was not associated with serum estrone or hormone replacement therapy in the women, but had a significant, negative association with testosterone in the men that was independent of SAT, but not VAT. Leptin was significantly associated with fasting insulin in both sexes independent of age, sex hormones, sex hormone-binding globulin, VAT and SAT. Discussion Sex difference in serum leptin is partly explained by different amounts of SAT. Studies including both men and women should adjust for SAT rather than total body fat that includes VAT. The sex difference in serum leptin is not due to estrogen, but may be partly explained by testosterone. Testosterone is negatively associated with leptin in men, but the association is confounded with VAT. Leptin is associated with fasting insulin in non-diabetic elderly men and women independent of body fat, fat distribution. or sex hormones.     

Leptin Levels Are Associated with Fat Oxidation and Dietary‐Induced Weight Loss in Obesity

Objective: To examine the relationship between fasting plasma leptin and 24‐hour energy expenditure (EE), substrate oxidation, and spontaneous physical activity (SPA) in obese subjects before and after a major weight reduction compared with normal weight controls. To test fasting plasma leptin, substrate oxidations, and SPA as predictive markers of success during a standardized weight loss intervention. Research Methods and Procedures: Twenty‐one nondiabetic obese (body mass index: 33.9 to 43.8 kg/m²) and 13 lean (body mass index: 20.4 to 24.7 kg/m²) men matched for age and height were included in the study. All obese subjects were reexamined after a mean weight loss of 19.2 kg (95% confidence interval: 15.1–23.4 kg) achieved by 16 weeks of dietary intervention followed by 8 weeks of weight stability. Twenty‐four‐hour EE and substrate oxidations were measured by whole‐body indirect calorimetry. SPA was assessed by microwave radar. Results: In lean subjects, leptin adjusted for fat mass (FM) was correlated to 24‐hour EE before (r = ?0.56, p < 0.05) but not after adjustment for fat free mass. In obese subjects, leptin correlated inversely with 24‐hour and resting nonprotein respiratory quotient (r = ?0.47, p < 0.05 and r = ?0.50, p < 0.05) both before and after adjustments for energy balance. Baseline plasma leptin concentration, adjusted for differences in FM, was inversely related to the size of weight loss after 8 weeks (r = ?0.41, p = 0.07), 16 weeks (r = ?0.51, p < 0.05), and 24 weeks (r = ?0.50, p < 0.05). Discussion: The present study suggests that leptin may have a stimulating effect on fat oxidation in obese subjects. A low leptin level for a given FM was associated with a greater weight loss, suggesting that obese subjects with greater leptin sensitivities are more successful in reducing weight.     

Biologic Response to Peripheral and Central Administration of Recombinant Human Leptin in Dogs

LEBEL, CARL, AMY BOURDEAU, DAVID LAU, AND PAMELA HUNT. Biologic response to peripheral and central administration of recombinant human leptin in dogs. Obes Res. Objective: Because leptin is believed to act within the central nervous system, the objective of this study was to test that presumption by comparing the biologic responses to recombinant human leptin (rHuLeptin) when delivered either subcutaneously or intrathecally in a large animal species, the beagle dog. Methods and Procedures: Adult beagle dogs were used for all studies (n = 3 to 14). Treatment with rHuLeptin was either as daily subcutaneous or intermittent intrathecal injections. Results: Subcutaneously administered rHuLeptin was absorbed with peak concentrations appearing at 2 to 4 hours. After intrathecal administration, cerebral spinal fluid concentrations declined in a bi-phasic manner with a terminal half-life of ?6 to 8 hours. When lean beagles were given leptin subcutaneously, at 0. 05 to 5 gkglday for up to 6 months, reductions in body weight (up to 30%) and food intake (up to 75%) were observed. Body fat loss was observed in both lean and obese dogs, and confirmed by dual energy X-ray absorptiometry and histology of adipose tissue. When rHuleptin was delivered intrathecally at 4 to 1000 μg/dose for up to 3 months, the primary effects observed were reductions in body weight and food intake. In general all findings reported in the intrathecal studies were consistent with those noted in the subcutaneous studies; however, the required intrathecal dose was substantially lower than that for subcutaneous delivery. Discussion: These studies demonstrate that both subcutaneous and intrathecal treatment of rHuLeptin was associated with effects on body weight, food intake, and body fat in dogs. These results support the concept that the central nervous system is the probable primary site of action for leptin and suggest that rHuLeptin has similar physiologic activities that influence body weight, body fat, and metabolism in large animals to those reported previously in rodents.     

Association between Serum Leptin Levels and 24‐Hour Blood Pressure in Obese Women

Objective: To assess the relationship between serum leptin and 24‐hour blood pressure (BP) in obese women, according to body fat distribution. Research Methods and Procedures: A cross‐sectional study was carried out in a population of 70 nondiabetic, normotensive, obese women (40 with android and 30 with gynoid type of obesity) and 20 nonobese healthy women as a control group. All subjects underwent 24‐hour ambulatory BP monitoring. Blood samples were collected for serum leptin and plasma insulin measurements. Total cholesterol and high‐density lipoprotein cholesterol were also measured. Results: Serum leptin levels were significantly higher in obese subjects than in controls, and they were more elevated in android obese women than in gynoid ones. Leptin levels were positively related to body mass index (BMI), insulin, and waist and hip circumferences in the android group. Among gynoid subjects, leptin levels showed positive associations with BMI and insulin. In women with android obesity, strong positive correlations (p < 0.001) were found between leptin levels and 24‐hour systolic BP (SBP), daytime SBP, nighttime SBP, 24‐hour diastolic BP (DBP), and daytime DBP. Multiple regression analyses, including age, insulin and leptin concentrations, BMI, and waist and hip circumferences on 24‐hour and daytime SBP and DBP, showed that only leptin levels contributed to the variability of BP. Conclusions: Our study shows that serum leptin levels are directly related to 24‐hour BP levels in normotensive women with android fat distribution, independently of BMI.     

The Presence of the “fa” Gene in Heterozygous (FA/fa) Lean Female Rats: Effects on Body Weight,Body Fat and Serum Leptin

CLEARY, MARGOT P., AND FREDERICK C. PHILLIPS. The presence of the “fa” gene in heterozygous (FA/fa) lean female rats: effects on body weight, body fat and serum leptin. Obes Res. Objective: In previous studies, suckling lean heterozygous (FA/fa) pups had higher body fat levels in comparison to lean homozygous (FA/FA) pups. However, in older male rats fed either low- or high-fat diets, we found no effects of the “fa” gene in heterozygous lean rats compared to homozygous lean rats. Other studies have reported effects of the “fa” gene on aspects of insulin metabolism for lean heterozygous female rats compared to their homozygous counterparts. In the present study, the effect of the “fa” gene on body weight and body fat in lean female rats was investigated. Research Methods and Procedures: Homozygous lean female rats were obtained by mating homozygous lean male and female rats. Heterozygous lean female rats were obtained by mating homozygous obese male rats with heterozygous lean female rats. Following weaning, rats were maintained on a standard laboratory diet until 10 weeks of age when they were killed after an overnight fast. Results: Body weight (p<0. 03) and inguinal (p = 0. 01) and combined retroperitoneal+parametrial (p = 0. 06) fat pad weights were heavier in heterozygous lean compared to homozygous lean female rats. Combined fat pad-to-body weight ratio (p = 0. 05) and fat cell sizes (p = 0. 06) were also higher in the heterozygous lean compared to homozygous lean rats. No differences in serum triacylglycerol, cholesterol, glucose, or insulin concentrations were found between the two groups, but serum leptin levels were significantly higher (p<0. 004) in heterozygous lean rats. Discussion: These results indicate that effects of the “fa” gene are present during the postweaning period in lean female rats. Implications for increased body fat and leptin with respect to sexual maturation and fertility are discussed.