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Experimental Studies |
Departments of Medicine (A.K., T.W.G., Pa.W., Pe.W., E.G., W.T.G.), Biochemistry and Molecular Biology (T.W.G.), and Biometry and Epidemiology (Q.P.), Medical University of South Carolina, and the Charleston Veterans Affairs Medical Center, Charleston, South Carolina 29425
Address all correspondence and requests for reprints to: W. Timothy Garvey, M.D., Division of Endocrinology, Diabetes, and Medical Genetics, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425. E-mail: garveywt{at}musc.edu
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Abstract |
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The data indicate that there are important gender-based differences in the regulation and action of leptin in humans. Serum leptin levels increase with progressive obesity in both men and women. However, for any given measure of obesity, leptin levels are higher in women than in men, consistent with a state of relative leptin resistance. These findings have important implications regarding differences in body composition in men and women. The observation that serum leptin is not related to energy expenditure rates suggests that leptin regulates body fat predominantly by altering eating behavior rather than calorigenesis.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Mutations in the leptin gene have not been linked with obesity in humans (10). However, circulating leptin concentrations are positively correlated with measures of obesity, including body mass index (BMI) and percent body fat (11, 12). In addition, expression of leptin messenger ribonucleic acid (mRNA) in adipose tissue is greater in obese than in lean individuals (13). Progressive weight loss during hypocaloric dieting is accompanied by a decline in circulating leptin levels and adipose tissue mRNA expression; however, plasma levels then increase once isocaloric diets are initiated to maintain the reduced body weight (12). These observations are consistent with the hypothesis that human obesity is characterized by leptin resistance. To understand the basis of hyperleptinemia and leptin resistance, factors that modulate leptin release and mechanisms by which leptin regulates body weight must be identified. For example, it is unclear in humans whether leptin influences energy expenditure or eating behavior as homeostatic effector systems for the maintenance of body weight. Obesity is also associated with diabetes, insulin resistance, and other characteristics of syndrome X (14); however, the relationship of leptin to these metabolic traits has not been studied. We addressed these issues by measuring serum leptin in metabolically well characterized subjects. For the first time, we have demonstrated important gender-based differences in the leptin-obesity axis and that leptin is not likely to influence body fat by modulating resting energy expenditure.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The clinical characteristics of the study groups are shown in
Table 1
. Informed consent was obtained from 85
nondiabetic subjects (50 men and 35 women) and 31 patients with
noninsulin-dependent diabetes mellitus (NIDDM; 12 men and 19 women)
encompassing a wide range of body weight. Diagnosis of NIDDM was made
according to criteria of the National Diabetes Data Group (15), and
mean disease duration was 3.5 ± 0.3 yr. Therapy for diabetes
included insulin in 4 patients, oral hypoglycemic agents in 21, and
diet alone in 6; however, before the study, all NIDDM patients were
withdrawn from therapy for at least 3 weeks and followed on an
out-patient basis. All subjects studied were chemically euthyroid and
without renal, hepatic, or cardiac disease. No subject was ingesting
pharmacological agents know to effect carbohydrate homeostasis.
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In vivo insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique as previously described (16). Briefly, after a 12-h overnight fast, a catheter was inserted into the brachial vein in a antegrade manner to administer infusates. A dorsal hand vein was also cannulated in a retrograde manner and kept in a warming device (65 C) to provide arterialized venous blood for sampling. Regular insulin (Humulin, Eli Lilly Co., Indianapolis, IN) was administrated at a rate of 200 mU/m2·min through the brachial vein. This infusion rate produced a mean steady state serum insulin concentration of 577 ± 22.2 µU/mL, a range of serum insulin that we have found to maximally stimulate glucose uptake and completely suppress hepatic glucose output (17). Blood glucose was clamped at euglycemia (5.0 mmol/L) by measuring glucose in blood taken every 5 min from the dorsal hand vein and adjusting the infusion rate of 20% dextrose solution. To prevent hypokalemia and hypophosphatemia, KPO4 was infused throughout the study. All studies were performed for at least 3 h, and the glucose infusion rate was constant for the final 60 min of the study. The glucose uptake rate was quantitated in each individual as the mean glucose uptake over the final three 20-min intervals. Whole body glucose uptake was calculated on the basis of the glucose infusion rate corrected for changes in glucose pool size, assuming a distribution volume of 19% body weight and a pool fraction of 0.65. Glucose uptake rates were normalized for lean body mass (excluding bone mass) determined by dual energy x-ray absorptiometry. Mean arterial pressure and heart rate were monitored throughout the study using a Space Labs Recorder (Redmond, WA).
Body composition was measured in all subjects by dual energy x-ray absorptiometry scanning (Lunar Radiation, Madison, WI), except that seven subjects were too large or too tall to be accommodated by the scanning device and had body composition determined by underwater weighing. Dual energy x-ray absorptiometry scan measurement of body fat correlates highly with that obtained from underwater weighing (data not shown). Lean body mass determined by these methods reflects muscle mass and was used to normalize glucose uptake data and substrate metabolic rates. Body fat distribution was calculated with waist to hip/thigh measurements. Waist, hip, and thigh circumferences were measured to the nearest 0.5 cm. The waist circumference was taken to the smallest standing horizontal circumference between the ribs and the iliac crest; the hip circumference was taken as the largest standing horizontal circumference of the buttocks, and the thigh circumference was measured at a level 50% of the distance between the knee and the groin.
Respiratory calorimetry
After an overnight fast, resting metabolic rate was measured over a 30-min period at baseline and at the end of the hyperinsulinemic clamp. Substrate utilization rates were determined by computerized open circuit indirect calorimetry (Deltratrac II, SensorMedics, Yorba Linda, CA). Whole body oxygen consumption (VO2) and CO2 production (VCO2) were calculated by measuring gradients across the face and the flow rates of air using Haldane transformation. Energy expenditure and rates of lipid and carbohydrate oxidation were determined from the respiratory quotient value and the tables of Lusk (17a). Insulin-induced thermogenesis represents energy expenditure during the final 30 min of the hyperinsulinemic clamp minus the resting metabolic rate. Metabolic rates were normalized per kg metabolically active body mass according to the method of Ravussin et al. (18). Nonoxidative glucose metabolism was calculated by subtracting glucose oxidation rates from total glucose uptake measured during the clamp and was normalized per kg lean body mass.
Oral glucose tolerance test and blood pressure
Oral glucose tolerance tests were performed as advocated by the National Diabetes Data Group (14). All blood pressure measurements were taken in the dominant arm with the patient having been in the supine position for 30 min. Measurements were made using a calibrated automated cuff device (DynaMap 8100, Johnson and Johnson, New Brunswick, NJ); diastolic and systolic values represent the mean of two readings.
Leptin assay
Serum for leptin determination was obtained from blood drawn
between 0800–0900 h after an overnight fast. Quantification of serum
leptin was determined using a RIA and immunopurified rabbit antibodies
raised against highly purified recombinant human leptin (Linco, St.
Louis, MO). Leptin was labeled with 125I and purified by
gel filtration using Sephadex G-25 (Pharmacia, Piscataway, NJ). For the
RIA, duplicate 100-µL serum samples were added to assay buffer (0.05
mol/L phosphosaline, pH 7.4, containing 25 mmol/L ethylenediamine
tetraacetate, 0.1% sodium azide, 0.5% Triton X-100, and 1% RIA grade
BSA). Replicate aliquots of quality control pools were included for
each assay. After the addition of recombinant leptin and leptin
antibody, the samples were vortexed and allowed to incubate at 4 C for
24 h. On the following day, antibody-bound
[125I]leptin was precipitated and counted in a
-counter. The standard curves were calibrated by the method of
Gettys et al. (19), and serum leptin levels were estimated
by inverse calibration. The sensitivity of the assay was 0.5 ng/mL, and
the concentration of leptin producing 50% displacement from total
binding was 5.13 ± 0.23 ng/mL. The interassay coefficient of
variation for the quality control values was 6.12%; the intraassay
coefficient of variation was less than 5%.
Other analyses and statistics
Plasma glucose concentrations were measured using the glucose oxidase method and a glucose analyzer (Yellow Springs Instrument Co., Yellow Springs, OH). Fasting serum free insulin levels were measured in all subjects using a double antibody RIA (Abbott Laboratories, Diagnostic Division, Chicago, IL). A fasting lipid profile was assessed after an overnight fast using the Kodak Ektachem Clinical Chemistry Slide (Johnson and Johnson, Rochester, NY).
All data analysis was performed with the use of SAS program version 6.10 (SAS Institute, Cary, NC). Data are the mean ± SEM, with sample numbers indicated in the figures and tables. Statistical methods included ANOVA, simple linear regression, and multiple and stepwise regression where indicated. Differences were accepted as significant at P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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To determine the metabolic significance of leptin, 116 subjects
were studied over the full range of human obesity (BMI, 17–54
kg/m2; percent body fat, 7–50%) and were characterized on
a metabolic ward with respect to obesity, body composition, glucose
tolerance, insulin sensitivity, energy expenditure, substrate
metabolism, and blood pressure. As shown in Table 1
, the study group
included 85 individuals with normal glucose tolerance and 31 patients
with NIDDM. Serum leptin was measured by RIA in blood obtained between
0800–0900 h after an overnight fast. Figure 1
demonstrates that leptin levels were positively correlated with both
BMI (Fig. 1A) and percent body fat (Fig. 1B) in men (r = 0.87;
P < 0.0001 and r = 0.82; P <
0.0001, respectively) and women (r = 0.88; P <
0.0001 and r = 0.88; P < 0.0001, respectively).
Importantly, however, we found distinct gender-based differences in the
slopes of the regression lines. Leptin levels rose 3.4-fold more
rapidly as a function of BMI in women [leptin = 1.815 (BMI) -
31.103] than in men [leptin = 0.534 (BMI) - 8.487]. As a
result, women exhibited higher leptin concentrations than men (within
95% confidence limits) for any given BMI value above 20
kg/m2.
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, there are women, but no men, with percent body fat values
greater than 40%, and there is also a marked preponderance of men with
low percent body fat values. As nonoverlapping data points may have
unduly influenced the relative slopes of the regression lines, we
performed regression analysis of leptin vs. percent body fat
for only those men and women with body fat between 29–41%. Over this
range there was complete overlap of data points, allowing comparison
between genders. Over this delimited range of body fat, leptin levels
also rose 3 times more rapidly in women [leptin = 1.5562 (% body
fat) - 35.3971] than in men [leptin = 0.4704 (% body fat) -
6.4216]. This is important because it illustrates in men and women
with similar percent body fat that leptin levels rise more rapidly in
women with progressive increments in body fat than in men. Multiple regression analyses substantiated an impact of gender. BMI and gender independently accounted for 35% and 32% of the variability in leptin levels, respectively (both P < 0.0001). When percent body fat was taken as the measure of obesity, percent body fat explained 70% and gender explained 7% of the leptin variance (both P < 0.0001), and the interaction between these two variables contributed to an additional 4% (P = 0.003). Together, percent body fat and gender explained 81% of variance for serum leptin concentrations in humans. Thus, leptin concentrations were higher in women after adjusting for the degree of obesity.
Leptin and energy expenditure
Leptin can reduce adiposity by both suppressing eating behavior
and increasing energy expenditure in mice (1, 4). To assess whether
leptin regulates energy expenditure in humans, we measured the resting
metabolic rate, which accounts for the major portion of overall energy
expenditure (20), in all subjects using indirect calorimetry. As shown
in Fig. 2, leptin was not correlated (P
= NS) with the resting metabolic rate normalized per kg metabolically
active body mass in either men or women. In addition, the resting
metabolic rate, when included as a covariable with percent body fat or
BMI in multiple regression analysis, was not correlated with serum
leptin (P = NS) in either men or women (not shown).
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The presence of overt NIDDM did not affect the relationship
between leptin levels and obesity in either gender. Although leptin
levels were disproportionately high in women, Fig. 3
demonstrates that mean values of BMI and plasma leptin were similar
when comparing nondiabetic and diabetic subgroups in both men and women
(P = NS). Furthermore, in stepwise and multiple
regression models with leptin as the dependent variable and BMI (or
percent body fat), gender, and presence/absence of NIDDM as independent
variables, NIDDM did not enter the equations at a level even
approaching statistical significance.
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. Interestingly, leptin levels were
negatively correlated with maximal glucose uptake rates in men (r
= -0.57; P < 0.0001), whereas these parameters were
not clearly related in women (r = 0.27; P = 0.31).
Stepwise regression analysis models were tested with leptin as the
dependent variable and percent fat and maximal glucose uptake rate
(i.e. insulin sensitivity) as independent covariables. In
men, both percent fat (P < 0.0001) and maximal glucose
uptake rates entered the equation at a statistically significant level.
Therefore, insulin sensitivity was related to serum leptin independent
of percent body fat in men. In women, only the percent body fat was
correlated with leptin; maximal glucose uptake did not enter the
regression model at a statistically significant level.
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, an approximately 20% increase in leptin
concentrations was observed in women; mean leptin concentrations at
120, 150, and 180 min were all significantly greater than the basal
level at 0 min (P < 0.05). In contrast, leptin levels
were not affected (P = NS) during identical clamp
studies in men.
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. With respect to
fat distribution, leptin levels were highly correlated with upper body
obesity, as measured by the waist to hip ratio (r = 0.75;
P < 0.0001) and the waist to thigh ratio (r =
0.69; P = 0.0006) in men. In women, the correlation
between leptin and the waist to hip ratio was less strong (r =
0.45; P = 0.05) and was not statistically significant
compared with the waist to thigh ratio (r = -0.10;
P = 0.68).
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). In men, high leptin levels are associated with both
elevated fasting insulin and reduced insulin-mediated glucose uptake
values. Insulin resistance in syndrome X is also associated with elevated blood pressures (14). Consistent with the strong relationship between leptin and insulin resistance in men, it is not surprising that leptin levels were highly correlated with mean arterial, systolic, and diastolic blood pressures (P = 0.0001, P = 0.001, and P = 0.0007, respectively) in men, but not in women (P = NS). However, leptin was not correlated with other parameters that are altered in syndrome X. For example, there was no relationship between leptin and serum triglycerides, high density lipoprotein (HDL) cholesterol, or the triglyceride/HDL ratio in either men or women (P = NS).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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It is as yet unclear why there is a gender difference in circulating leptin levels for given measures of generalized obesity. One hypothesis that may explain the higher leptin levels in women involves the role of the sex hormones. It is well known that extremes of body weight are associated with abnormalities in sex hormones and hypothalamic function (25). Marked obesity in women can be associated with dysmenorrhea and infertility, and patients with polycystic ovarian syndrome are characterized by obesity, oligomenorrhea, elevated serum LH/FSH ratio, and hyperandrogenemia (27). On the other hand, patients with anorexia nervosa exhibit suppression of the hypothalamic-pituitary-gonadal axis (28) as well as low levels of serum leptin concentrations, consistent with a reduced amount of adipose tissue mass (Kennedy, A., T. Brewerton, and W. T. Garvey, unpublished data). In remission, these patients gain weight, leptin levels increase, and reproductive endocrine function normalizes. In the current study, we observed higher leptin levels in women over a range of body weight that includes individuals with ideal body weight and modest degrees of obesity. Therefore, it does not appear that abnormalities in sex hormones and hypothalamic function operative at extremes of body weight can explain gender-based differences in leptin. It is more likely that relative leptin resistance in women is due to a physiological effect of sex hormones to modulate leptin at the level of effector systems activated to control body weight. In any event, leptin resistance may provide a partial explanation of why women have a greater percent body fat than men. Predictably, leptin resistance may also make it more difficult for women to sustain diet-induced weight loss. Obviously, these are hypotheses that merit further study. It is important to consider that leptin resistance is a hypothesis based on evidence in rodents that leptin restrains eating behavior and body weight via effects on the hypothalamus. These physiological effects have not been proven in humans. Thus, high circulating leptin in the face of obesity should be considered an apparent state of leptin resistance pending rigorous confirmatory studies in humans.
The lipostatic hypothesis, first proposed by Kennedy in 1953 (29), predicted that the body monitors the amount of energy stored in fat and acts to prevent changes from an equilibrium set-point for stored fuel. This theory requires a circulating signal to allow the brain to measure the amount of energy stored in body fat. The adipocyte-derived protein, leptin, is an excellent candidate signal to satisfy this aspect of the hypothesis. However, the mechanism by which leptin regulates body fat has not been fully elucidated. After secretion from adipocytes, leptin appears to interact with specific receptors in the hypothalamus (6, 7, 8) and acts to decrease levels of neuropeptide Y (NYP) in the arcuate nucleus and the hypothalamic paraventricular nucleus (30). NPY is implicated in the regulation of energy homeostasis by stimulating food intake and lowering energy expenditure (31, 32). Suppression of NPY by leptin has been hypothesized to activate the sympathetic nervous system and increase energy expenditure via the ß3-adrenergic receptor (33, 34, 35) in adipose tissue. If this theory is correct, leptin levels would probably be correlated with energy expenditure rates. The relationship between leptin and energy expenditure has not been studied in humans. We measured the resting metabolic rate, which accounts for the major portion of overall energy expenditure (20, 36), and found no correlation between serum leptin levels and resting metabolic rate in either men or women. This does not exclude a potential influence of leptin on the thermic effect of food or the thermic effect of exercise, which were not measured in this study. However, we also demonstrated that leptin levels were not correlated with insulin-induced thermogenesis, a component of overall energy expenditure not reflected in the resting metabolic rate. The data inferentially suggest that leptin may regulate body weight in humans predominantly by affecting behavioral mechanisms and satiety, rather than calorigenesis.
We also studied the relationship between serum leptin and metabolic traits associated with syndrome X, including glucose tolerance, insulin sensitivity, and fat distribution. We found that overt diabetes did not alter the relationship between leptin and body weight in either men or women, and this is consistent with another recent study (37). Insulin sensitivity was assessed using the hyperinsulinemic clamp technique (37a). Leptin levels were negatively correlated with maximally stimulated glucose uptake rates in men. Thus, serum leptin levels are higher in insulin-resistant men, a finding noted recently (38). In contrast, leptin and maximal glucose uptake rates were not significantly correlated in women. This again highlights gender-based differences in the metabolic significance of leptin. In the male subjects, serum leptin correlated with the pattern of fat distribution, as measured by waist to hip and waist to thigh ratios, whereas these relationships were less pronounced in women. This may be explained by the influence of androgens on fat deposition. Higher androgen levels would consistently determine a pattern of upper body obesity in men, and the gynoid pattern would be more common in women. It is also well known that upper fat distribution is associated with relative insulin resistance (39). In interpreting our data, we favor the hypothesis that leptin regulates overall body fat content, which can then be directed by prevailing androgen levels to an upper body distribution. Relative insulin resistance as a function of truncal fat distribution would then explain its association with higher leptin concentrations in obese men. Body fat could accumulate with a lower or upper body distribution in women, and, therefore, insulin resistance (which is exacerbated only by upper body obesity) would less clearly be related to the hyperleptinemia of obesity. In this view, insulin resistance is not the direct consequence of hyperleptinemia but, rather, the by-product of accumulated truncal fat that occurs in the setting of progressive generalized obesity.
Serum leptin was also correlated with elevated blood pressures (diastolic, systolic, and mean arterial pressure) in men, but not in women. These observations can be explained by the facts that leptin is associated with insulin resistance only in men and that insulin resistance is associated with increased blood pressure (14). However, hyperleptinemia was not accompanied by all the characteristics of syndrome X (14). There was no significant correlation with dyslipidemia (triglycerides, HDL, or triglycerides/HDL ratio) in men or women. Also, the relationship between obesity and leptin levels was not affected by the presence of NIDDM. Dyslipidemia and diabetes are components of the ob/ob mouse phenotype and are reversed by exogenous leptin administration. Leptin also influences energy expenditure in mice (1, 4), whereas leptin was not correlated with metabolic rates in humans (resting metabolic rate, insulin-induced thermogenesis, and carbohydrate and lipid oxidation). These combined data indicate that the metabolic effects of leptin may be different in mice and men.
The hyperinsulinemic state induced during the clamp led to a
significant increase in serum leptin over the basal level in women.
This represents an additional gender difference in leptin regulation,
because no rise in serum leptin was observed during the 3-h clamp study
in men. Insulin-induced hyperleptinemia in women is the first example
of acute hormonal or metabolic regulation of leptin demonstrated in
humans. It remains possible that, had the hyperinsulinemic clamp been
extended for a longer duration, an increase in leptin may have become
manifest in men. Other studies (40, 41) have recently assessed the
effects of insulin on leptin. Kolacynski et al. (40)
reported that leptin levels do not increase acutely with insulin
stimulation; however, over an extended time period (i.e.
48 h), hyperinsulinemia led to an increase in circulating leptin
levels in both men and women. This study included a preponderance of
men over women (69 vs. 8), which could have masked an acute
ability of insulin to augment leptin in women but not men. Dagogo-Jack
et al. (41) concluded that insulin did not cause an acute
increase in leptin on the average; however, inspection of individual
curves shows an increase in 25–30% of the subjects. It was not
indicated which of these subjects may be male or female. Our data are
consistent with studies in mice and rats demonstrating that leptin mRNA
levels are positively regulated by hyperinsulinemia in adipose tissue
(42).
In our studies, we have assessed the metabolic significance of morning leptin concentrations. It is now clear that although daytime leptin levels are fairly constant, a large nocturnal rise in serum leptin is observed (43). Therefore, our conclusions pertain only to awake ambient leptin levels. The metabolic importance and influence of gender on the nocturnal leptin increment is unknown. If the nocturnal rise serves only to restrain eating impulses during sleep, then nighttime leptin levels may not have a large impact on the metabolic parameters assessed in our studies.
In summary, we have demonstrated a marked influence of gender on the leptin-obesity axis and regulation of serum leptin. Leptin levels increased 3 times more rapidly with progressive obesity in women, as measured by either BMI or percent body fat. Therefore, data suggest that higher levels of leptin are required in women to achieve similar biological end points. This suggests that there may be a difference in the biological homeostatic set-point for obesity in women. In men, leptin levels were highly correlated with measures of insulin resistance and upper body fat distribution, whereas these relationships were less pronounced in women. These latter observations are consistent with the hypothesis that leptin regulates overall body fat mass, which is directed to an upper body distribution by androgens; increasing truncal fat mass can then be more directly implicated in the reduced state of insulin sensitivity. An additional gender-based difference is that induced hyperinsulinemia during euglycemic clamp studies led to an increase in leptin concentrations in women, but not men. Leptin levels were not correlated with resting metabolic rates or insulin-induced thermogenesis in men or women, suggesting that leptin may predominantly regulate adiposity by affecting eating behavior rather than energy expenditure. Additional research is necessary to assess regulation of the leptin-hypothalamic axis by sex steroids and the role of relative leptin resistance in maintaining higher percent body fat in women. Obviously, gender will have to be taken into account when assessing pharmacological interventions using leptin-related drugs to treat human obesity.
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Acknowledgments |
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Footnotes |
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Received August 15, 1996.
Revised October 14, 1996.
Revised November 26, 1996.
Accepted December 5, 1996.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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 S. C. Woods, K. Gotoh, and D. J. Clegg Gender Differences in the Control of Energy Homeostasis Experimental Biology and Medicine, November 1, 2003; 228(10): 1175 - 1180. [Abstract] [Full Text] [PDF]
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C. Anderwald, G. Brabant, E. Bernroider, R. Horn, A. Brehm, W. Waldhausl, and M. Roden Insulin-Dependent Modulation of Plasma Ghrelin and Leptin Concentrations Is Less Pronounced in Type 2 Diabetic Patients Diabetes, July 1, 2003; 52(7): 1792 - 1798. [Abstract] [Full Text] [PDF]
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 G. Coatmellec-Taglioni, J.-P. Dausse, Y. Giudicelli, and C. Ribiere Sexual Dimorphism in Cafeteria Diet-Induced Hypertension Is Associated with Gender-Related Difference in Renal Leptin Receptor Down-Regulation J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 362 - 367. [Abstract] [Full Text]
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W. T. Garvey, S. Kwon, D. Zheng, S. Shaughnessy, P. Wallace, A. Hutto, K. Pugh, A. J. Jenkins, R. L. Klein, and Y. Liao Effects of Insulin Resistance and Type 2 Diabetes on Lipoprotein Subclass Particle Size and Concentration Determined by Nuclear Magnetic Resonance Diabetes, February 1, 2003; 52(2): 453 - 462. [Abstract] [Full Text] [PDF]
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S. M. Willi, A. Kennedy, P. Wallace, E. Ganaway, N. L. Rogers, and W. T. Garvey Troglitazone Antagonizes Metabolic Effects of Glucocorticoids in Humans: Effects on Glucose Tolerance, Insulin Sensitivity, Suppression of Free Fatty Acids, and Leptin Diabetes, October 1, 2002; 51(10): 2895 - 2902. [Abstract] [Full Text] [PDF]
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 R. M. Koivunen, L. C. Morin-Papunen, A. Ruokonen, J. S. Tapanainen, and H. K. Martikainen Ovarian steroidogenic response to human chorionic gonadotrophin in obese women with polycystic ovary syndrome: effect of metformin Hum. Reprod., December 1, 2001; 16(12): 2546 - 2551. [Abstract] [Full Text] [PDF]
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 C. G. Solomon and E. W. Seely Brief Review: Hypertension in Pregnancy : A Manifestation of the Insulin Resistance Syndrome? Hypertension, February 1, 2001; 37(2): 232 - 239. [Abstract] [Full Text] [PDF]
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D. R. Brown, D. E. Berkowitz, and M. J. Breslow Weight Loss Is Not Associated with Hyperleptinemia in Humans with Pancreatic Cancer J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 162 - 166. [Abstract] [Full Text]
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R. Lucantoni, E. Ponti, M. E. Berselli, G. Savia, A. Minocci, G. Calò, C. De Medici, A. Liuzzi, and A. M. Di Blasio The A19G Polymorphism in the 5' Untranslated Region of the Human Obese Gene Does Not Affect Leptin Levels in Severely Obese Patients J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3589 - 3591. [Abstract] [Full Text]
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S. Blanc, S. Normand, C. Pachiaudi, M. Duvareille, and C. Gharib Leptin responses to physical inactivity induced by simulated weightlessness Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2000; 279(3): R891 - R898. [Abstract] [Full Text] [PDF]
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 P. Stenvinkel Leptin and blood pressure--is there a link? Nephrol. Dial. Transplant., August 1, 2000; 15(8): 1115 - 1117. [Full Text] [PDF]
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C. Chin-Chance, K. S. Polonsky, and D. A. Schoeller Twenty-Four-Hour Leptin Levels Respond to Cumulative Short-Term Energy Imbalance and Predict Subsequent Intake J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2685 - 2691. [Abstract] [Full Text]
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M. Maccario, G. Aimaretti, G. Corneli, C. Gauna, S. Grottoli, M. Bidlingmaier, C. J. Strasburger, C. Dieguez, F. F. Casanueva, and E. Ghigo Short-term fasting abolishes the sex-related difference in GH and leptin secretion in humans Am J Physiol Endocrinol Metab, August 1, 2000; 279(2): E411 - E416. [Abstract] [Full Text] [PDF]
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M. B. HORLICK, M. ROSENBAUM, M. NICOLSON, L. S. LEVINE, B. FEDUN, J. WANG, R. N. PIERSON Jr., and R. L. LEIBEL Effect of Puberty on the Relationship between Circulating Leptin and Body Composition J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2509 - 2518. [Abstract] [Full Text]
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J. R Gingras, V. Harber, C. J Field, and L. J McCargar Metabolic assessment of female chronic dieters with either normal or low resting energy expenditures Am. J. Clinical Nutrition, June 1, 2000; 71(6): 1413 - 1420. [Abstract] [Full Text] [PDF]
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A. Polito, A. Fabbri, A. Ferro-Luzzi, M. Cuzzolaro, L. Censi, D. Ciarapica, E. Fabbrini, and D. Giannini Basal metabolic rate in anorexia nervosa: relation to body composition and leptin concentrations Am. J. Clinical Nutrition, June 1, 2000; 71(6): 1495 - 1502. [Abstract] [Full Text] [PDF]
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L. Rossetti Perspective: Hexosamines and Nutrient Sensing Endocrinology, June 1, 2000; 141(6): 1922 - 1925. [Full Text] [PDF]
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A. M. Isidori, F. Strollo, M. Morè, M. Caprio, A. Aversa, C. Moretti, G. Frajese, G. Riondino, and A. Fabbri Leptin and Aging: Correlation with Endocrine Changes in Male and Female Healthy Adult Populations of Different Body Weights J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 1954 - 1962. [Abstract] [Full Text]
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 C Berry and A.L Clark Catabolism in chronic heart failure Eur. Heart J., April 1, 2000; 21(7): 521 - 532. [PDF]
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 M. S. Buchowski, L. A. Simmons, K. Y. Chen, P. J. Flakoll, B. G. Mellen, and E. A. Turner Plasma Leptin Association with Body Composition and Energy Expenditure in Sickle Cell Disease J. Am. Coll. Nutr., April 1, 2000; 19(2): 228 - 236. [Abstract] [Full Text] [PDF]
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S. Klein, J. F. Horowitz, M. Landt, S. J. Goodrick, V. Mohamed-Ali, and S. W. Coppack Leptin production during early starvation in lean and obese women Am J Physiol Endocrinol Metab, February 1, 2000; 278(2): E280 - E284. [Abstract] [Full Text] [PDF]
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J. S. Fisher, R. C. Hickner, S. B. Racette, E. F. Binder, M. Landt, and W. M. Kohrt Leptin Response to Insulin in Humans Is Related to the Lipolytic State of Abdominal Subcutaneous Fat J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3726 - 3731. [Abstract] [Full Text] [PDF]
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T. L. Bützow, J. M. Moilanen, M. Lehtovirta, T. Tuomi, O. Hovatta, R. Siegberg, C.-G. Nilsson, and D. Apter Serum and Follicular Fluid Leptin during in Vitro Fertilization: Relationship among Leptin Increase, Body Fat Mass, and Reduced Ovarian Response J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3135 - 3139. [Abstract] [Full Text]
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M. Rosenbaum and R. L. Leibel Role of Gonadal Steroids in the Sexual Dimorphisms in Body Composition and Circulating Concentrations of Leptin J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 1784 - 1789. [Full Text]
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M. A. Pelleymounter, M. B. Baker, and M. McCaleb Does estradiol mediate leptin's effects on adiposity and body weight? Am J Physiol Endocrinol Metab, May 1, 1999; 276(5): E955 - E963. [Abstract] [Full Text] [PDF]
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G. L. Carlson, M. Saeed, R. A. Little, and M. H. Irving Serum leptin concentrations and their relation to metabolic abnormalities in human sepsis Am J Physiol Endocrinol Metab, April 1, 1999; 276(4): E658 - E662. [Abstract] [Full Text] [PDF]
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B. Gutin, L. Ramsey, P. Barbeau, W. Cannady, M. Ferguson, M. Litaker, and S. Owens Plasma leptin concentrations in obese children: changes during 4-mo periods with and without physical training Am. J. Clinical Nutrition, March 1, 1999; 69(3): 388 - 394. [Abstract] [Full Text] [PDF]
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R. B. S. Harris Parabiosis between db/db and ob/ob or db/+ Mice Endocrinology, January 1, 1999; 140(1): 138 - 145. [Abstract] [Full Text]
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J. Licinio, A. B. Negrão, C. Mantzoros, V. Kaklamani, M.-L. Wong, P. B. Bongiorno, P. P. Negro, A. Mulla, J. D. Veldhuis, L. Cearnal, et al. Sex Differences in Circulating Human Leptin Pulse Amplitude: Clinical Implications J. Clin. Endocrinol. Metab., November 1, 1998; 83(11): 4140 - 4147. [Abstract] [Full Text]
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M. Miyakawa, T. Tsushima, H. Murakami, O. Isozaki, H. Demura, and T. Tanaka Effect of Growth Hormone (GH) on Serum Concentrations of Leptin: Study in Patients with Acromegaly and GH Deficiency J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3476 - 3479. [Abstract] [Full Text]
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W. W. Wong, M. Nicolson, J. E. Stuff, N. F. Butte, K. J. Ellis, A. C. Hergenroeder, R. B. Hill, and E. O. Smith Serum Leptin Concentrations in Caucasian and African-American Girls J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3574 - 3577. [Abstract] [Full Text]
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V. Luukkaa, U. Pesonen, I. Huhtaniemi, A. Lehtonen, R. Tilvis, J. Tuomilehto, M. Koulu, and R. Huupponen Inverse Correlation between Serum Testosterone and Leptin in Men J. Clin. Endocrinol. Metab., September 1, 1998; 83(9): 3243 - 3246. [Abstract] [Full Text]
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G. Paolisso, M. R. Rizzo, G. Mazziotti, M. R. Tagliamonte, A. Gambardella, M. Rotondi, C. Carella, D. Giugliano, M. Varricchio, and F. D'Onofrio Advancing age and insulin resistance: role of plasma tumor necrosis factor-alpha Am J Physiol Endocrinol Metab, August 1, 1998; 275(2): E294 - E299. [Abstract] [Full Text] [PDF]
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L. C. Morin-Papunen, R. M. Koivunen, C. Tomás, A. Ruokonen, and H. K. Martikainen Decreased Serum Leptin Concentrations during Metformin Therapy in Obese Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2566 - 2568. [Abstract] [Full Text]
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M. A. Llopis, M. L. Granada, G. Cuatrecasas, X. Formiguera, L. Sánchez-Planell, A. SanmartÍ, A. Alastrué, M. Rull, A. Corominas, and M. Foz Growth Hormone-Binding Protein Directly Depends on Serum Leptin Levels in Adults with Different Nutritional Status J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 2006 - 2011. [Abstract] [Full Text]
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J. G. Langendonk, H. Pijl, A. C. Toornvliet, J. Burggraaf, M. Frölich, R. C. Schoemaker, J. Doornbos, A. F. Cohen, and A. E. Meinders Circadian Rhythm of Plasma Leptin Levels in Upper and Lower Body Obese Women: Influence of Body Fat Distribution and Weight Loss J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1706 - 1712. [Abstract] [Full Text]
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 M. Landt, R. L. Gingerich, P. J. Havel, W. M. Mueller, B. Schoner, J. E. Hale, and M. L. Heiman Radioimmunoassay of rat leptin: sexual dimorphism reversed from humans Clin. Chem., March 1, 1998; 44(3): 565 - 570. [Abstract] [Full Text] [PDF]
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 S. M. Willi, M. J. Oexmann, N. M. Wright, N. A. Collop, and L. L. Key Jr The Effects of a High-protein, Low-fat, Ketogenic Diet on Adolescents With Morbid Obesity: Body Composition, Blood Chemistries, and Sleep Abnormalities Pediatrics, January 1, 1998; 101(1): 61 - 67. [Abstract] [Full Text] [PDF]
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T. R. Nagy, B. A. Gower, R. M. Shewchuk, and M. I. Goran Serum Leptin and Energy Expenditure in Children J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 4149 - 4153. [Abstract] [Full Text] [PDF]
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M. Rosenbaum, M. Nicolson, J. Hirsch, E. Murphy, F. Chu, and R. L. Leibel Effects of Weight Change on Plasma Leptin Concentrations and Energy Expenditure J. Clin. Endocrinol. Metab., November 1, 1997; 82(11): 3647 - 3654. [Abstract] [Full Text] [PDF]
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