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Body Fat Mass and Macronutrient Intake in Relation to Circulating Soluble Leptin Receptor, Free Leptin Index, Adiponectin, and Resistin Concentrations in Healthy Humans

Department of Nutrition-Dietetics (M.Y., A.-L.M.) and Department of Home Economics and Ecology (N.Y.), Harokopio University, 17671 Athens, Greece; Division of Endocrinology (S.B., C.S.M.), Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215; and Department of Food Science and Human Nutrition (D.K.-Z.), University of Maine, Orono, Maine 04469

Address all correspondence and requests for reprints to: Christos S. Mantzoros, M.D., Division of Endocrinology, RN 325, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts 02215. E-mail: cmantzor{at}caregroup.harvard.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The adipocyte-derived hormones leptin [which circulates in a free form and bound to a soluble leptin receptor (sOB-R)], adiponectin, and resistin play a key role in regulating energy homeostasis and metabolism. We assessed the association between body composition, total energy, and macronutrient intake and serum leptin, sOB-R, free leptin index, adiponectin, and resistin concentrations in 61 female and 53 male consecutively enrolled healthy Greek students. In this cross-sectional study, total energy and macronutrient intake were determined using 3-d food records. Body composition was assessed by bioelectrical impedance analysis; fasting blood samples were taken for the measurement of total leptin, sOB-R, adiponectin, and resistin; and the ratio leptin/sOB-R was used as an index of free leptin. Serum sOB-R concentrations were lower in the female subjects compared with the males (27.24 ± 29.06 vs. 50.14 ± 39.74 ng/ml, P < 0.001), whereas leptin, adiponectin, and resistin concentrations were significantly higher in females (leptin: 9.93 ± 6.01 vs. 3.27 ± 2.54 ng/ml, P < 0.001; adiponectin: 11.40 ± 6.73 µg/ml vs. 4.90 ± 2.79 µg/ml; P < 0.001; resistin: 16.86 ± 5.39 ng/ml in females vs. 14.00 ± 7.16 ng/ml in males, P < 0.02). Simple regression analysis showed that, in both genders, leptin, free leptin index, adiponectin, and resistin correlated positively with body fat mass and negatively with waist to hip ratio. sOB-R correlated negatively with body fat mass and positively with waist to hip ratio. Multiple regression analysis models controlling for gender, body fat, and total energy intake demonstrated that sOB-R is positively associated with energy intake from carbohydrates and negatively with energy intake from dietary fat, whereas free leptin index is negatively associated with energy intake from carbohydrates and positively with energy intake from dietary fat. No statistically significant correlations were observed between serum adiponectin or resistin concentrations and total energy or macronutrient intake. Thus, total energy intake and macronutrient composition of the diet are associated with sOB-R and free leptin index but do not play a role of comparable significance in predicting adiponectin and resistin concentrations in healthy young subjects.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
LEPTIN IS AN adipocyte-derived hormone that acts to reduce food intake and increase energy expenditure by binding and activating its specific receptor in the hypothalamus (1, 2, 3). Although in the fed state circulating concentrations of leptin reflect the amount of energy stored in fat and correlate positively with indices of adiposity, individuals with similar degrees of adiposity exhibit great variations in serum leptin concentrations. Hormonal and nutritional factors as well as the recently identified specific soluble leptin receptor, sOB-R (4, 5, 6), have been proposed to influence total as well as free leptin concentrations in humans (1, 2). Adiponectin is another recently identified adipocyte-derived hormone (7), the serum levels of which are decreased in obese and insulin-resistant humans (8), and nonhuman primates (9). Recent studies have suggested that adiponectin plays an important role in the regulation of insulin resistance, glucose, and lipid homeostasis (10). Adiponectin knockout mice are insulin resistant and glucose intolerant (11), and adiponectin administration to lipoatrophic insulin-resistant mice corrects in part their insulin resistance, whereas administration of both leptin and adiponectin fully normalizes it (12). Resistin, another almost exclusively white adipose tissue-expressed polypeptide, has also been linked to energy homeostasis, diet-induced obesity, and insulin resistance (13, 14), but available data are controversial. Circulating resistin levels are elevated in ob/ob-, db/db-, and diet-induced obese mice (13), although another study reported decreased resistin mRNA levels in white adipose tissue of different mouse models of obesity (15). Reduced adipocyte-expression of resistin is accompanied by increased insulin sensitivity in a mouse model of insulin resistance, and acute administration of recombinant resistin to normal mice leads to impaired glucose tolerance (16).

Although total energy and macronutrient intake have been associated with both obesity and insulin resistance, no previous studies have assessed total energy and macronutrient intake in relation to sOB-R, free leptin as well as circulating adiponectin and resistin concentrations in humans. In addition, the association between adiponectin and body fat mass or fat distribution has not yet been fully elucidated, whereas the association between resistin and body fat mass or distribution has not been evaluated in humans. The aim of the present study was to explore whether body fat mass, fat distribution, and dietary variables are associated with circulating total leptin, sOB-R, and free leptin index as well as serum adiponectin and resistin concentrations in a group of healthy young Greek subjects, after adjusting for potential confounding factors.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study included 120 consecutively enrolled healthy Greek students. The study protocol was approved by the Ethics Committee of Harokopio University and the laboratory work by the Institutional Review Board of the Beth Israel Deaconess Medical Center. After being informed on the purpose and procedures of the study, all subjects and their parents signed an informed consent form. Their mean age was 17.7 ± 1.8 yr (range, 14–26 yr). Fasting blood samples were taken, and serum was immediately frozen in -70 C until coded samples were shipped, packed in dry ice, for analyte determination in Boston. Anthropometric and body composition measurements were performed in all study participants by one investigator. Participants were also asked to complete specific self-administered demographic questionnaires as well as 3-d food records. Blood samples were not obtained from two students, and six of them did not return their food records. Thus, the final multivariate analysis is based on data obtained from 114 subjects.

Dietary intake

Dietary intake was assessed using 3-d food records. Subjects were asked to record the type and amount of food and beverage consumed for two consecutive weekdays and one weekend day, using standard household measures (cups, tablespoons, etc.). Trained interviewers reviewed the records along with the subject to clarify servings, recipes, and forgotten foods. Food intake data, obtained from 61 female and 53 male subjects, were analyzed and energy and nutrient intake calculated using the Nutritionist V Diet Analysis software (FirstDataBank Inc., San Bruno, CA) as modified for the Greek population (17).

Anthropometry and body composition

Anthropometric and body composition measurements were performed in the morning, before breakfast, with the subject wearing light clothing, without shoes. Body weight and height were measured by the same observer using a scale and a wall-mounted stadiometer to the nearest 0.5 kg and 0.5 cm, respectively. Waist and hip circumferences were measured, and the waist to hip ratio (WHR), which provides valuable information about the distribution of body fat, was calculated as the ratio of waist and hip circumferences. Standard procedures were followed (18), and the average of the two measurements was taken. Body composition was assessed by bioelectrical impedance analysis, using a single frequency bio-impedance analyzer (Model 101, RJL Systems, Mt. Clemens, MI), as previously described by Lukaski et al. (19), with the subject lying in a supine position.

Leptin, soluble leptin receptor, adiponectin, and resistin measurements

Serum total leptin (ng/ml) and adiponectin concentrations (µg/ml) were evaluated in one run using a commercially available RIA (Linco Research, Inc., St. Louis, MO). The sensitivity of the kits was 0.5 ng/ml for leptin and 1.0 ng/ml for adiponectin, respectively. The interassay coefficients are 7.9% for leptin and 8.5% for adiponectin, and the intra-assay coefficients are 7.2% for leptin and 3.9% for adiponectin, respectively. sOB-R concentrations (ng/ml) as well as resistin concentrations (ng/ml) were evaluated using a commercially available ELISA (BioVendor Laboratory Medicine, Inc., Brno, Czech Republic), the sensitivities of which were 0.8 ng/ml and 0.2 ng/ml, respectively. The interassay coefficients are 3.7% for sOB-R and 6.7% for resistin, and the intra-assay coefficients are 5.0% for sOB-R and 4.3% for resistin. The characteristics of the assay for sOB-R have been evaluated extensively and have been compared with those obtained using a newly developed ligand-immunofunctional assay (20, 21).

Statistical analyses

Descriptive statistics are presented as mean values ± SD. Differences between males and females were analyzed using parametric (t test) and nonparametric tests. Spearman correlation coefficients were calculated using untransformed variables. In addition, we examined the potential role of either total energy intake or energy from specific macronutrients on serum analyte concentrations in micrograms/milliliter or nanograms/milliliter, as appropriate, using bivariate and multivariate models. Outcome variables that were not normally distributed (leptin, sOB-R, leptin/sOB-R, adiponectin) were log transformed before regression analyses to normalize their distribution. Total energy intake is associated with intake of nutrients that contribute directly to energy intake and may also be associated with hormone concentrations as well as other potentially confounding variables, such as body size, physical activity, etc. (22). Because associations between macronutrient intake and energy intake or body composition on one hand, as well as between leptin status and body fatness on the other, can introduce confounding and might influence results of bivariate models, multivariate linear regression analysis models were also built. In the first multivariate model, outcome variables were regressed on caloric intake from macronutrients after adjustment for gender and body fat mass, as indicated (see Table 3). In the other multivariate regression analysis models, outcome variables were regressed on 1) total energy intake only; or 2) gender, body fat mass, and total energy intake (see Table 4). Thus, we have used standard multivariate energy partition and nutrient density models as previously described (23). Although these models may be considered as formulations of the same model, each one provides a different perspective of the data, and use of both can lead to a better insight of the relation between diet and serum hormone concentrations. More specifically, in energy partition models, the coefficients for the specific macronutrients represent the full effect of the specific nutrient, unconfounded by other sources of energy, whereas in the multivariate nutrient density model the coefficient for the nutrient density term represents the relation of the nutrient composition of the diet with the outcome of interest, i.e. hormone levels, holding total energy intake constant. The multivariate nutrient density model is an isocaloric analysis controlling for confounding by total energy intake, where an increase in the intake of a nutrient would correspond to reduced intake of other nutrient(s), i.e. substitution. In contrast, the energy partition model implies that more of a nutrient could simply be added to the diet, keeping the other nutrients constant, and, thus, is not a truly isocaloric comparison. All analyses were performed using the SPSS statistical package (SPSS, Inc. for Windows, release 5.0.1). P values presented in this paper are two tailed.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

Bivariate correlation analyses were performed to assess relationships between serum adiponectin, resistin, leptin, or sOB-R concentrations and body composition or dietary intake parameters. Spearman’s correlation coefficients are presented in Table 2. Leptin was found to correlate positively and significantly with the total amount of body fat (r = 0.68, P < 0.001). sOB-R and leptin correlated significantly with the amount of energy intake (sOB-R: r = 0.23, P = 0.01; leptin: r = -0.45, P < 0.001), but not with macronutrient intake, expressed as a percentage of total energy intake. Similar to leptin, the ratio leptin/sOB-R, used as an index of free leptin, correlated positively and strongly with the total amount of body fat mass: r = 0.53, P < 0.001), but negatively with total energy intake (r = -0.41, P < 0.001). A negative correlation was detected between sOB-R concentration and the percentage of dietary fat (r = -0.19, P = 0.03).

The findings from the above bivariate correlation analyses were further explored using multivariate analyses, to control for successively introduced potential confounders. Results are presented in Tables 3 and 4. Table 3 shows standardized regression coefficients (ß) of logarithmically transformed leptin, adiponectin, sOB-R, and the ratio leptin/sOB-R as well as untransformed resistin, regressed on total energy intake as well as on the energy intake provided by each macronutrient (in kilocalories). Bivariate analysis revealed statistically significant associations between leptin and dietary variables. These correlations became nonsignificant after adjustment for gender, body fat mass, and caloric intake from sources other than the variables of interest. Similar analysis using sOB-R as a dependent variable revealed that, after controlling for gender, body fat mass, and caloric intake from sources other than the variables of interest, energy provided by carbohydrates was positively related to sOB-R (ß = 0.39, P < 0.01). Additionally, the ratio leptin/sOB-R was negatively related to the energy provided by carbohydrates (ß = -0.42, P < 0.001), whereas a marginally significant positive association was detectable with energy provided by proteins. These data indicate that an increase of 400 kcal in the mean carbohydrate energy intake, while keeping the other nutrients constant, corresponds to an increase of the log sOB-R concentration by 0.32 and to a decrease of the log ratio leptin/sOB-R by 0.73 (controlling for gender, body fat mass, and caloric intake from sources other than the variable of interest). Finally, although serum adiponectin tended to be related to the total amount of energy derived from protein by bivariate analysis, no significant associations were detected after adjusting for potential confounders including gender, body fat mass, and caloric intake from sources other than the variable of interest.

Similar results were obtained using a multivariate nutrient density model (Table 4). The percentage of energy intake derived from carbohydrates shows a positive association with sOB-R (ß = 0.24, P < 0.01) and a negative one with the ratio leptin/sOB-R (ß = -0.24, P < 0.01), after controlling for gender, body fat mass, and total energy intake. In other words, increasing the percentage of energy intake provided by carbohydrates by 10% results in an increase of log sOB-R concentration by 0.37 and a decrease of the log ratio leptin/sOB-R by 0.74. Opposite results were obtained for the percentage of energy intake derived from dietary fat. When total energy intake is kept constant, a relative increase in the percentage of energy intake provided by dietary fat by 10% (i.e. a parallel decrease of calories provided by carbohydrates and protein) corresponds to a decrease of log sOB-R concentration by 0.39 and to an increase of the log ratio leptin/sOB-R by 0.72 (controlling for gender, body fat mass, and total energy intake).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Serum leptin concentrations reflect closely the amount of fat stored in adipose tissue, and leptin plays an important role in energy homeostasis and metabolism by acting either directly on specific target tissues or indirectly through leptin-induced alterations of neuroendocrine function (1, 2). Adiponectin and resistin are another two recently identified adipokines that have also been suggested to play a role in regulating energy homeostasis and insulin resistance (7, 8, 9, 10, 11, 12, 13, 14, 15, 16). Although the effect of dietary factors on total leptin concentrations and the influence of acute and chronic caloric excess or deficiency have been extensively investigated, no previous studies have focused on the role of diet in predicting circulating sOB-R, free leptin, or serum adiponectin and resistin concentrations in healthy humans (24, 25, 26, 27, 28, 29). In addition, the role of body fat mass and distribution in determining serum adiponectin concentrations has not been fully elucidated, whereas their role in predicting resistin concentrations has not yet been studied in humans. Given the role fat mass and distribution as well as total energy and macronutrient intake play in both obesity and insulin resistance, the identification of body composition and dietary factors that could be associated with circulating adiponectin, resistin, and bioactive serum leptin concentrations could be of clinical importance.

Circulating leptin rises by 40% after acute overfeeding and more than 3-fold after chronic overfeeding (28), whereas fasting is associated with significantly decreased leptin concentrations (29, 30). However, whether specific macronutrients alter serum leptin concentrations independently of energy intake remains largely unknown since previous studies have revealed conflicting results. Thus, although habitual carbohydrate intake (26) and a high glycemic index diet have been reported to decrease leptin concentrations (25, 31, 32), glucose infusion or isoenergetic or ad libitum overfeeding of carbohydrates or sucrose has been shown to result in a significant increase of leptin concentrations and/or to prevent a fasting-induced fall in leptin (33, 34, 35). Studies on the association of fat intake with total leptin concentrations have largely revealed conflicting results that range from positive over zero to negative. More specifically, although a Western dietary pattern (27) and high-fat diet have been positively associated with plasma leptin concentrations in women (36) and men (37), negative associations have been shown in other studies in women (26, 38), whereas leptin concentrations were reported not to be altered in response to high- or low-fat diets (36, 39), or reduced dietary fat content (from 37% to 10% of total calories) for several weeks (40).

The above conflicting data may reflect variations in the study design and experimental conditions, but more importantly they may reflect the lack of adjustment for potential confounding factors, i.e. gender, total energy intake, and body mass. In addition, all previous observational studies have used Food Frequency Questionnaires, which assess habitual food intake over prolonged periods of time and not short-term diet recalls, which could provide much more meaningful information regarding short-term hormonal regulation. Finally, observational or interventional studies mentioned above have measured only total leptin concentrations without having considered sOB-R and/or free leptin levels.

Bound leptin and leptin binding capacity has been found recently to vary physiologically in relation to increasing adiposity (41), with free leptin reflecting accurately the body fat mass (42, 43). In this study, we confirmed these findings, and we assessed the effect of gender, body fat mass, and food intake, as estimated by a 3-d food record, not only on total leptin, but also on sOB-R and free leptin index as well as on circulating adiponectin and resistin levels. The novel finding of this study is the significant association of total energy intake and macronutrient intake with free leptin index and sOB-R concentrations, whereas no significant associations could be detected with adiponectin and resistin concentrations. Free leptin, as expressed by the ratio leptin/sOB-R, was weakly, but significantly and negatively associated with the energy intake provided by carbohydrates (expressed either as absolute caloric intake or as a percentage of total energy intake), and weakly positively associated with fat intake. These results indicate that in free-living, healthy young subjects, the macronutrient composition of the diet may have a significant influence on the serum concentrations of free leptin, the presumed biologically important form of leptin. However, other, dietary or nondietary, factors may also determine leptin concentrations in the steady state as previously proposed (1, 25).

Another finding of this study is that total leptin as well as adiponectin and resistin concentrations in the fasting state were higher in women compared with men, whereas soluble leptin receptor concentrations were 2-fold higher in men. Our results are in accordance with a recent study reporting that free leptin serum concentrations are higher in women than in men, as well as in obese compared with lean individuals (44). We also report for the first time that there is a negative correlation between sOB-R and the amount of body fat and a positive one between sOB-R and the WHR.

In contrast to leptin, limited data are available regarding the regulation of serum adiponectin levels, and none regarding the regulation of serum resistin in humans. Serum adiponectin levels have been reported to rise in response to chronic caloric restriction in rodents (10), and injections of the globular head region of adiponectin (gACRP30, the highly active proteolytic cleavage product) to mice resulted in a reduction of body weight independently of food intake (45). In humans, adiponectin concentrations are not affected by intake of meals in type II diabetics (46). Our study indicates that neither total caloric intake nor the macronutrient composition of the diet have any substantial effect on serum adiponectin or resistin concentrations in young healthy subjects. However, serum adiponectin and resistin concentrations are negatively associated with WHR. These associations are in accordance with the proposed role of these hormones as mediators of insulin resistance, although it should be noted that the role of circulating resistin in regulating insulin resistance has not yet been fully clarified. Further interventional and observational studies controlling for potential confounding factors and focusing on the role of these hormones in mediating the effect of body fat distribution on insulin resistance are warranted. Finally, we report for the first time that, similar to leptin, females have higher serum adiponectin and resistin concentrations than males, even after adjustment for body fat mass. It remains to be elucidated whether, similar to leptin, the sexual dimorphism of body fat distribution or differences in sex steroids are responsible for the observed differences in adiponectin and resistin levels.

Among the strengths of the current study is the use of state of the art methodology including food records for evaluating the subjects’ dietary intake. Three-day food records provide quantitatively accurate information on food consumed during the recording period: by recording food while it is consumed, the problem of reporting bias or omission is lessened, whereas subjects are not restricted to selecting from a predetermined list of foods included in food frequency questionnaires (22, 47). Recent data indicate that there is a significant diurnal and seasonal variation in leptin concentrations (48). We have controlled for potential bias by using fasting blood samples, by performing the study over a short time period and by adjusting for potential confounders in the analysis. In addition, the focus on a group of healthy young controls offers the advantage of minimizing the potential effect of age, disease, and/or related treatments. Although confounding was appropriately controlled for through standard statistical procedures, residual confounding by other serum hormones or unmeasured factors remains a possibility that should be tested by future studies. Differential misclassification is unlikely, given the blinded laboratory analysis, but potential consequences of random misclassification due to random laboratory error or the diurnal rhythms of leptin concentrations are possible. Such error would be expected to bias results toward null, however, and alter the P values toward nonsignificant values. Thus, if anything, random misclassification might have led to underestimation of the associations observed in this study. Confirmation of our results by future studies and assessment of the potential more prolonged effects of diet on adipokines is warranted.

Finally, we acknowledge that observational studies cannot elucidate mechanisms or determine the direction of causality. This study raises, however, the hypothesis that body composition regulates circulating levels of all three adipokines studied herein and that dietary carbohydrates and dietary fat regulate the biologically active free leptin concentrations, a finding with possible clinical implications. Further interventional studies are needed to confirm these findings, to explore whether these hormones mediate the effect of body fat distribution on insulin resistance and cardiovascular risk factors, to assess the direction of causality, and to more precisely quantify these effects after controlling for potential confounders.

	Acknowledgments

 
We thank Mrs. Constantina Papoutsakis-Tsarouhas for her assistance in processing and analyzing food records.

	Footnotes

 
This project was supported in part by Grant KA-0008 from Harokopio University and an R01-DK-58785 award (to C.S.M.).

Abbreviations: sOB-R, Soluble leptin receptor; WHR, waist to hip ratio.

Received October 16, 2002.

Accepted January 15, 2003.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Mantzoros CS 1999 The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med 130:671–680[Abstract/Free Full Text]
2. Friedman JM, Halaas JL 1998 Leptin and the regulation of body weight in mammals. Nature 395:763–769[CrossRef][Medline]
3. Woods AJ, Stock MJ 1996 Leptin activation in hypothalamus. Nature 381:745[Medline]
4. Sinha MK, Opentanova I, Ohannesian JP Kolaczynski JW, Heiman ML, Hale J, Becker GW, Bowsher RR, Stephens TW, Caro JF 1996 Evidence of free and bound leptin in human circulation: studies in lean and obese subjects and during short-term fasting. J Clin Invest 98:1277–1282[Medline]
5. Houseknecht KL, Mantzoros CS, Kuliawat R, Hadro E, Flier JS, Kahn BB 1996 Evidence for leptin binding to proteins in serum of rodents and humans: modulation with obesity. Diabetes 45:1638–1643[Abstract]
6. Diamond FB, Eichler DC, Duckett G, Jorgensen EV, Shulman D, Root AW 1997 Demonstration of a leptin binding factor in human serum. Biochem Biophys Res Commun 233:818–822[CrossRef][Medline]
7. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF 1995 A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746–26749[Abstract/Free Full Text]
8. Weyer C, Funahashi T, Tanaka S Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA 2001 Hypoadiponectiemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935[Abstract/Free Full Text]
9. Hotta K, Funahashi T, Bodkin NL Ortmeyer HK, Arita Y, Hansen BC, Matsuzawa Y 2001 Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50:1126–1133[Abstract/Free Full Text]
10. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE 2001 The adipocyte-secreted protein ACRP30 enhances hepatic insulin action. Nat Med 7:947–953[CrossRef][Medline]
11. Kubota N, Terauchi Y, Yamauchi T Kubota T, Moroi M, Matsui M, Eto K, Yamashita T, Kamon J, Satoh H, Yano W, Froguel P, Nagai R, Kimura S, Kadowaki T, Noda T 2002 Disruption of adiponetin causes insulin resistance and neointimal formation. J Biol Chem 277:25863–25866[Abstract/Free Full Text]
12. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T 2001 The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946[CrossRef][Medline]
13. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banernee RR, Wright CM, Patel HR, Ahima RS, Lazar MA 2001 The hormone resistin links obesity to diabetes. Nature 409: 307–312
14. Kim KH, Lee K, Moon YS, Sul HS 2001 A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J Biol Chem 276:11252–11256[Abstract/Free Full Text]
15. Way JM, Gorgun CZ, Tong Q, Uysal KT, Brown KK, Harrington WW, Oliver Jr WR, Willson TM, Kliewer SA, Hotamisligil GS 2001 Adipose tissue resisitin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor agonists. J Biol Chem 276:25651–25653[Abstract/Free Full Text]
16. Yamauchi T, Waki H, Kamon J, Murakami K, Motojima K, Komeda K, Miki H, Kubota N, Terauchi Y, Tsuchida A, Tsuboyama-Kasaoka N, Yamauchi N, Ide T, Hori W, Kato S, Fukayama M, Akanuma Y, Ezaki O, Itai A, Nagai R, Kimura S, Tobe K, Kagechika H, Shudo K, Kadowaki T 2001 Inhibition of RXR and PPAR ameliorates diet-induced obesity and type 2 diabetes. J Clin Invest 108:1001–1013[CrossRef][Medline]
17. Kafatos A, Verhagen H, Moschandreas J, Apostolaki I, van Westerop J 2000 Mediterranean diet of Crete: foods and nutrient content. J Am Diet Assoc 100:1487–1493[CrossRef][Medline]
18. World Health Organization (WHO) 1988 Measuring obesity—classification and description of anthropometric data. Copenhagen: WHO (EUR/ICP/NUT 125)
19. Lukaski HC, Johnson PE, Bolonchuk WW, Lykken GI 1985 Assessment of fat-free mass using bioelectrical impedance measurements of the human body. Am J Clin Nutr 41:810–817[Abstract/Free Full Text]
20. Chan JL, Blüher S, Yiannakouris N, Suchard MA, Kratzsch J, Mantzoros CS 2002 regulation of circulating soluble leptin receptor levels by gender, adiposity, sex steroids, and leptin: observational and interventional studies in humans. Diabetes 51:2105–2112[Abstract/Free Full Text]
21. Lammert A, Kiess W, Bottner A, Glasow A, Kratzsch J 2001 Soluble leptin receptor represents the main leptin binding activity in human blood. Biochem Biophys Res Commun 283:982–988[CrossRef][Medline]
22. Willett W, Stampfer M 1998 Implications of total energy intake for epidemiologic analysis. In: Willet W, ed. Nutritional epidemiology. 2nd ed. New York: Oxford University Press; 273
23. Kaklamani VG, Linos A, Kaklamani E, Markaki I, Koumantaki Y, Mantzoros CS 1999 Dietary fat and carbohydrates are independently associated with circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 concentrations in healthy adults. J Clin Oncol 10:3291–3298
24. Baile CA, Della-Fera MA 2000 Regulation of metabolism and body fat mass by leptin. Annu Rev Nutr 20:105–127[CrossRef][Medline]
25. Mantzoros CS and Moschos SJ 1998 Leptin: in search of role(s) in human physiology and pathophysiology. Clin Endocrinol 49:551–567[CrossRef][Medline]
26. Larsson H, Elmståhl S, Berglund G, Ahrén B 1998 Evidence of leptin regulation of food intake in humans. J Clin Endocrinol Metab 83:4382–4385[Abstract/Free Full Text]
27. Fung TT, Rimm EB, Spiegelman D Rifai N, Tofler GH, Willett WC, Hu FB 2001 Association between dietary patterns and serum biomarkers of obesity and cardiovascular disease risk. Am J Clin Nutr 73:61–67[Abstract/Free Full Text]
28. Kolaczynski JW, Ohannesian JP, Considine RV, Marco CC, Caro JF 1996 Response of leptin to short-term and prolonged overfeeding in humans. J Clin Endocrinol Metab 81:4162–4165[Abstract/Free Full Text]
29. Dubuc GR, Stephen DP, Stern JS, Havel PJ 1998 Changes of serum leptin and endocrine and metabolic parameters after 7 days of energy restriction in men and woman. Metabolism 47:429–434[CrossRef][Medline]
30. Scholz GH, Englaro P, Thiele I Scholz M, Klusmann T, Kellner K, Rascher W, Blum WF 1996 Dissociation of serum leptin concentration and body fat content during long-term dietary intervention in obese individuals. Horm Metab Res 28:718–723[Medline]
31. Kabir M, Guerre-Millo M, Laromiguiere M, Slama G, Rizkalla SW 2000 Negative regulation of leptin by chronic high-glycemic indet starch diet. Metabolism 49:764–769[CrossRef][Medline]
32. Agus MSD, Swain JF, Larson CL, Eckert EA, Ludwig DS 2000 Dietary composition and physiologic adaptations to energy restriction. Am J Clin Nut 71:901–907[Abstract/Free Full Text]
33. Kolaczynski JW, Considine RV, Ohannesian JP Marco C, Opentanova I, Nyce MR, Myint M, Caro JF 1996 Response of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves. Diabetes 45:1511–1515[Abstract]
34. Lammert O, Grunnet N, Faber P, Bjornsbo KS, Dich J, Larsen LO, Neese RA, Hellerstein MK, Quistorff B 2000 Effects of isoenergetic overfeeding of either carbohydrate or fat in young men. Br J Nutr 84:233–245[Medline]
35. Raben A, Astrup A 2000 Leptin is influenced both by predisposition to obesity and diet composition. Int J Obes 24:450–459
36. Lovejoy JC, Windhauser MM, Rood JC, de la Bretonne JA 1998 Effect of a controlled high-fat versus low-fat diet on insulin sensitivity and leptin concentration in African-American and Caucasian women. Metabolism 47:1520–1524[CrossRef][Medline]
37. Chu NF, Stampfer MJ, Spiegelman D, Rifai N, Hotamisligil GS, Rimm EB 2001 Dietary and lifestyle factors in relation to serum leptin concentrations among normal weight and overweight men. Int J Obes 25:106–114[CrossRef]
38. Havel PJ, Townsend R, Chaump L, Teff K 1999 High-fat meals reduce 24-h circulating leptin concentrations in women. Diabetes 48:334–341[Abstract]
39. Schrauwen P, van Marken Lichtenbelt WD, Westerterp KR, Saris WHM 1997 Effect of diet composition on leptin concentration in lean subjects. Metabolism 46:420–424[CrossRef][Medline]
40. Weigle DS, Duell BP, Connor WE, Steiner RA, Soules MR, Kuijper JL 1997 Effect of fasting, refeeding and dietary fat restriction on plasma leptin levels. J Clin Endocrinol Metab 82:561–565[Abstract/Free Full Text]
41. Landt M 2000 Leptin binding and binding capacity in serum. Clin Chem 46:379–384[Abstract/Free Full Text]
42. Lahlou N, Clement K, Carel JC Vaisse C, Lotton C, Le Bihan Y, Basdevant A, Lebouc Y, Froguel P, Roger M, Guy-Grand B 2000 Soluble leptin receptor in serum of subjects with complete resistance to leptin. Diabetes 49:347–352
43. Brabant G, Horn R, von zur Mühlen A Mayr B, Wurster U, Heidenreich F, Schnabel D, Gruters-Kieslich A, Zimmermann-Belsing T, Feldt-Rasmussen U 2000 Free and protein bound leptin are distinct and independently controlled factors in energy regulation. Diabetologia 43:438–442[CrossRef][Medline]
44. McConway MG, Johnson D, Kelly A, Griffin D, Smith J, Wallace AM 2000 Differences in circulating concentrations of total, free and bound leptin relate to gender and body composition in adult humans. Ann Clin Biochem 37:717–723
45. Fruebis J, Tsao TS, Javorschi S Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF 2001 Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 98:2005–2010[Abstract/Free Full Text]
46. Hotta K, Funahashi T, Arita Y Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y 2000 Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595–1599[Abstract/Free Full Text]
47. Thompson FE, Byers T 1994 Dietary assessment resource manual. J Nutr 124:2245S–2317S
48. Perry HM 3rd, Miller DK, Patrick P, Morley JE 2000 Testosterone and leptin in older African-American men: relationship to age, strength, function and season. Metabolism 49:1085–1091[CrossRef][Medline]

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