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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 10 3408-3413
Copyright © 1997 by The Endocrine Society

Original Studies

Leptin Concentrations in Relation to Body Mass Index and the Tumor Necrosis Factor-{alpha} System in Humans1

Christos S. Mantzoros2, Stergios Moschos, Iraklis Avramopoulos, Virginia Kaklamani, Antonios Liolios, Dimitrios E. Doulgerakis, Ioannis Griveas, Nicholas Katsilambros and Jeffrey S. Flier

The Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory of the Beth Israel Deaconess Medical Center (C.S.M., S.M., V.K., J.S.F.), Department of Internal Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215; Department of Propedeutic Medicine (I.A., N.K.), Athens University Medical School, Athens; 401 Military Hospital (A.L., D.E.D., I.G.), Athens, Greece

Address correspondence and requests for reprints to: Jeffrey S. Flier, MD, Division of Endocrinology, RN 325, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Boston, Massachusetts 02215; E-mail: jflier{at}bidmc.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The expression of leptin, an adipocyte-derived protein whose circulating levels reflect energy stores, can be induced by tumor necrosis factor (TNF){alpha} in rodents, but an association between the TNF{alpha} system and leptin levels has not been reported in humans. To evaluate the potential association between serum leptin and the TNF{alpha} system, we measured the levels of soluble TNF{alpha}-receptor (sTNF{alpha}-R55), which has been validated as a sensitive indicator of activation of the TNF{alpha} system. We studied two groups: 1) 82 young healthy normal controls and 2) 48 patients with noninsulin dependent diabetes mellitus (NIDDM) and 24 appropriately matched controls. By simple regression analysis in controls, there was a strong positive association between leptin and 3 parameters: body mass index, sTNF{alpha}-R55, and insulin levels. In a multiple regression analysis model, leptin remained significantly and strongly associated with body mass index, and the association of leptin with both insulin and sTNF{alpha}-R55, although weakened, remained significant. Patients with NIDDM had leptin concentrations similar to controls of similar weight. Importantly, serum levels of sTNF{alpha}-R55 were also positively and independently associated with leptin in this group of diabetic subjects and matched controls. These data are consistent with the hypothesis that the TNF{alpha} system plays a role in regulating leptin levels in humans. Further elucidation of a possible role of the TNF{alpha} system in leptin expression and circulating levels may have important implications for our understanding of obesity and cachexia in humans.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
LEPTIN, the product of the ob gene (1), is an adipose-tissue secreted protein that signals the magnitude of energy stores to the brain (2, 3, 4, 5, 6), affecting food intake and whole body energy balance (5, 6). When administered to ob/ob mice that lack this protein, leptin increases energy expenditure (6), decreases body weight, and normalizes hyperglycemia, insulin resistance, and hyperinsulinemia (6, 7, 8, 9).

Another system that may play an important role in both insulin resistance and energy expenditure/body weight regulation is the TNF{alpha} system (10). Although it has recently been shown that TNF{alpha} administration increases leptin expression and circulating concentrations in rodents (11, 12), an association between the TNF{alpha} system and leptin in humans remains unknown. Such an association would be intriguing for several reasons. First, although leptin correlates with obesity in multiple studies, it is clear that individuals with similar body mass indexes (BMI) have highly variable leptin levels (13, 14). It is therefore important to find the additional factors that influence leptin levels. Second, activation of the TNF{alpha} system has been associated with increased energy expenditure and weight loss in humans (15, 16, 17, 18). Because leptin induces weight loss and increases energy expenditure in rodents (6, 7, 8, 9), it could be hypothesized that the TNF{alpha} system may regulate, or even act through, the leptin system to increase energy expenditure and decrease body weight in inflammatory diseases, collagen vascular disease, and cancer (12). If the cytokine-leptin hypothesis (12) is supported by findings in humans, it can open a novel approach to understanding and potentially combating this important comorbidity of the above disease states. Third, activation of the immune/TNF{alpha} system results in altered neuroendocrine function (19). As leptin has recently been proposed to be a mediator of the neuroendocrine response to fasting (20), the possibility exists that leptin could be regulated by and thus could mediate one or more of the effects of the immune/TNF{alpha} system on neuroendocrine function. Finally, in addition to a possible role of the TNF{alpha} system in energy expenditure and weight loss, what may be a compensatory activation of this system has been observed in the adipose tissue of obese animals and humans and has been implicated in the development of insulin resistance in these disease states (10, 21, 22). Thus, an elucidation of the potentially important interactions of the TNF{alpha} system with insulin and leptin may provide insights into the pathophysiology of obesity and cachexia in humans.

The purpose of this study was to explore whether activation of the TNF{alpha} system, as measured by the levels of circulating soluble human 55 kDa tumor necrosis factor {alpha}-receptor (sTNF{alpha}-R55) (23, 24), is related to serum leptin levels in healthy and diabetic adults. Furthermore, we attempted to clarify whether a potential association between the TNF{alpha} system and circulating leptin levels is independent of obesity and serum insulin, both of which have previously been associated with TNF{alpha} system activation and circulating leptin levels.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study populations

Cross-sectional study: normal controls. Participants in this part of the study were 82 consecutively enrolled young men, age 18–28 yr, who consented to having a single blood sample drawn during a routine physical examination between 0900 and 1100 in the morning. Subjects were healthy and were taking no medication. Quetelet’s index (body mass index) was calculated as weight/height2. Blood samples for the hormone determinations were centrifuged immediately, and serum was frozen at -34 C until determination.

Case-control study: diabetic subjects and controls. We studied 48 consecutively enrolled patients with noninsulin-dependent diabetes mellitus (NIDDM), on treatment with oral hypoglycemic agents and/or insulin, who were attending the outpatient diabetes clinic of the 1st Department of Propedeutic Medicine in Laikon Hospital, Athens, Greece. Subjects were in their usual state of health, and their glycemic control had been stable for at least 4 weeks before entry into the study. We also studied 24 controls of similar age recruited among healthy volunteers of Red Cross, Athens, Greece. Their BMI and waist-to-hip girth ratios (WHR) were determined as described previously (25). Controls were selected to be similar to the diabetic subjects with respect to BMI and were matched to the diabetic subjects by ethnicity. Control subjects were healthy and had no first or second degree relatives with NIDDM. Additionally, controls had no evidence of either diabetes or impaired glucose tolerance as indicated by a normal standard oral glucose tolerance test (OGTT) evaluated by World Health Organization (WHO) criteria (26, 27). Blood samples were obtained from diabetics and controls after a 12- to 14-h overnight fast and were stored until leptin and sTNF{alpha}-R were determined. All participants were informed about the nature of the study by one of the investigators (I.A.), and all consented to participate. The study was approved by the Ethics Committee of Laikon Hospital, Athens, Greece.

Laboratory methods

Serum hormone concentrations were determined by commercially available RIA kits (Linco Research for leptin, ICN ImmuChem Coated Tube for insulin) as previously described (28, 29). sTNF{alpha}-R55 concentrations were measured in duplicate using a commercially available ELISA (Bender Medsystems, Vienna, Austria) as described previously (30).

Statistical methods

Data are reported as mean ± standard error (SE). Variables not normally distributed were logarithmically transformed before analysis by parametric methods. Means of anthropometric and demographic data as well as hormonal concentrations were compared by Student’s t test. Relationships between serum leptin, sTNF{alpha}-R55, and other independent variables were assessed by simple and/or multiple linear regression analysis. Two-sided significance levels are reported. Statistical analyses were performed using the Statview Statistical Package (Berkeley, CA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Normal controls

The mean (±SE) age of participants in this part of the study was 22 ± 0.2 yr, their mean height 178.8 ± 0.7 cm, mean weight 79.6 ± 1.5 kg, mean WHR 0.86 ± 0.011, and their mean BMI was 24.86 ± 0.42. Baseline serum sTNF{alpha}-R55 concentration was 3.14 ± 0.10 ng/mL, their leptin concentration was 7.43 ± 0.83 ng/mL (median: 4.89), and their insulin concentration was 16.82 ± 1.68 IU/mL (median: 11.09 IU/mL). Although sTNF{alpha}-R55 concentrations were approximately normally distributed, insulin and leptin concentrations were skewed to the right.

Serum leptin was significantly associated with BMI (r = 0.67, P = 0.0001), insulin (r = 0.50, P = 0.0001), and sTNF{alpha}-R55 concentrations (r = 0.33, P = 0.004) by simple regression analysis (Table 1Go). Although insulin has no acute effect on leptin production by adipocytes, chronic insulin administration increases leptin production in vitro (31, 32, 33, 34), and circulating insulin has been shown to correlate with serum leptin independently of BMI in humans (5, 35, 36). Additionally, BMI has been previously associated with serum leptin (5, 13, 14) and with activation of the TNF{alpha} system as indicated by increased expression of TNF{alpha} and sTNF{alpha}-R80 mRNA in adipose tissue (10, 21, 22, 30). Thus, although BMI has not been significantly associated with circulating TNF{alpha} levels in earlier studies (22) or with sTNF{alpha}-R55 concentrations in this study, the possibility exists that BMI may be a confounder of the association between serum leptin and sTNF{alpha}-R55 concentrations.


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  		Table 1. Simple and multiple linear regression analysis

 
To further evaluate the potential confounding effect that BMI and insulin concentrations could have on the association between leptin and sTNF{alpha}-R55 concentrations, we built two multiple regression analysis models. In the first model leptin was regressed on BMI and sTNF{alpha}-R55 concentrations only. sTNF{alpha}-R55 concentrations remained independently and strongly associated with leptin levels (P = 0.007). However, the resulting correlation coefficient weakened from r = 0.33 to r = 0.28, indicating that an underlying effect of BMI on both leptin and sTNF{alpha}-R55 concentrations may contribute to, but is not entirely responsible for, the observed association between leptin and sTNF{alpha}-R55 concentrations. Similarly, control for the potential confounding effect of both BMI and insulin concentrations in another multiple regression analysis model revealed that the association between leptin and sTNF{alpha}-R55 concentrations is further weakened but remains statistically significant (Table 1Go). Thus, the positive association between leptin and sTNF{alpha}-R55 concentrations is independent of the confounding effect of BMI and insulin concentrations in this group of young healthy men. Moreover, the explained leptin variance, as expressed by adjusted R2 increased from 45% to 54% when sTNF{alpha}-R55 was added to BMI as an independent variable.

Diabetic subjects and controls

Baseline serum leptin concentration in this group was 5.43 ± .45 ng/mL (median: 4.81 ng/mL). Diabetic subjects had WHR and systolic blood pressure levels that were significantly higher than those of controls (Table 2Go). However, their BMI, sTNF{alpha}-R55 concentrations and diastolic blood pressure levels were not statistically different from controls. Finally, diabetic subjects had similar leptin concentrations to the control subjects, as expected based on the similar BMI of the two groups (37, 38) (Table 2Go).


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  		Table 2. Baseline demographic, anthropometric, and hormonal parameters in diabetic subjects and controls

 
Furthermore, women had similar BMI as men in this study (26.39 ± 0.66 vs. 28.19 ± 0.83, P = 0.10). Interestingly, women had higher sTNF{alpha}-R55 (2.9 ± .35 vs. 1.9 ± 0.25 ng/mL, P < 0.05) and leptin (6.21 ± .8 vs. 4.28 ± 0.38 ng/mL, P < 0.05) concentrations than men. Additionally, when we compared the diabetic and control groups separately by sex, women continued to have significantly higher (P < 0.05) leptin concentrations than men (NIDDM women: 5.98 ± .98 ng/mL, nondiabetic women: 6.61 ± 1.37 ng/mL, NIDDM men: 4.41 ± 0.42 ng/mL, and nondiabetic men: 3.32 ± .30 ng/mL). Thus, it appears that despite the fact that BMIs were similar in women and men, both the serum leptin and sTNF{alpha}-R55 concentrations were significantly higher in women.

BMI was correlated with leptin in the entire study group (r = 0.36, P = 0.005). To assess the potentially confounding effect of gender or diabetes on this correlation we adjusted for gender and diabetic status. The correlation between BMI and leptin concentrations remained significant and was equally strong in men and women (women r = 0.64, men r = 0.62, and for the combined group after controlling for the effect of gender r = 0.63, P < 0.001 for all correlations). Additionally, the correlation between BMI and leptin concentrations was similar in diabetics and controls (diabetics r = 0.49, controls r = 0.50, and the combined group after controlling for the effect of diabetes r = 0.50).

Furthermore, sTNF{alpha}-R55 concentrations were significantly correlated with leptin concentrations (r = 0.54, P < 0.001) but not with BMI. To explore further the association between sTNF{alpha}-R55 and leptin concentrations we examined their association separately in diabetics and controls. Leptin concentrations remained associated with sTNF{alpha}-R55 in both diabetics (r = 0.39, P = 0.003) and controls (r = 0.55, P = 0.01) independently of the other variables evaluated, including BMI and WHR, i.e. the two estimates of obesity used in this study.

To assess the potential independent effect of sTNF{alpha}-R55 concentrations on serum leptin, we fit a multiple linear regression model with serum leptin concentrations as the dependent variable. BMI (r = 0.62, P < 0.0001), sex (male vs. female) (P = 0.0096), and sTNF{alpha}-R55 (r = 0.46, P < 0.0001) were independently associated with serum leptin concentrations (Table 2Go). Importantly, after adjusting for WHR, the association between leptin on the one hand and BMI and sTNF{alpha}-R55 on the other remained essentially unaffected, while the effect of sex was no longer apparent, indicating that the association between sex and leptin may be confounded by leptin’s association with WHR (Table 3Go) as previously suggested (39, 40). Similar results were obtained after adjusting for waist circumference instead of WHR. By contrast, age, blood pressure levels, and diabetic status were not significantly associated with leptin concentrations in this study. The variance of serum leptin concentrations explained by all the above independent variables was 62%.


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  		Table 3. Multiple linear regression analysis

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study addressed the possible association between two systems that are involved in the regulation of energy expenditure, body weight, and insulin sensitivity. The first is leptin, an adipocyte-secreted hormone that, by signaling the amount of adipose stores to the brain (2, 3), plays a key role in a feedback loop maintaining energy homeostasis (5, 6). Administration of leptin to ob/ob mice that lack protein reduces food intake, increases energy expenditure and physical activity, reverses insulin resistance and diabetes, and leads to weight loss (6, 7, 8, 9). The other system that influences energy balance and glucose homeostasis is the TNF{alpha} system (10, 15, 21, 22). The relationship of the TNF{alpha} system to energy and metabolic homeostasis is potentially complex. On the one hand, increased levels of TNF{alpha} have been associated with weight loss, hypermetabolism, and increased resting energy expenditure as measured by indirect calorimetry in several disease states (16, 17), and administration of TNF{alpha} is capable of producing some of these effects (18). On the other hand, increased TNF{alpha} expression in adipose cells is seen in obesity and has been linked to the development of insulin resistance (10, 21, 22). Given the major effects of these two systems on energy balance and metabolic control their potential interaction in humans is intriguing.

Our data demonstrate a positive and independent association between circulating concentrations of sTNF{alpha}-R55 and leptin, both in subjects with diabetes and in normal controls. Cytokines circulate bound to a number of binding proteins that appear to alter their clearance rates and/or enhance their biological activity (41). More specifically, TNF{alpha}, a multifunctional cytokine, binds to two distinct soluble TNF{alpha} receptors, sTNF{alpha}-R55 and sTNF{alpha}-R80 (42, 43, 44, 45, 46). Although the exact function of sTNF{alpha}-Rs remains unknown, it has been suggested that they represent a buffer system (44) that prolongs the biologic effects of TNF{alpha} by forming a "slow release reservoir" (44, 47) and impeding spontaneous denaturation of the cytokine (44, 47). Thus, compared with circulating TNF{alpha}, sTNF{alpha}-Rs levels remain elevated for longer periods of time and are of more value for monitoring inflammatory responses (44, 47). sTNF{alpha}-R55 represents the major soluble form of the TNF{alpha} receptor (42, 43) that has been found on a variety of human somatic cells including adipocytes, liver cells, endothelial cells, and granulocytes (42, 43, 48). Although sTNF{alpha}-R80 may have a permissive role, it appears that sTNF{alpha}-R55 has the primary role in controlling the cytotoxic activity of TNF{alpha} in general (49) and the TNF{alpha}-induced insulin resistance (30, 50). More specifically, although both sTNF{alpha}-R55 and sTNF{alpha}-R80 receptor expression increase in obesity and correlate with both BMI and fasting insulin levels (30), it appears that sTNF{alpha}-R55 is the receptor that most powerfully mediates the TNF{alpha} effect on obesity-induced insulin resistance (30, 50) and energy expenditure, and the subsequent development of weight loss (16, 44). Recent evidence suggests that circulating levels of sTNF{alpha}-R55 accurately reflect the degree of activation of the TNF{alpha} system (51, 52, 53) and that they reflect more accurately the degree of activation of the TNF{alpha} system than circulating TNF{alpha} levels per se (44, 54). Additionally, in disease states where activation of the TNF{alpha} system plays an important role pathophysiologically, circulating sTNF{alpha}-R55 represents a sensitive marker of disease activity (51, 55, 56, 57, 58, 59, 60, 61) and a reliable prognostic factor for disease outcome (50, 54, 55, 56) and weight loss (62, 63).

The independent positive association between circulating levels of leptin and sTNF{alpha}-R55 in this study might reflect an association between the leptin and the TNF{alpha} system in humans similar to that seen in rodents (11, 12), where TNF{alpha} and interleukins increase leptin gene expression and circulating leptin levels (11, 12). If so, the independent positive association between sTNF{alpha}-R55 and leptin in our study might reflect a direct effect of the TNF{alpha} system to increase leptin gene expression and serum levels in humans and could contribute to the variable leptin levels in obesity (5, 13, 14). A recent study compared leptin concentrations in normal subjects and patients with AIDS, a condition accompanied by activation of the immune system (64). Despite the fact that patients with AIDS had a significantly decreased BMI and percent fat mass in comparison with controls, their leptin concentrations were similar to those of controls (64), indicating that an increase of their leptin concentrations because of activation of their immune system could have compensated for the decreased leptin concentrations expected based on the decreased BMI and percent fat mass. Another interesting finding of this study is that after adjustment for the confounding effect of obesity and hyperinsulinemia the relationship between serum leptin and sTNF{alpha}-R55 was attenuated, but remained significant. Because percent fat, which is better than BMI as a predictor of leptin levels in humans, was not measured in this study, it remains unclear whether the association between circulating leptin and sTNF{alpha}-R55 concentrations would have remained significant after adjusting for percent fat mass. In any case, local activation of sTNF{alpha}-R55 in fat could be a factor influencing leptin levels in humans. Finally, our finding that women with a similar degree of obesity display higher serum leptin and sTNF{alpha}-R55 levels than men parallels the finding of higher leptin levels in women that has been observed in this and many other studies (65) and suggests that the sexually dimorphic levels of leptin and sTNF{alpha}-R55 (37, 65) may have a common explanation.

A potential effect of an activated TNF{alpha} system on circulating leptin levels in humans could have a significant impact on human physiology. First, activation of the TNF{alpha} system has been associated with increased energy expenditure and weight loss in humans (15, 16, 17, 18). The association between serum leptin and sTNF{alpha}-R55 levels raises the intriguing possibility that the TNF{alpha} system may act through the leptin system to increase energy expenditure and thereby induce weight loss in humans. Secondly, it is well recognized that neuroendocrine function is subject to regulation by the immune system in humans (19), and it has recently been shown that leptin is a potent mediator of the neuroendocrine response in mice (20). Thus, these data raise the possibility that one or more effects of the immune system on neuroendocrine function could, in addition to direct effects by cytokines on the central nervous system (66), be mediated through changes of the leptin system.

In summary, the association between circulating leptin concentrations and sTNF{alpha}-R55 that we report here raises the hypothesis that activation of the TNF{alpha} system may exert a significant influence over leptin levels in humans. Further elucidation of the potential interaction between these two systems could provide important insights into the feedback system for regulation of body weight and the mechanisms leading to obesity and cachexia in humans.


   Footnotes
 
1 This study was supported by grants to Dr. Jeffrey S. Flier from NIH, DK 28082; by Beth Israel Hospital General Clinical Research Center Grant M01 RR01032. Back

2 Christos Mantzoros is supported by the Division of Endocrinology, Beth Israel Deaconess Medical Center and by the Clinical Investigator Training Program, Beth Israel Hospital, Harvard–MIT Health Sciences and Technology, in collaboration with Pfizer Inc. Back

Received April 14, 1997.

Revised July 2, 1997.

Accepted July 7, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. 1994 Positional cloning of the mouse ob gene and its human homologue. Nature. 372:425–432.[CrossRef][Medline]
  2. Frederich RC, Hamann A, Anderson S, Lollman B, Lowell BB, Flier JS. 1995 Leptin reflects body lipid content in mice: evidence for diet-induced leptin resistance. Nature Med. 1:1311–1314.[CrossRef][Medline]
  3. Spiegelman BM, Flier JS. 1996 Adipogenesis and obesity. Rounding out the big picture. Cell. 87:377–389.[CrossRef][Medline]
  4. Rink TJ. 1995 In search of a satiety factor. Nature. 372:406–407.
  5. Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV. 1996 Leptin: the tale of an obesity gene. Diabetes. 45:1455–1462.[Medline]
  6. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. 1995 Recombinant mouse ob protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 269:546–548.[Abstract/Free Full Text]
  7. Halaas JL, Gajiwala KS, Maffei M, et al. 1995 Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 269:543–546.[Abstract/Free Full Text]
  8. Pelleymounter MA, Cullen MJ, Baker MB, et al. 1995 Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 269:540–543.[Abstract/Free Full Text]
  9. Weigle DS, Bukowski TR, Foster DC, et al. 1995 Recombinant ob protein reduces feeding and body weight in the ob/ob mouse. J Clin Invest. 96:2065–2070.
  10. Hotamisligil GS, Peraldi P, Spiegelman BM. 1996 The molecular link between obesity and diabetes. Curr Opin Endocr Diabetes. 3:16–23.
  11. Grunfeld C, Zhao C, Fuller J, et al. 1996 Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest. 97:2152–2157.[Medline]
  12. Sarraf P, Frederick RC, Turner EM, et al. 1997 Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J Exp Med. 185:171–175.[Abstract/Free Full Text]
  13. Considine RV, Sinha MK, Heiman ML, et al. 1996 Serum immunoreactive-leptin concentrations in normal weight and obese humans. N Engl J Med. 334:292–295.[Abstract/Free Full Text]
  14. Maffei M, Halaas J, Ravussin E, et al. 1995 Leptin levels in human and rodent: measurement of plasma leptin and ob mRNA in obese and weight-reduced subjects. Nature Med. 1:1155–1161.[CrossRef][Medline]
  15. Toomey D, Redmond P, Bouchier-Hayes D. 1995 Mechanisms mediating cancer cachexia. Cancer. 76:2418–2426.[CrossRef][Medline]
  16. Staal van den Brekel AJ, Dentener MA, Schols AM, Buurman WA, Wouters EF. 1995 Increased resting energy expenditure and weight loss are related to a systemic inflammatory response in lung cancer patients. J Clin Oncol. 13:2600–2605.[Abstract]
  17. Tracey KJ, Cerami A. 1992 Tumor necrosis factor and regulation of metabolism in infection: role of systemic versus tissue levels. Proc Soc Exp Biol Med. 200:233–239.[Abstract]
  18. Keller U. 1993 Pathophysiology of cancer cachexia. Support Care Cancer. 1:290–294.[CrossRef][Medline]
  19. Ojeda SR, Griffin JE. 1992 Organization of the endocrine system. In: Griffin JE, Ojeda SR (eds). Textbook of endocrine physiology. Oxford: Oxford University Press; 2nd ed.
  20. Ahima RS, Prabakaran D, Mantzoros CS, Qu D, Lowell B, Maratos-Flier E, Flier JS. 1996 Role of leptin in the neuroendocrine response to fasting. Nature. 382:250–252.[CrossRef][Medline]
  21. Hotamisligil GS, Spiegelman BM. 1994 Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes. 43:1271–1278.[Abstract]
  22. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. 1995 Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 95:2409–2415.
  23. Warzocha K, Bienvenu J, Coiffier B, Salles G. 1995 Mechanisms of action of the tumor necrosis factor and lymphotoxin ligand-receptor system. Eur Cytokine Netw. 6:83–96.[Medline]
  24. Diez-Ruiz A, Tilz GP, Zangerle R, Baier-Bitterlich G, Wachter H, Fuchs D. 1995 Soluble receptors for tumor necrosis factor in clinical laboratory diagnosis. Eur J Haematol. 54:1–8.[Medline]
  25. Mantzoros CS, Georgiadis EI, Evangelopoulou K, Katsilambros N. 1996 Dehydroepiandrosterone sulfate and testosterone are independently associated with body fat distribution in premenopausal women. Epidemiology. 7:513–516.[Medline]
  26. Mantzoros CS, Dunaif A, Flier JS. 1997 Leptin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metab. 82:1687–1691.[Abstract/Free Full Text]
  27. Modan M, Harris MI, Halkin H. 1989 Evaluation of WHO and NDDG criteria for impaired glucose tolerance. Diabetes. 38:1603–1635.
  28. 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]
  29. Mantzoros CS, Rosen HN, Greenspan SL, Flier JS, Moses AC. 1997 Short-term hyperthyroidism has no effect on leptin levels in man. J Clin Endocrinol Metab. 82:497–499.[Abstract/Free Full Text]
  30. Hotamisligil GS, Arner P, Atkinson RL, Spiegelmen BM. 1997 Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance. Diabetes. 46:451–455.[Abstract]
  31. Cusin I, Sainsbury A, Doyle P, Rohner-Jeanrenaud F, Jeanrenaud B. 1995 The ob gene and insulin. Diabetes. 44:1467–1470.[Abstract]
  32. Saladin R, De Vos P, Guerre-Millo M, et al. 1995 Transient increase in obese gene expression after food intake or insulin administration. Nature. 377:527–529.[CrossRef][Medline]
  33. Leroy P, Dessolin S, Villageois P, et al. 1996 Expression of ob gene in adipose cells. J Biol Chem. 271:2365–2368.[Abstract/Free Full Text]
  34. Kolaczynski JW, Nyce MR, Considine RV, et al. 1996 Acute and chronic effect of insulin on leptin production in humans: studies in vivo and in vitro. Diabetes. 45:699–701.[Abstract]
  35. Widjaja A, Stratton IM, Horn R, Holman RR, Turnenr R, Brabant G. 1997 UKPDS 20: Plasma leptin, obesity and plasma insulin in type 2 diabetic subjects. J Clin Endocrinol Metab. 82:654–657.[Abstract/Free Full Text]
  36. Segal KR, Landt M, Klein S. 1996 Relationship between insulin sensitivity and plasma leptin concentrations in lean and obese men. Diabetes. 45:988–991.[Abstract]
  37. Haffner SM, Stern MP, Miettinen H, Wei M, Gingerich RL. 1996 Leptin concentrations in diabetic and nondiabetic mexican-americans. Diabetes. 45:822–824.[Abstract]
  38. Sinha MK, Ohanessian JP, Heinman ML, Kriacinunas A, Stephens TN, Magosin SA, Marco C, Caro SF. 1996 Nocturnal rise of leptin in lean, obese, and noninsulin dependent diabetes mellitus subjects. J Clin Invest. 97:1344–1347.[Medline]
  39. Ronnemaa T, Karonen S-L, Rissanen A, Koskenvuo M, Koivisto VA. 1997 Relation between plasma leptin levels and measures of body fat in identical twins discordant for obesity. Ann Intern Med. 126:26–31.[Abstract/Free Full Text]
  40. Montague CT, Prins JB, Sanders L, Digby JE, O’Rahilly S. 1997 Depot- and sex-specific differences in human leptin mRNA expression. Diabetes. 46:342–347.[Abstract]
  41. Heaney ML, Golde DW. 1993 Soluble hormone receptors. Blood. 82:1945–1948.[Free Full Text]
  42. Brockhaus M, Schoenfeld HJ, Schlager EJ, Hunziker W, Lesslauer W, Loetscher H. 1990 Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci USA. 87:3127–3131.[Abstract/Free Full Text]
  43. Loetscher H, Pan YE, Lahm HW, et al. 1990 Molecular cloning and expression of the human 55 kd tumor necrosis factor receptor. Cell. 61:351–359.[CrossRef][Medline]
  44. Bemelmans MHA, van Tis LJH, Buurman WA. 1996 Tumor Necrosis Factor: Function, release and clearance. Crit Rev Immunol. 16:1–11.[Medline]
  45. Engelman H, Novick D, Wallach D. 1990 Two tumor necrosis factor-binding proteins purified from human urine: evidence from immunological cross-reactivity with cell surface tumor necrosis factor receptors. J Biol Chem. 265:1531.[Abstract/Free Full Text]
  46. Hohmann HP, Remy R, Brockhaus M, van Loon APGM. 1989 Two different cell types have different major receptors for human tumor necrosis factor (TNF{alpha}). J Biol Chem. 264:14927.[Abstract/Free Full Text]
  47. Aderka D, Engelmann H, Maor Y, Brockhaus C, Wallach D. 1992 Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med. 175:323–329.[Abstract/Free Full Text]
  48. Bonner JC, Brody AP. 1995 Cytokine-binding proteins in the lung. Am J Physiol. 12:L869–L878.
  49. Tartaglia LA, Rothe M, Hu YF, Goeddel DV. 1993 Tumor necrosis factor’s cytotoxic activity is signaled by the p55 TNF receptor. Cell. 73:213.[CrossRef][Medline]
  50. Peraldi P, Hotamisligil GS, Buurman WA, White MF, Spiegelman BM. 1996 Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. J Biol Chem. 271:13018–13022.[Abstract/Free Full Text]
  51. Moller B, Ellermann-Eriksen S, Storgard M, Obel N, Bendtzen K, Petersen CM. 1996 Soluble tumour necrosis factor (TNF) receptors conserve TNF bioactivity in meningitis patient spinal fluid. J Infect Dis. 174:557–563.[Medline]
  52. Steiner G, Studnicka-Benke A, Witzman G, Hofler E, Smolen J. 1995 Soluble receptors for tumour necrosis factor and interleukin-2 in serum and synovial fluid of patients with rheumatoid arthritis, reactive arthritis, and osteoarthritis. J Rheumatol 1995;22:406–412.
  53. Kupferminc MJ, Peaceman AM, Aderka D, Wallach D, Sokol ML. 1996 Soluble tumor necrosis factor receptors and interleukin-6 levels in patients with severe preeclampsia. Obstet Gynecol. 88:420–427.[Abstract]
  54. Samsonov MY, Tilz GP, Egorova O, et al. 1995 Serum soluble markers of immune activation and disease activity in systemic lupus erythematosus. Lupus. 4:29–32.[Abstract/Free Full Text]
  55. Schroder J, Stuber F, Galatti H, Schade FU, Kremer B. 1995 Pattern of soluble TNF receptors I and II in sepsis. Infection. 23:143–148.[CrossRef][Medline]
  56. Bilello JA, Stellrecht K, Drusano GL, Stein DS. 1996 Soluble tumor necrosis factor-alpha receptor type II correlates with human immunodeficiency virus (HIV) RNA copy number in HIV-infected patients. J Infect Dis. 173:464–7.[Medline]
  57. Gattorno M, Picco P, Buoncompagni A, et al. 1996 Serum p55 and p75 tumour necrosis factor receptors as markers of disease activity in juvenile chronic arthritis. Ann Rheum Dis. 55:243–247.[Abstract/Free Full Text]
  58. Nakayama T, Hashimoto S, Amemiya E, Horie T. 1996 Evaluation of plasma-soluble tumour necrosis factor receptors (TNF-R) in sarcoidosis. Clin Exp Immunol. 104:318–324.[CrossRef][Medline]
  59. Salles G, Bienvenu J, Bastion Y, et al. 1996 Elevated circulating levels of TNFalfa and its p55 soluble receptor are associated with an adverse prognosis in lymphoma patients. Br J Hematol. 93:352–359.[CrossRef][Medline]
  60. Bemelmans MH, Greve JW, Gouma DJ, Buurman WA. 1996 Increased concentrations of tumour necrosis factor (TNF) and soluble TNF receptors in biliary obstruction in mice; soluble TNF receptors as prognostic factors for mortality. Gut. 38:447–453.[Abstract/Free Full Text]
  61. Deloron P, Roux Lombard P, Ringwald P, et al. 1994 Plasma levels of TNF-alpha soluble receptors correlate with outcome in human falciparum malaria. Eur Cytokine Netw. 5:331–336.[Medline]
  62. Staal-van der Brekel AJ, Dentener MA, Schols AM, Buurman WA, Wouters EF. 1995 Increased resting energy expenditure and weight loss are related to a systemic inflammatory response in lung cancer patients. J Clin Oncol. 13:2600–2605.
  63. Denz H, Orth B, Weiss G, et al. 1993 Serum soluble tumour necrosis factor receptor 55 is increased in patients with haematological neoplasias and is associated with immune activation and weight loss. Eur J Cancer. 29A:2232–2235.
  64. Grunfeld C, Pang M, Shigenaga JK, et al. 1996 Serum leptin levels in the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 81:4342–4346.[Abstract]
  65. Rosenbaum M, Nicolson M, Hirsch J, et al. 1996 Effects of gender, body composition and menopause on plasma concentrations of leptin. J Clin Endocrin Metab. 81:3424–3427.[Abstract]
  66. Rothwell NJ, Luheshi G, Toulmond S. 1996 Cytokines and their receptors in the central nervous system: physiology, pharmacology and pathology. Pharmacol Ther. 69:85–95.[CrossRef][Medline]



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