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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 8 2907-2910
Copyright © 1998 by The Endocrine Society

Original Studies

Tumor Necrosis Factor-{alpha} in Sera of Obese Patients: Fall with Weight Loss

Paresh Dandona, Ruth Weinstock, Kuldip Thusu, Ehad Abdel-Rahman, Ahmad Aljada and Thomas Wadden

Division of Endocrinology-Diabetes (P.D., K.T., E.A.-R., A.A.), Department of Medicine, Millard Fillmore Health System, State University of New York at Buffalo, Buffalo, New York 14209; Endocrine Unit (R.W.), Department of Medicine, State University of New York at Syracuse, Syracuse, New York 13210; and Department of Psychiatry (T.W.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Paresh Dandona, Director, Diabetes-Endocrine Center of Western New York, Millard Fillmore Health Systems, 3 Gates Circle, Buffalo, New York 14209.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
In view of the recent demonstration that obesity in animals and humans is associated with an increase in tumor necrosis factor-{alpha} (TNF{alpha}) expression, that this expression falls with weight loss, and that TNF{alpha} may specifically inhibit insulin action, the possibility that TNF{alpha} may be a mediator of insulin resistance has been raised. We have undertaken this study to investigate whether serum TNF{alpha} concentrations are elevated in obese subjects, whether they fall after weight loss, and whether this fall parallels the fall in insulin release after glucose challenge. Obese patients (age range: 25–54, weight mean ± SD: 96.4 ± 13.8 kg, body mass index: 35.7 ± 5.6 kg/m2) were started on a diet program. The mean weight fell to 84.5 ± 11.3 (P < 0.0001) and body mass index to 31.3 ± 4.9 (P < 0.0001). Plasma TNF{alpha} concentrations were markedly elevated in the obese (3.45 ± 0.16 pg/mL), when compared with controls (0.72 ± 0.28 pg/mL), and fell significantly (2.63 ± 1.40 pg/mL) after weight loss (P < 0.02). The magnitude of insulin release after glucose (75 g) challenge (area under the curve) also fell significantly (P < 0.01) after weight loss. The magnitude of weight loss and fall in TNF{alpha} were related to basal body weight (r = 0.57, P < 0.001) and basal TNF{alpha} (r = 0.55, P < 0.001) concentrations, respectively, but not to each other or to the glucose-induced insulin release (area under the curve). We conclude that obesity is associated with increased plasma TNF{alpha} concentrations, which fall with weight loss. Because circulating TNF{alpha} may mediate insulin resistance in the obese, a fall in TNF{alpha} concentrations may contribute to the restoration of insulin resistance after weight loss, Thus, TNF{alpha} may be an important circulating cytokine, which may provide a potentially reversible mechanism for mediating insulin resistance.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IT HAS recently been demonstrated that: 1) tumor necrosis factor-{alpha} (TNF{alpha}) is constitutively expressed by adipose tissue; 2) genetically obese mice (ob/ob mice) and rats (fa/fa Zucker) have increased expression of TNF{alpha} in their adipose tissue (1, 2); and 3) TNF{alpha} may be a mediator of insulin resistance (1, 2) known to occur in these animals. TNF{alpha} interferes with insulin action, probably by inhibiting tyrosine kinase activity of the insulin receptor (3). Phosphorylation of the insulin receptor by this tyrosine kinase is known to be a cardinal step in the postreceptor events that follow the binding of insulin to its receptor (2). Though this effect of TNF{alpha} may induce a resistance to the action of insulin, such a reduction of insulin action may also limit adipocyte lipogenesis, stimulate lipolysis, and reduce the magnitude of further lipid accumulation (4). In this way, TNF{alpha} may be a local modulator of adipocyte’s activity and its ability to accumulate fat. Administration of soluble TNF{alpha} receptor, which binds to TNF{alpha} and serves as an inhibitor of TNF{alpha} action to insulin-resistant obese animals, normalized their insulin sensitivity (1). Following the lead of these elegant experiments, Kern et al. (5) and Hotamisligil et al. (6, 7) have recently shown that human adipocytes and adipose tissue also constitutively express TNF{alpha} and that, unlike macrophages, the adipose tissue does not respond to endotoxin by increasing the expression/synthesis of TNF{alpha} (5, 6). Furthermore, they have also shown that, in adipocytes from obese subjects, the expression of TNF{alpha} message and protein falls markedly after weight loss (5, 6).

Because TNF{alpha} probably accomplishes its insulin inhibitory action by acting at various tissue sites of insulin action, it is possible that the obese have a higher-than-normal concentration of TNF{alpha} in plasma/serum. In this way, TNF{alpha} may act as a circulating hormone with supranormal secretion and serum concentrations in the obese. To test this hypothesis, we measured serum concentration of TNF{alpha} in a series of obese patients before and after weight loss.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Thirty-eight obese female patients (age range: 25–54 yr; weight: 69.3–112 kg) were included in this study. All patients signed an informed consent. They were started on low-calorie diets (925–1150 kcal) and behavior modification for a period of 1–2 yr. Behavior modification included a program of aerobic exercise, starting with 12 min per day, increasing by 2 min every week, reaching a maximum of 40 min over 14 weeks.

Controls were 30 normal women (age range: 20–60 yr) with a mean body weight of 65 ± 5 kg and a body mass index (BMI) of 24 ± 3 kg/m2. Fasting blood samples were obtained from the antecubital vein before and at the end of the treatment period. Blood samples were allowed to clot and were centrifuged. Serum was separated and frozen at -70 C until the time of the assay. Serum samples were assayed for lipids, insulin, and TNF{alpha}.

All patients were challenged with 75 g glucose (dissolved in 300 mL water) administered orally. Blood samples were collected at 0, 30, 60, 90, and 120 min. Serum was separated and frozen at -70 C, as above. Total cholesterol, triglycerides, low-density-lipoprotein cholesterol, and high-density-lipoprotein cholesterol were measured by standard techniques. Insulin was assayed by RIA using a kit from Linco Laboratories (St. Louis, Mo.) TNF{alpha} was measured by a kit from R & D Systems (Minneapolis, MN). This enzyme-linked immunosorbent assay kit (Quantikine HS) has a sensitivity of 0.3 pg/mL TNF{alpha} in serum. This allows the measurement of TNF{alpha} in the normal range in human plasma/serum. The coefficient of variation for this kit is 7% at high concentrations and 10% at low concentrations.

Statistical analysis

Basal serum TNF{alpha} concentrations in the obese patients and normal subjects were compared by Student’s t test for unpaired data, whereas the serum concentrations of TNF{alpha} and lipids before and after weight loss in the obese were compared by t test for paired data. Linear regression analysis was used to assess the degree of association between various indices.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Basal (pretreatment) TNF{alpha} concentration was significantly greater in the obese (3.45 ± 0.16 pg/mL) than in a group of normal subjects (0.82 ± 0.25 pg/mL); normal range: 0.3–1.3 pg/mL (Fig. 1Go). TNF{alpha} concentrations were not related to body weight or BMI. TNF{alpha} concentrations were not correlated with fasting insulin concentrations. After the treatment period, the mean weight fell from 96.4 ± 13.8 kg to 84.5 ± 11.3 kg (P < 0.001) (Table 1Go), and the BMI fell from 35.7 ± 5.6 kg/m2 to 31.3 ± 4.9 kg/m2 (P < 0.001). The magnitude of weight loss was significantly related to basal weight (r = 0.57; P < 0.001). Fasting TNF{alpha} concentrations in the obese fell from 3.45 ± 0.16 to 2.63 ± 1.40 pg/mL (P < 0.02) (Fig. 2Go).



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  		Figure 1. Serum TNF{alpha} in the controls and in obese subjects, before and after weight loss. The TNF{alpha} in the obese was significantly greater than in the controls (P < 0.001). TNF{alpha} concentrations fell significantly after weight loss (P < 0.02). The data are presented as mean ± SD.

 

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  		Table 1. Body weight and BMI before and after the period of dieting

 


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  		Figure 2. Regression analysis of basal body weight vs. percent fall in body weight. The magnitude of the weight loss was significantly related to basal weight (r = 0.57, P < 0.001). The data are presented as the regression line, with 2 SD of the confidence interval.

 
The magnitude of fall in TNF{alpha} was not related to basal body weight or to the degree of weight loss but was related to basal TNF{alpha} concentration (r = 0.55; P < 0.001). (Fig. 3Go)



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  		Figure 3. Regression analysis of basal TNF{alpha} vs. fall in TNF{alpha} after weight loss. The magnitude of fall in TNF{alpha} was related to basal TNF{alpha} concentration (r = 0.55, P < 0.001) The data are presented as the regression line, with 2 SD of the confidence interval.

 
The fall in serum TNF{alpha} concentrations after weight loss was not related to the fall in fasting insulin concentrations. Area under the curve (AUC) for insulin, after glucose challenge, fell significantly after weight loss (9355.59 ± 1407.07 vs. 6591.56 ± 1508.52; P < 0.01) (Fig. 4Go), but there was no correlation between the fall in TNF{alpha} and the decrease in AUC. The changes in lipid concentrations were as follows: total cholesterol fell from 5.7 ± 1.06 to 5.01 ± 0.01 mmol/L (P < 0.01); low-density-lipoprotein cholesterol fell from 3.53 ± 0.80 to 3.13 ± 0.61 mmol/L (P < 0.01). High-density-lipoprotein cholesterol increased from 1.43 ± 0.32 mmol/L to 1.48 ± 0.33 mmol/L (not significant). Serum triglycerides fell from 1.62 ± 0.90 to 1.13 ± 0.52 mmol/L (P < 0.01).



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  		Figure 4. AUC for insulin concentrations, before and after weight loss. AUC for insulin fell significantly after weight loss (P < 0.001). The data are presented as mean ± SD.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our data show clearly, for the first time, that serum TNF{alpha} concentrations in the obese are significantly greater than those in normal subjects and that after weight loss, TNF{alpha} concentrations fall significantly. In our patients, they fell by approximately 25%. The fall in serum TNF{alpha} concentrations after weight loss parallels the data on the diminution in the expression of TNF{alpha} in adipose tissue (40%), as demonstrated by Kern et al. (5) and Hotamisligil et al. (6, 7). It is possible that TNF{alpha} in serum reflects the level of expression of TNF{alpha} message and protein synthesis in adipose tissue.

Although we have no evidence for the source of plasma TNF{alpha} in the obese, it is probable that the adipose tissue is the immediate source of TNF{alpha} in these patients, because there is an overexpression of the TNF{alpha} gene in the obese.

The fall in serum TNF{alpha} concentrations after weight loss may contribute to the restoration of insulin sensitivity in obese patients who lose weight (8). The concomitant fall in AUC for insulin after glucose challenge in these patients is consistent with concept. Because there is no direct correlation between the fall in serum TNF{alpha} and the AUC for insulin, there are probably other factors that also contribute to the fall in insulin resistance after weight loss.

Weight loss in the obese leads to a fall in metabolic rate (9, 10); although this may be accounted for by a parallel decrease in lean body mass, it is tantalizing to suggest that TNF{alpha} may be the modulator of metabolic rate that is elevated in the obese and falls with weight loss. Experimental data from animals, however, suggests that very high TNF{alpha} infusion rates and plasma concentrations are required for inducing weight loss and cachexia (11, 12, 13). These concentrations may be relevant to clinical cachexia of malignancy and chronic infection. However, smaller increases in TNF{alpha} may be sufficient to induce changes in metabolic rates observed in obesity and after weight loss.

It has been suggested that insulin resistance at the adipose tissue level may be a mechanism to prevent lipid deposition in this tissue and that it may be a way to limit obesity (lipostat function) (4). This effect may be achieved through a combination of inhibition of lipogenesis and stimulation of lipolysis: in both of these actions, TNF{alpha} may play a role through antagonism of insulin action. It has also been observed that, whereas some obese patients have remarkable resistance to weight loss, some lean subjects have an equally remarkable inability to gain weight (14, 15).

In view of previous experimental data reported by Hotamisligil et al. (1, 2) and data on obese patients from Kern et al. (4), allied to our data reported in this paper, we would suggest that: 1) TNF{alpha} is a peptide constitutively expressed and secreted by adipose tissue, which increases in the obese; 2) this increased expression of TNF{alpha} is reflected in supranormal TNF{alpha} concentrations in serum and may contribute to insulin resistance; 3) after weight loss, TNF{alpha} expression and secretion fall, in association with a fall in serum TNF{alpha} concentration and a decrease in insulin secretion after glucose challenge, reflecting a fall in insulin resistance. Because TNF{alpha}, constitutively secreted by adipose tissue, may arrive through circulation at distal sites (like the skeletal muscle, the liver, and the heart) to induce an effect antagonistic to insulin, through the inhibition of the insulin receptor tyrosine kinase, TNF{alpha} may well be qualified to be termed a hormone, whose constitutive source, the adipose organ, may thus be termed an endocrine organ.

Received June 30, 1997.

Revised April 21, 1998.

Accepted April 30, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Hotamisligil GS, Shargill NS, Spiegelman BM. 1993 Adipose expression of tumor necrosis factor-{alpha}: direct role in obesity-linked insulin resistance. Science. 259:87–91.[Abstract/Free Full Text]
  2. Hotamisligil GS, Budavari A, Murray D, Spiegelman BM. 1994 Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-{alpha}. J Clin Invest. 94:1543–1549.
  3. Cheatham B, Kahn CR. 1995 Insulin action and insulin signalling network. Endocr Rev. 16:117–142.[CrossRef][Medline]
  4. Eckel RH. 1992 Insulin resistance: an adaption for weight maintenance. Lancet. 340:1452–1453.[CrossRef][Medline]
  5. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. 1995 The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 95:2111–2119.
  6. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. 1995 Increased adipose expression of tumor necrosis factor-{alpha} in human obesity and insulin resistance. J Clin Invest. 95:2409–2415.
  7. Hotamisligil GS, Arner P, Atkinson RL, Spiegelman BM. 1997 Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance. Diabetes. 46:451–455.[Abstract]
  8. Friedenberg GR, Reichart D, Olefsky JM, Henry RR. 1988 Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin dependent diabetes mellitus. Effect of weight loss. J Clin Invest. 82:1398–1406.
  9. Amatruda JM, Statt MC, Welle SL. 1993 Total and resting energy expenditure in obese women reduced to ideal body weight. J Clin Invest. 92:1236–1242.
  10. Leibel RL, Rosenbaum M, Hirsch J. 1995 Changes in energy expenditure resulting from altered body weight. N Engl J Med. 332:621–628.[Abstract/Free Full Text]
  11. Oliff A, Defeo-Jones D, Boyer BC, et al. 1987 Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 50:555–563.[CrossRef][Medline]
  12. Grunefeld C, Wilking H, Neese R, et al. 1989 Persistence of the hypertriglyceridemic effect of tumor necrosis factor despite development of tachyphylaxis to its anorectic/cachectic effects in rats. Cancer Res. 49:2554–2560.[Abstract/Free Full Text]
  13. Spiegelman BM, Hotamisligil GS. 1993 Through thick and thin: fasting, obesity, and TNF{alpha}. Cell. 73:625–627.[CrossRef][Medline]
  14. Sims, EAH. 1976 Experimental obesity, dietary induced thermogenesis and their clinical implications. J Clin Endocrinol Metab. 5:377–395.
  15. Bouchard C, Tremblay A, Després J-P, et al. 1990 The response to long-term overfeeding in identical twins. N Engl J Med. 322:1477–1482.[Abstract]



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Diabetes, December 1, 2003; 52(12): 2882 - 2887.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
V. De Leo, A. la Marca, and F. Petraglia
Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome
Endocr. Rev., October 1, 2003; 24(5): 633 - 667.
[Abstract] [Full Text] [PDF]

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 J ANIM SCIHome page
J. A. Daniel, T. H. Elsasser, C. D. Morrison, D. H. Keisler, B. K. Whitlock, B. Steele, D. Pugh, and J. L. Sartin
Leptin, tumor necrosis factor-{alpha} (TNF), and CD14 in ovine adipose tissue and changes in circulating TNF in lean and fat sheep
J Anim Sci, October 1, 2003; 81(10): 2590 - 2599.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
J. M. Bruun, A. S. Lihn, C. Verdich, S. B. Pedersen, S. Toubro, A. Astrup, and B. Richelsen
Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans
Am J Physiol Endocrinol Metab, September 1, 2003; 285(3): E527 - E533.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
T. Alon, J. M. Friedman, and N. D. Socci
Cytokine-induced Patterns of Gene Expression in Skeletal Muscle Tissue
J. Biol. Chem., August 22, 2003; 278(34): 32324 - 32334.
[Abstract] [Full Text] [PDF]

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 DiabetesHome page
G. Engstrom, B. Hedblad, L. Stavenow, P. Lind, L. Janzon, and F. Lindgarde
Inflammation-Sensitive Plasma Proteins Are Associated With Future Weight Gain
Diabetes, August 1, 2003; 52(8): 2097 - 2101.
[Abstract] [Full Text] [PDF]

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 DiabetesHome page
T. Gohda, Y. Makita, T. Shike, M. Tanimoto, K. Funabiki, S. Horikoshi, and Y. Tomino
Identification of Epistatic Interaction Involved in Obesity Using the KK/Ta Mouse as a Type 2 Diabetes Model: Is Zn-{alpha}2 Glycoprotein-1 a Candidate Gene for Obesity?
Diabetes, August 1, 2003; 52(8): 2175 - 2181.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
P. Dandona, A. Aljada, A. Chaudhuri, and A. Bandyopadhyay
The Potential Influence of Inflammation and Insulin Resistance on the Pathogenesis and Treatment of Atherosclerosis-Related Complications in Type 2 Diabetes
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2422 - 2429.
[Full Text] [PDF]

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 EndocrinologyHome page
C. J. Lyon, R. E. Law, and W. A. Hsueh
Minireview: Adiposity, Inflammation, and Atherogenesis
Endocrinology, June 1, 2003; 144(6): 2195 - 2200.
[Abstract] [Full Text] [PDF]

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 Obstet GynecolHome page
G. Amato, M. Conte, G. Mazziotti, E. Lalli, G. Vitolo, A. T. Tucker, A. Bellastella, C. Carella, and A. Izzo
Serum and Follicular Fluid Cytokines in Polycystic Ovary Syndrome During Stimulated Cycles
Obstet. Gynecol., June 1, 2003; 101(6): 1177 - 1182.