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Original Studies |
in Sera of Obese Patients: Fall with Weight Loss
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.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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(TNF)
expression, that this expression falls with weight loss, and that
TNF may specifically inhibit insulin action, the possibility that
TNF may be a mediator of insulin resistance has been raised. We have
undertaken this study to investigate whether serum TNF
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 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 were related to basal body weight
(r = 0.57, P < 0.001) and basal TNF
(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 concentrations, which fall with weight
loss. Because circulating TNF may mediate insulin resistance in the
obese, a fall in TNF concentrations may contribute to the
restoration of insulin resistance after weight loss, Thus, TNF may
be an important circulating cytokine, which may provide a potentially
reversible mechanism for mediating insulin resistance. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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(TNF) is constitutively expressed by
adipose tissue; 2) genetically obese mice (ob/ob mice) and rats (fa/fa
Zucker) have increased expression of TNF in their adipose tissue (1, 2); and 3) TNF may be a mediator of insulin resistance (1, 2) known
to occur in these animals. TNF 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
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 may be a local modulator of adipocyte’s activity
and its ability to accumulate fat. Administration of soluble TNF
receptor, which binds to TNF and serves as an inhibitor of TNF
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 and that, unlike macrophages, the adipose
tissue does not respond to endotoxin by increasing the
expression/synthesis of TNF (5, 6). Furthermore, they have also
shown that, in adipocytes from obese subjects, the expression of TNF
message and protein falls markedly after weight loss (5, 6).
Because TNF 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 in
plasma/serum. In this way, TNF 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 in a series
of obese patients before and after weight loss.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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.
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 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 in serum. This
allows the measurement of TNF 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 concentrations in the obese patients and
normal subjects were compared by Student’s t test for
unpaired data, whereas the serum concentrations of TNF 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.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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. 1
). TNF concentrations were not
related to body weight or BMI. TNF 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 1), 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 concentrations in the obese
fell from 3.45 ± 0.16 to 2.63 ± 1.40 pg/mL
(P < 0.02) (Fig. 2).
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was not related to basal body weight or
to the degree of weight loss but was related to basal TNF
concentration (r = 0.55; P < 0.001). (Fig. 3)
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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. 4), but there was no correlation between
the fall in TNF 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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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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concentrations in the obese are significantly greater than those in
normal subjects and that after weight loss, TNF concentrations fall
significantly. In our patients, they fell by approximately 25%. The
fall in serum TNF concentrations after weight loss parallels the
data on the diminution in the expression of TNF in adipose tissue
(40%), as demonstrated by Kern et al. (5) and Hotamisligil
et al. (6, 7). It is possible that TNF in serum reflects
the level of expression of TNF message and protein synthesis in
adipose tissue.
Although we have no evidence for the source of plasma TNF in the
obese, it is probable that the adipose tissue is the immediate source
of TNF in these patients, because there is an overexpression of the
TNF gene in the obese.
The fall in serum TNF 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
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 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 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 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 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 is a peptide constitutively expressed and
secreted by adipose tissue, which increases in the obese; 2) this
increased expression of TNF is reflected in supranormal TNF
concentrations in serum and may contribute to insulin resistance; 3)
after weight loss, TNF expression and secretion fall, in association
with a fall in serum TNF concentration and a decrease in insulin
secretion after glucose challenge, reflecting a fall in insulin
resistance. Because TNF, 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 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.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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H. F. Escobar-Morreale, R. M. Calvo, J. Sancho, and J. L. San Millan TNF-{alpha} and Hyperandrogenism: A Clinical, Biochemical, and Molecular Genetic Study J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3761 - 3767. [Abstract] [Full Text] [PDF]
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 F. Nishimura and Y. Murayama CONCISE REVIEW Biological: Periodontal Inflammation and Insulin Resistance-- Lessons from Obesity Journal of Dental Research, August 1, 2001; 80(8): 1690 - 1694. [Abstract] [PDF]
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P. A. Kern, S. Ranganathan, C. Li, L. Wood, and G. Ranganathan Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance Am J Physiol Endocrinol Metab, May 1, 2001; 280(5): E745 - E751. [Abstract] [Full Text] [PDF]
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J. M. Bruun, S. B. Pedersen, and B. Richelsen Regulation of Interleukin 8 Production and Gene Expression in Human Adipose Tissue in Vitro J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1267 - 1273. [Abstract] [Full Text]
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H. Ghanim, R. Garg, A. Aljada, P. Mohanty, Y. Kumbkarni, E. Assian, W. Hamouda, and P. Dandona Suppression of Nuclear Factor-{{kappa}}B and Stimulation of Inhibitor {{kappa}}B by Troglitazone: Evidence for an Anti-inflammatory Effect and a Potential Antiatherosclerotic Effect in the Obese J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1306 - 1312. [Abstract] [Full Text]
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D. Le Roith and Y. Zick Recent Advances in Our Understanding of Insulin Action and Insulin Resistance Diabetes Care, March 1, 2001; 24(3): 588 - 597. [Abstract] [Full Text]
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P. Dandona, P. Mohanty, H. Ghanim, A. Aljada, R. Browne, W. Hamouda, A. Prabhala, A. Afzal, and R. Garg The Suppressive Effect of Dietary Restriction and Weight Loss in the Obese on the Generation of Reactive Oxygen Species by Leukocytes, Lipid Peroxidation, and Protein Carbonylation J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 355 - 362. [Abstract] [Full Text]
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N. Zeghari, H. Vidal, M. Younsi, O. Ziegler, P. Drouin, and M. Donner Adipocyte membrane phospholipids and PPAR-gamma expression in obese women: relationship to hyperinsulinemia Am J Physiol Endocrinol Metab, October 1, 2000; 279(4): E736 - E743. [Abstract] [Full Text] [PDF]
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J.-P. Bastard, C. Jardel, E. Bruckert, P. Blondy, J. Capeau, M. Laville, H. Vidal, and B. Hainque Elevated Levels of Interleukin 6 Are Reduced in Serum and Subcutaneous Adipose Tissue of Obese Women after Weight Loss J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3338 - 3342. [Abstract] [Full Text]
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T. Rönnemaa, K. Pulkki, and J. Kaprio Serum Soluble Tumor Necrosis Factor-{alpha} Receptor 2 Is Elevated in Obesity But Is Not Related to Insulin Sensitivity: A Study in Identical Twins Discordant for Obesity J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2728 - 2732. [Abstract] [Full Text]
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A. Aljada, R. Saadeh, E. Assian, H. Ghanim, and P. Dandona Insulin Inhibits the Expression of Intercellular Adhesion Molecule-1 by Human Aortic Endothelial Cells through Stimulation of Nitric Oxide J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2572 - 2575. [Abstract] [Full Text]
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N. Paquot, M. J. Castillo, P. J. Lefèbvre, and A. J. Scheen No Increased Insulin Sensitivity after a Single Intravenous Administration of a Recombinant Human Tumor Necrosis Factor Receptor: Fc Fusion Protein in Obese Insulin-Resistant Patients J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1316 - 1319. [Abstract] [Full Text]
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L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]
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Y. Nakai, S. Hamagaki, R. Takagi, A. Taniguchi, and F. Kurimoto Plasma Concentrations of Tumor Necrosis Factor-{alpha} (TNF-{alpha}) and Soluble TNF Receptors in Patients with Anorexia Nervosa J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1226 - 1228. [Abstract] [Full Text]
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