| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Department of Anesthesiology and Critical Care, Mayo Clinic (D.R.B.), Rochester, Minnesota 55905; Department of Anesthesiology, Johns Hopkins University School of Medicine (D.E.B.), Baltimore, Maryland 21287; and ICUSA, Inc. (M.J.B.), Baltimore, Maryland 21224
Address all correspondence and requests for reprints to: Daniel R. Brown, M.D., Ph.D., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: brown.daniel{at}mayo.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Leptin is an adipocyte product that is thought to represent the afferent signal in a feedback mechanism regulating fat mass (3, 4). After release by adipocytes, leptin modulates food intake and energy balance (5, 6) through its actions at specific receptors in the hypothalamus (7). Downstream effects after activation of central leptin receptors include inhibition of hypothalamic biosynthesis and release of neuropeptide Y, a hormone that stimulates appetite and food intake and reduces energy expenditure (8). Mice that lack the ability to produce (ob) or respond to (db) leptin are characterized by obesity and energy-conserving behavior (4, 9). Leptin repletion in ob mice produces weight loss and resumption of energy-consuming behavior (6). Weight loss may also occur with exogenous administration of leptin in normal, and even lean, animals (10) and humans (11). By what mechanism(s) leptin secretion is regulated remains to be elucidated, although leptin expression has been shown to be dramatically altered by cytokines.
Tumor necrosis factor-
(TNF), interleukin-6 (IL-6), and IL-1
increase ob gene expression and leptin secretion
(12, 13, 14). These same cytokines have been suggested to play
a role in cancer cachexia as well, although this association is less
clear. TNF administration causes cachexia in humans and animals,
although it does not appear to be elevated in animal cancer models or
human cancer patients. It has been postulated that TNF acts as a
paracrine/autocrine mediator rather than being the circulating
messenger in cachexia (1). In contrast, increasing levels
of IL-6 have been shown to correlate with the development of cachexia
in the murine colon-26 adenocarcinoma model (15).
Furthermore, elevated levels of IL-6 have been reported in cancer
patients (16, 17), although this is not a universal
finding. Again, it is possible that systemic IL-6 concentrations need
not be elevated, as IL-6 may act as a paracrine/autocrine mediator.
Supporting this is work showing increased peripheral blood mononuclear
cell IL-6 production in pancreatic cancer patients despite normal serum
IL-6 concentrations (2). Less information is available
regarding IL-1 and cachexia, although IL-1 modulates IL-6 production
and may thereby play a role in cancer cachexia (18).
These observations prompted speculation that elevated leptin levels may contribute to the pathological weight loss of cancer cachexia (12). A study of lung cancer patients with pathological weight loss found no increase in leptin levels, and the researchers speculated that a disturbance in hypothalamic responses to leptin may contribute to negative energy balance in these patients (19). As multiple different mechanisms probably contribute to pathological weight loss in cancer and may differ between cancers of different cell types, we investigated the relationship among plasma leptin concentrations, weight loss, and appetite in patients with pancreatic cancer.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Preoperatively, patients were interviewed about body weight and appetite during the 6 months before surgery. Baseline weight was defined as the patient’s weight 6 months before surgery. A calibrated balance beam scale determined body weight with patients wearing standard clothes and no shoes. Height was directly measured. Cachexia was defined as an unintentional 10% decrease in body weight occurring during the 6 months before surgery. Patients were asked whether their appetite over the past 6 months was increased, decreased, or unchanged.
All patients had their surgery performed as the first case of the day having fasted after midnight according to standard preoperative orders. Blood samples for plasma leptin determinations were obtained between 0800–0900 h. Samples were collected in ethylenediamine tetraacetate vacuum tubes, placed on ice, and immediately centrifuged at 5 C. Serum was frozen at -80 C, and leptin assays were performed in batches. Leptin levels were determined in duplicate with a commercial double antibody RIA using rabbit antihuman leptin, 125I-labeled human leptin as tracer, and human leptin standards (Linco Research, Inc., St. Louis, MO). The lower level of detection is 0.5 ng/mL. The intra- and interassay coefficients of variation were less than 10%. Reported leptin concentrations are the mean of two determinations of the same sample.
Statistics
Demographic data are reported as mean ± SD.
2 analysis was performed to evaluate
relationships between changes in body weight and appetite. Linear
regression analysis was used to evaluate the relationships between
plasma leptin and weight loss. Leptin concentrations were corrected for
body mass index (BMI) using published population data for men and women
(20). Corrected leptin concentrations greater than 2 times
those predicted were considered elevated. 2
analysis was performed to evaluate whether hyperleptinemic patients had
an increased incidence of cachexia or appetite loss. P
< 0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. Thirty-nine patients were male.
Overall, slightly less than half of the patients were cachectic, a
similar proportion of patients reported decreased appetite. There was a
significant association between patients with weight loss and decreased
appetite (P < 0.025).
|
presents the relationship
between plasma leptin concentration and BMI. The solid lines
represent previously reported regression lines for BMI and leptin in
healthy volunteers (20). There was no relationship between
leptin concentration and weight loss (Fig. 2). Despite significant weight loss in
some patients, all but four patients had leptin levels above the lower
limit of detection of the leptin assay. The majority of tumors (n
= 59) were adenocarcinomas with four islet cell tumors
(squares in graphs) and one histiocytoma (circles
in graphs).
|
|
). Thirteen of 25 women and 16 of
39 men had leptin concentrations less than 50% of those expected based
on BMI. There was no difference in the incidence of cachexia and change
in appetite in this subgroup from those in the remaining patients. Of
note, five men and one woman had leptin concentrations more than twice
the level expected. The incidence of cachexia and change in appetite
were not different from those in the remaining patients. |
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Although our data suggest that hyperleptinemia is not associated with pancreatic cancer, the interpretation is limited by the lack of a simultaneously studied control group with similar body composition. Unfortunately, patients in the present study were not available for preoperative determination of body composition. We used a previously reported leptin to BMI relationship (20) as the control to which our patients were compared. This previously reported relationship encompasses the range of BMIs in our population, the assay was performed with the same type of commercial assay, and our intra- and interassay coefficients of variation were within acceptable limits. Of note, several patients underwent surgery in which no cancer was found, and none of the leptin concentrations in these patients was more than twice or less than half of that expected based on BMI, suggesting that our leptin assay and comparison group were appropriate.
Another limitation of the current study is the use of self-evaluated changes in weight and appetite. It is possible that reported appetite changes might be weighted to very recent changes in appetite. However, we were most interested in recent appetite and its relationship with recent changes in body weight, as we assumed that were leptin to be playing a role in cachexia, its influence would parallel changes in appetite and/or body weight. In an effort to provide the most accurate history of weight and appetite, all interviews were performed preoperatively, and family and friends (when available) were used to confirm the accuracy of responses.
Although we did observe lower than expected leptin concentrations in many patients, there was no correlation with weight loss or decreased appetite. We speculate that low leptin concentrations in these patients may be due to altered body composition. Prior studies have shown that fat mass is decreased in patients with cancer (19). Leptin levels are highly correlated with the amount of body fat (20). Thus, lower than expected leptin levels may reflect reduced body fat mass in these cachectic patients. Simons et al. reported even more pronounced alterations in leptin concentrations in patients with lung cancer; levels were undetectable in 15 of 21 patients (19). It is interesting to note that Simons’ work was performed in The Netherlands, and it is possible that cultural differences in eating patterns and body habitus may have contributed to lower leptin concentrations in the patients with lung cancer. Alternatively, different tumor types may account for the differing results in these two studies.
Several of the pancreatic cancer patients had markedly elevated leptin levels. Although these patients did not report excessive weight loss or decreased appetite, the numbers were small, and it is unknown how long these patients were hyperleptinemic. It is interesting to speculate whether these individuals would have gone on to develop weight loss if the tumors were not removed. Alternatively, hypercortisolism, which may be associated with neoplasms and is associated with elevated leptin concentrations, may have contributed to hyperleptinemia in this group. No plasma cortisol levels were determined in these patients.
Despite our data suggesting that hyperleptinemia is not associated with pancreatic cancer cachexia, this does not preclude a role for leptin in this form of pathological weight loss. We did not perform a rigorous evaluation of leptin secretion over time. It is possible that there are pulsatile and/or circadian differences in leptin secretion that contribute to cachexia. Furthermore, abnormalities in the leptin pathway distal to the adipocyte (increased central sensitivity, altered neuropeptide Y synthesis/sensitivity) (21) could contribute to weight loss in cancer patients. Finally, leptin may act as a paracrine or autocrine pathway for other factors. A cachexia factor has been isolated in the urine of cachectic cancer patients as well as in murine models of cancer cachexia (22). The relationship between this factor and leptin remains unknown. The mechanism by which this or other cytokines may cause cachexia remains to be defined, although activation of the ATP-ubiquitin-proteasome pathway, which results in protein breakdown, has been shown in several models of cancer cachexia (23, 24).
Cachexia in cancer patients is a difficult subject to study, as there are many factors that determine net caloric balance. Tumor burden, direct gastrointestinal tract effects of the tumor, mood depression, and side-effects of treatment, such as chemotherapy-associated nausea, may also contribute to pathological weight loss. In the present population, tumors were uniformly small, as patients with pancreatic cancer are surgical candidates at our institution only early in their disease course. Although it is possible that tumors in the head of the pancreas may block pancreatic enzyme secretion and thereby influence nutrient absorption, we attempted to correct for this by excluding patients who were receiving pancrease therapy. No attempt was made to evaluate whether depression contributed to the loss of appetite. None of the patients studied had received chemotherapy.
In conclusion, in this group of pancreatic cancer patients, elevated fasting plasma leptin concentrations were not associated with cachexia or changes in appetite. The leptin axis may still contribute to pathological weight loss in other states or by other mechanisms. Cachexia remains a significant clinical problem that deserves further investigation to determine its pathophysiology and possible therapeutic interventions.
|
Footnotes |
|---|
Received November 5, 1999.
Revised June 5, 2000.
Revised August 28, 2000.
Accepted September 14, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  E. R. Ropelle, J. R. Pauli, K. G. Zecchin, M. Ueno, C. T. de Souza, J. Morari, M. C. Faria, L. A. Velloso, M. J. A. Saad, and J. B. C. Carvalheira A Central Role for Neuronal Adenosine 5'-Monophosphate-Activated Protein Kinase in Cancer-Induced Anorexia Endocrinology, November 1, 2007; 148(11): 5220 - 5229. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Huang, X. Zhang, Z.-W. Jiang, B.-Z. Liu, N. Li, and J.-S. Li Hypoleptinemia in Gastric Cancer Patients: Relation to Body Fat Mass, Insulin, and Growth Hormone JPEN J Parenter Enteral Nutr, July 1, 2005; 29(4): 229 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Basso, C Millino, E Greco, C Romualdi, P Fogar, A Valerio, M Bellin, C-F Zambon, F Navaglia, N Dussini, et al. Altered glucose metabolism and proteolysis in pancreatic cancer cell conditioned myoblasts: searching for a gene expression pattern with a microarray analysis of 5000 skeletal muscle genes Gut, August 1, 2004; 53(8): 1159 - 1166. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Santolaria, A. Perez-Cejas, M.-R. Aleman, E. Gonzalez-Reimers, A. Milena, M.-J. De La Vega, A. Martinez-Riera, and M.-A. Gomez-Rodriguez LOW SERUM LEPTIN LEVELS AND MALNUTRITION IN CHRONIC ALCOHOL MISUSERS HOSPITALIZED BY SOMATIC COMPLICATIONS Alcohol Alcohol., January 1, 2003; 38(1): 60 - 66. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
