| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Special Articles |
Nutrition and Toxicology Research Center, NUTRIM, University of Maastricht (C.J.H., W.H.M.S., M.S.W.-P.), 6200 MD Maastricht, The Netherlands; Hoffmann-La Roche, Inc. (A.R.F.), Nutley, New Jersey 07110; and Department of Food Science and Human Nutrition, Colorado State University (F.J.S., L.A.C.), Fort Collins, Colorado 80523
Address correspondence and requests for reprints to: Wim H. M. Saris, Nutrition and Toxicology Research Center "NUTRIM," Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. E-mail: w.saris{at}hb.unimaas.nl
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
New scientific information concerning the regulation of energy balance and fat mass has emerged since the discovery of leptin (also known as OB protein). Evidence from many animal studies and observational studies in humans suggests that this hormone, which is secreted primarily from adipocytes in proportion to cell size, seems to play a role in the control of body fat stores by acting within the central nervous system to coordinate the regulation of feeding behavior, metabolism, autonomic nervous system, and body energy balance in rodents, primates, and humans (4, 5, 6). Although obese individuals have increased serum concentrations of leptin (7, 8) and concomitant decreased sensitivity to leptin, therapeutic augmentation of the circulating leptin levels, by administration of leptin, may result in increased leptin signaling and action in a manner similar to use of exogenous insulin to increase insulin signaling in noninsulin-dependent diabetes mellitus (4, 5). Thereby, reductions of food intake, body fat mass, and body weight in obese patients may result from treatment with recombinant leptin.
Since its identification, interest within the medical community
in the effects (if any) of treatment of obese individuals with leptin
has been significant (4). However, only initial
interventional studies in humans are available to support these
suggestions. In trials sponsored by Amgen Inc.,
significant dose-related reductions in body fat and body weight (up to
-7.1 kg in the highest dose group) were observed following daily sc
treatment with from 0.01–0.30 mg/kg recombinant human met-leptin for
24 weeks in obese subjects (9). In the treatment of a
young very obese girl with a mutated ob gene, daily sc
injection of low doses of met-leptin (dose of 0.028 mg/kg of lean mass
calculated to cause a circulating concentration 
10% of what would
be predicted based on her body fat) has been reported. Daily met-leptin
treatment caused a dramatic reduction in appetite, food-seeking
behavior, food intake, and body weight (10). The results
of treatment of this girl with congenital leptin deficiency
(10), taken together with the results of the clinical
trials in obese adults (9), indicate that leptin has
biological activity in at least some obese humans and that among its
activities are reductions in appetite and food intake at low doses and
reductions in body fat and body weight at the maximal dose studied.
Leptin has been reported to have a very short apparent half-life in animals (11, 12) and humans (13). Polyethylene glycols (PEG) are amphiphilic polymers of ethylene glycol with varying average molecular weights that can be activated and covalently attached to proteins. Modification of proteins through pegylation, covalent linkage of PEG polymers to the protein, has resulted in increased serum half-life and reduced immunogenicity for a number of proteins (14, 15, 16). This technology was applied to leptin to produce pegylated recombinant native human leptin or PEG-OB protein (PEG-OB), which was used in this study. Preclinical studies with PEG-OB indicate an extended half-life in rodents (>48 h) compared with that reported for recombinant native human leptin (data not shown) and efficacy for reduction of food intake and body weight of rats treated daily with sc PEG-OB for 8 days (17, 18).
We undertook a double blind, randomized study to determine the biological activity and safety of elevating serum levels of leptin using PEG-OB in comparison with placebo in obese men on a mild hypocaloric diet.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This single center trial had a prospective, randomized double blind placebo-controlled group design. This study was conducted according to the guidelines for Good Clinical Practice and was monitored by Hoffmann-La Roche, Inc. (Welwyn, UK).
Obese [body mass index (BMI), 
27.0 kg/m2] men
18–60 yr of age were eligible for inclusion. Recruitment was from the
Institute waiting list or by local advertising. All aspects of the
study conformed to the declaration of Helsinki. The ethics committee of
the University of Maastricht approved the study, and all participants
gave written informed consent. Patients with obesity-related diseases
requiring pharmacological treatment (e.g. diabetes,
hypertension, dyslipidemia) were excluded. Other exclusion criteria
were: weight loss more than 3 kg in the previous 3 months; presence of
any significant illness, including laboratory or electrocardiogram
abnormalities; history or presence of drug abuse or alcoholism; and
smoking more than five cigarettes or equivalent per day. Also, known
allergy, history of atopy or hypersensitivity to pegylated proteins,
and use of any drug that might have influenced body weight or serum
lipids led to exclusion.
Study design
After screening, 30 patients were selected and enrolled. Baseline energy expenditure, body composition, and metabolic profile (including lipid profile and insulin sensitivity) were measured. Patients were stratified and matched into pairs according to age, BMI, and serum leptin and insulin concentrations to achieve balanced treatment groups. Randomization numbers for patients were generated and incorporated into the double blind labeling by a third party. During the treatment period, either an injection of 20 mg PEG-OB (2 mL, 10 mg/mL-1) or placebo (2 mL) were given sc, in the para-umbilical region, weekly for 12 weeks. In addition, all subjects were prescribed a hypocaloric diet (500 kcal or 2 MJ/day deficit). The energy content of the diet was based on the measured energy expenditure of each subject (see below). The dietary prescription was discussed every 2 weeks with a dietitian. Subjects came to the laboratory in the morning, in a fasting state, each week to receive treatment. Vital signs and body weight were recorded, and blood samples were taken for standard laboratory tests. At the end of the 12-week treatment period, energy expenditure, body composition, and metabolic profile were measured again.
Measurements of energy expenditure and body composition
Energy expenditure and substrate utilization were measured during a 36-h stay in a respiration chamber while the subjects were maintained in energy balance by adjusting the food provided (19). Macronutrient composition of the diet was fixed at 45/15/40% of energy for carbohydrate, protein, and fat, respectively. The respiration chamber is a 14 m2 room furnished with a bed, chair, wash bowl, toilet, and radio/TV set and telephone. While in the chamber, subjects had to follow a standardized physical activity program, including controlled exercise for 35 min on a bicycle ergometer (starting at 40 W for 5 min, followed by 80 W for 30 min). Two exercise sessions took place; one in the morning at 1000 h and the other one in the afternoon at 1500 h. Gas sampling and analysis from the chamber is described in detail elsewhere (20).
Total energy expenditure, sleeping metabolic rate (SMR), and respiratory quotient (RQ) were calculated during the last 24 h in the chamber. Energy expenditure was calculated from the O2 consumption and CO2 production according to the method of Weir (21). SMR was calculated from the sleep period between 0300 and 0600 h, controlled for physical activity by a Doppler radar system. Body weight was measured (with a calibrated digital scale accurate to 0.01 kg), and height was measured to the nearest 0.001 m. Body composition was determined after leaving the respiration chamber in the morning by using hydrodensitometry and deuterium dilution (22). Body composition was calculated using the combined equation of Siri (23).
Blood chemistry and pharmacokinetics
Fasting serum concentrations of glucose, insulin, free fatty acids, glycerol, triglycerides, total cholesterol, and high-density lipoprotein (HDL) cholesterol were measured at baseline (day 1) and after 12 weeks of treatment (day 85). Samples were stored at -80 C and analyzed by a certified laboratory. Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald equation (24).
Insulin sensitivity was assessed by the short insulin tolerance test (25). After an overnight fast, sampling and injection catheters were placed. Arterialized venous blood samples were collected after insulin was iv injected (Human Actrapid; Novo Nordisk A/S, Bagsvaerd, Denmark; 0.1 U kg-1 body weight). The test was terminated after 16 min by an iv glucose injection. The rate constant for plasma glucose disappearance (Kitt) was calculated using a linear regression line fitted through the blood glucose values from 4–16 min because no changes in blood glucose were noted within 4 min after insulin injection.
Fasting blood samples for the measurement of serum concentrations of leptin and PEG-OB were collected weekly before the next dosing and analyzed at Hoffman-La Roche Inc. (Nutley, NJ). For the pharmacokinetics of leptin and PEG-OB, a frequent sampling schedule was applied in weeks 1 and 12. Serum leptin concentrations were measured using a double-antibody "sandwich" enzyme-linked immunosorbent assay using a monoclonal antibody specific for human leptin. The lower level of detection is 0.5 ng/mL, and the upper limit is 50 ng/mL. The intra- and interassay variations were 9% and 12%, respectively. The leptin levels of normal weight subjects ranged from 2–12 ng/mL. PEG-OB concentrations were measured using a similar enzyme-linked immunosorbent assay after separating PEG-OB from leptin by size exclusion. Quality control samples covering a range of leptin and PEG-OB concentrations were included in each assay. Both assays were verified by appropriate recovery and cross-reaction experiments.
Safety
Safety of PEG-OB was monitored during each visit by documentation of adverse events and the recording of vital signs on Case Report Forms. Routine clinical hematology and biochemical tests and urine analysis were done weekly.
PEG-OB
Recombinant native human leptin, expressed and purified from Escherichia coli, was chemically conjugated to a species of branched PEG molecule with an average molecular weight of 42 kD in a 1:1 ratio. The result was a globular PEG—native human leptin polymer with increased molecular size (26, 27). PEG-OB at a concentration of 10 mg/mL was placed in sterile glass vials containing 1.3 mL.
Statistical analysis
The number of subjects needed was calculated as follows. Results of clinical trials using a hypocaloric diet and orlistat treatment (120 mg t.i.d.) for 12 weeks reported weight loss in 1022 placebo-treated subjects as 2.23 kg with a SD of 3.04 kg (Roche orlistat protocols 14119B, M14119, M14149, M14161, and M14185). With this information, power calculation indicated that 25 subjects per treatment group were needed to detect an additional weight reduction in the PEG-OB group of 4.0 kg over that seen in the placebo group with a power of 90%, assuming a SD of 3 kg. Assuming a 20% dropout rate, 30 subjects per treatment group would be required. This number of subjects was also sufficient to detect a difference in change from baseline SMR between the groups of 0.21 kJ per min with a power of 90%. This calculation was based on a SD of SMR in a single subject of 0.16 kJ per min with an estimated SMR of 5.3 kJ per min, accordingly to the WHO equation (28). However, after the first 30 subjects completed the study, a planned interim analysis was conducted and the study of weekly 20-mg sc PEG-OB was prematurely stopped by the sponsor due to lack of efficacy for weight loss at the dose tested.
Changes from baseline after 12 weeks of treatment were compared between the PEG-OB-treated and placebo group using factorial ANOVA. Post hoc, for each comparison separately, ANOVA with repeated measures was used. Additional statistical tests were used when appropriate. All statistical tests were two-sided, and significance was defined as P < 0.05. All data are presented as mean ± SEM, unless otherwise indicated.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
. The characteristics
of the 15 subjects randomized to each treatment group were similar. All
30 subjects who were randomized into the two treatment groups completed
the trial.
|
Serum concentrations of PEG-OB during the study are shown in Fig. 1. Following weekly sc dosing, sustained
serum levels of PEG-OB, measured just before the next dose, ranging
from 200–300 ng/mL, were observed. The PEG-OB serum profile after sc
injection was similar after the first (day 1) and 12th weekly (day 78)
dose (Fig. 1). Following a sc injection, mean peak serum PEG-OB
concentrations were achieved 72 h after dosing, followed by a
return to the elevated pre-dose levels after 1 week.
|
. Baseline total leptin
concentrations were 20.4 ± 4.9 and 21.9 ± 4.9 ng/mL
(mean ± SEM) in the placebo and PEG-OB treatment
groups, respectively. Total leptin serum concentrations increased
slightly to a new steady-state level (24.0 ng/mL during weeks 9–12 of
the study) in subjects treated with PEG-OB, whereas total leptin
concentrations fell with weight loss in placebo-treated subjects (14.6
ng/mL during weeks 9–12 of the study) (Fig. 2).
|
The effect of PEG-OB treatment or placebo treatment on body
weight, body composition, and energy expenditure are given in Table 2. The mean body weight change was
-5.4 ± 0.8 kg in all 30 subjects studied. Subjects in both the
placebo (n = 15) and PEG-OB (n = 15) treatment groups lost
weight, and the amount of weight loss was similar in both groups (day
85 body weight: placebo, 102.2 ± 4.1 kg, delta, -6.4 kg; PEG-OB,
103.0 ± 3.0; delta, -4.3 kg). There was no significant
difference in the delta or percent weight loss between the PEG-OB and
placebo groups (Table 2). The mean changes in percent body fat and
sleeping metabolic rate of all 30 subjects were -1.4 ± 0.4% and
-0.4 ± 0.07 kJ/min, respectively, and there were no significant
differences between PEG-OB and placebo. No differences were observed in
RQ between the treatment groups. Using a technique pioneered in the
clinical trials with the lipase inhibitor orlistat, subjects were
classified as "good" losers (delta body weight at 4 weeks 2.5 kg)
and "poor" losers (delta body weight at 4 weeks <2.5 kg) in each
treatment groups (29, 30, 31). An imbalance of the
distribution was observed with more good losers (8 of 15 or 53%) in
the placebo group than the PEG-OB group (5 of 15 or 33%).
|
The effect of 20 mg PEG-OB or placebo treatment on the metabolic
profile is shown in Table 3. No
significant differences in serum glucose or insulin concentrations from
baseline were observed at the end of the 12-week treatment period, and
there were no differences between the treatment groups. Insulin
sensitivity (measured by the short insulin tolerance test) also showed
no significant differences between both groups before and after
treatment.
|
), no significant differences were
observed. Although larger reductions in serum concentrations of
triglycerides within subjects were observed at the end of the 12-week
treatment period in the PEG-OB treatment compared with the placebo
treatment group (PEG-OB, delta = -0.35 ± 0.15 mmol/L
vs. placebo, delta = -0.17 ± 0.12 mmol/L), these
differences were not statistically significant. The change in serum
tri-glycerides from baseline as a function of body weight loss is shown
in Fig. 3. Percent change in serum
triglycerides from baseline was significantly correlated with the
amount of body weight loss in the PEG-OB treatment group
(P < 0.01) but not in the placebo treatment group. No
significant differences in serum glycerol, LDL-cholesterol, and
HDL-cholesterol concentrations from baseline were observed at the end
of the 12-week treatment period, and there were no differences between
the treatment groups.
|
The most common adverse events related to PEG-OB treatment are
shown in Table 4. The most significant
findings were pain at the injection site and pruritis. These occurred
with similar frequency in both the placebo and the PEG-OB groups and
generally occurred only with the first or second series of
injections.
|
Safety data were reviewed as one composite group first and then by treatment group. There were no clinically relevant changes in the mean values of laboratory measurements or vital signs during the study. No difference was detected between the groups with regard to standard chemistry or hematology assessments. The mean total serum protein was reduced (-2.3%) in the PEG-OB group, but not in the placebo group (-0.5%). However, no difference in urinary protein was observed between the groups. In summary, at the dose studied, PEG-OB seemed to be generally well tolerated and safe.
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
No significant differences in the delta or percent weight loss, percent body fat, or sleeping metabolic rate were observed between the PEG-OB and placebo groups. No differences were observed in RQ between the treatment groups. Due to the premature termination of the study based on the interim analysis, the power of the study was suboptimal and it remains unknown whether PEG-OB has no effect on weight loss.
Percent change in serum triglycerides from baseline was significantly correlated with the amount of body weight loss in the PEG-OB treatment group, but not in the placebo treatment group. Although larger reductions in serum concentrations of triglycerides were observed at the end of the 12-week treatment period in the PEG-OB group compared with the placebo treatment group, these differences were not statistically significant. The trends in serum triglycerides are consistent with similar changes repeatedly observed in studies in which obese rats or mice were treated with leptin at doses that did not reduce body weight (4, 5, 6, 32). It has been proposed by Unger et al. (33) that an important function of leptin is to confine the storage of triglycerides to the adipocytes, while limiting triglyceride storage in nonadipocytes and to selectively mobilize fat. Together with a small but consistent reduction in hunger ratings after overnight fasts throughout the treatment period and a reduction in generalized hunger as measured by the three-factor eating inventory in the PEG-OB group (34), these trends in serum triglycerides suggest that weekly 20-mg sc treatment with PEG-OB may have biological effects in obese men.
In trials sponsored by Amgen Inc., lean and obese subjects received multiple daily sc injections of met-leptin ranging from 0.01–0.3 mg/kg. Significant dose-related reductions in body fat and body weight were observed following daily sc treatment with up to 0.30 mg/kg met-leptin for 24 weeks (9). Mean weight loss from baseline increased with increasing met-leptin dose in obese subjects at 24 weeks of treatment. The most effective dose for weight and fat loss was 0.3 mg/kg and would be equivalent to an average dose of 30 mg/week in our 100-kg subjects. Mild and moderate injection site reactions were the most common adverse events reported (9).
The treatment of a young very obese girl with a mutated
ob gene, with daily sc injection of low doses of met-leptin
(dose of 0.028 mg/kg of lean mass calculated to cause a circulating
concentration 10% of what would be predicted based on her body
fat), has been reported. Daily met-leptin treatment for 12 months
caused a dramatic reduction in appetite, food-seeking behavior, food
intake, and body weight (10). After 12 months of
treatment, her body weight was reduced by 16.4 kg, 95% of which was
body fat. As in the studies reported here with PEG-OB, met-leptin
treatment had no effect on metabolic rate or energy expenditure in this
girl. However, her lipid profile, which was normal prior to treatment,
was not effected by met-leptin administration. The results of treatment
of this girl with congenital leptin deficiency (10), taken
together with the results of the Amgen trials in obese adults
(9), indicate that leptin has biological activity in at
least some obese humans and that among its activities are reductions in
appetite and food intake at low doses and reductions in body fat and
body weight at the maximal dose studied.
Other biological effects of leptin and PEG-OB observed in animal studies were not observed in this study. Most prominent among these were serum glucose and insulin concentrations (5, 6). We failed to observe any treatment effects on these variables possibly due to the small sample size or 20-mg PEG-OB dose or weekly dosing schedule. However, neither parameter was elevated in the group of obese men enrolled in this trial. We also failed to observe a reduction in body fat, as well as total energy expenditure and sleeping metabolic rate (5, 6).
The steady-state concentrations of PEG-OB (200–300 ng/mL) following weekly 20-mg sc PEG-OB were lower than the blood levels of met-leptin associated with efficacy (13). Given the similarities in the biological activity to reduce appetite between weekly sc 20 mg PEG-OB (34) and daily low-dose met-leptin in congenital leptin deficiency (10) and the difference in blood levels, it is possible that increasing the dose of PEG-OB or altering the dosing schedule may result in significant reductions in body fat and body weight in addition to larger decreases in appetite, hunger, food intake, and serum triglycerides concentrations. The testing of this hypothesis will be the subject of future research.
|
Acknowledgments |
|---|
Received January 19, 2000.
Revised June 28, 2000.
Accepted July 12, 2000.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  K. L. KNUTSON and E. VAN CAUTER Associations between Sleep Loss and Increased Risk of Obesity and Diabetes Ann. N.Y. Acad. Sci., May 1, 2008; 1129(1): 287 - 304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. G. Gosman, H. I. Katcher, and R. S. Legro Obesity and the role of gut and adipose hormones in female reproduction Hum. Reprod. Update, September 1, 2006; 12(5): 585 - 601. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. le Roux, R. L. Batterham, S. J. B. Aylwin, M. Patterson, C. M. Borg, K. J. Wynne, A. Kent, R. P. Vincent, J. Gardiner, M. A. Ghatei, et al. Attenuated Peptide YY Release in Obese Subjects Is Associated with Reduced Satiety Endocrinology, January 1, 2006; 147(1): 3 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Boon, G. B. Hul, N. Viguerie, A. Sicard, D. Langin, and W. H. Saris Effects of 3 diets with various calcium contents on 24-h energy expenditure, fat oxidation, and adipose tissue message RNA expression of lipid metabolism-related proteins Am. J. Clinical Nutrition, December 1, 2005; 82(6): 1244 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Mitchell, D T Armstrong, R L Robker, and R J Norman Adipokines: implications for female fertility and obesity Reproduction, November 1, 2005; 130(5): 583 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Hukshorn, J. H. N. Lindeman, K. H. Toet, W. H. M. Saris, P. H. C. Eilers, M. S. Westerterp-Plantenga, and T. Kooistra Leptin and the Proinflammatory State Associated with Human Obesity J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1773 - 1778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. V. Tortoriello, J. McMinn, and S. C. Chua Dietary-Induced Obesity and Hypothalamic Infertility in Female DBA/2J Mice Endocrinology, March 1, 2004; 145(3): 1238 - 1247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Plasqui, A. D. M. Kester, and K. R. Westerterp Seasonal variation in sleeping metabolic rate, thyroid activity, and leptin Am J Physiol Endocrinol Metab, August 1, 2003; 285(2): E338 - E343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. Franks, I. S. Farooqi, J.'a. Luan, M.-Y. Wong, I. Halsall, S. O'Rahilly, and N. J. Wareham Does Physical Activity Energy Expenditure Explain the Between-Individual Variation in Plasma Leptin Concentrations after Adjusting for Differences in Body Composition? J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3258 - 3263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Weigle Pharmacological Therapy of Obesity: Past, Present, and Future J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2462 - 2469. [Full Text] [PDF]
|
|
|
|
|
|
C. J Hukshorn, M. S Westerterp-Plantenga, and W. H. Saris Pegylated human recombinant leptin (PEG-OB) causes additional weight loss in severely energy-restricted, overweight men Am. J. Clinical Nutrition, April 1, 2003; 77(4): 771 - 776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. H. van Dielen, C. van 't Veer, W. A. Buurman, and J. W. M. Greve Leptin and Soluble Leptin Receptor Levels in Obese and Weight-Losing Individuals J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1708 - 1716. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Z. Yanovski and J. A. Yanovski Obesity N. Engl. J. Med., February 21, 2002; 346(8): 591 - 602. [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Havel Peripheral Signals Conveying Metabolic Information to the Brain: Short-Term and Long-Term Regulation of Food Intake and Energy Homeostasis Experimental Biology and Medicine, December 1, 2001; 226(11): 963 - 977. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zarkesh-Esfahani, G. Pockley, R. A. Metcalfe, M. Bidlingmaier, Z. Wu, A. Ajami, A. P. Weetman, C. J. Strasburger, and R. J. M. Ross High-Dose Leptin Activates Human Leukocytes Via Receptor Expression on Monocytes J. Immunol., October 15, 2001; 167(8): 4593 - 4599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S Westerterp-Plantenga, W. H. Saris, C. J Hukshorn, and L A. Campfield Effects of weekly administration of pegylated recombinant human OB protein on appetite profile and energy metabolism in obese men Am. J. Clinical Nutrition, October 1, 2001; 74(4): 426 - 434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Mantzoros and J. S. Flier Leptin as a Therapeutic Agent--Trials and Tribulations J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4000 - 4002. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
) and PEG-OB treatment (•) groups, respectively. Total
leptin serum concentrations in blood samples taken just before the next
weekly dose of PEG-OB increased to a new steady-state level during
weeks 9–12 of the study in subjects treated with PEG-OB, whereas total
leptin concentrations fell with weight loss in placebo-treated subjects
during weeks 9–12 of the study. More frequent blood sampling occurred
after the first (day 1) and 12th weekly (day 78) dose. Note that total
leptin serum profile following the first and 12th weekly sc PEG-OB
injection were similar. Following a sc PEG-OB injection, mean peak
serum total leptin concentrations were achieved 72 h after dosing,
followed by a return to the elevated pre-dose levels after 1 week. *,
Significant differences between the PEG-OB and placebo groups.
) and PEG-OB treatment (•)
groups is plotted as a function of the body weight loss. Regression
lines were determined in both groups. In the placebo group, the slope
was 0.2 with a P = 0.9, whereas in the PEG-OB group,
the slope was 3.9 with P = 0.01. Thus, percent change
in serum triglycerides from baseline was significantly correlated with
the amount of body weight loss in the PEG-OB treatment group but not in
the placebo treatment group. When the data points for all 30 subjects
were combined, the slope of the regression line between decrease in
triglycerides (expressed as percent change from baseline) in the PEG-OB
group was significantly different from the regression line in the
placebo group (analysis of covariance; P < 0.05).