ORIGINAL
E n d o c r i n e
ARTICLE
C a r e
Reductions in Basal Metabolic Rate and Physical
Activity Contribute to Hypothalamic Obesity
M. Guftar Shaikh, Richard G. Grundy, and Jeremy M. W. Kirk
Departments of Endocrinology (M.G.S., J.M.W.K.) and Oncology (R.G.G.), Birmingham Children’s Hospital, Birmingham, B4 6NH, United
Kingdom
Context: Obesity after hypothalamic damage is often severe and resistant to lifestyle changes. It
is postulated that differences in basal metabolic rate (BMR) and physical activity may contribute to
hypothalamic obesity (HO).
Objective: Our objective was to investigate the role of energy expenditure, BMR, and physical
activity in the etiology of hypothalamic obesity.
Design: This was a cross-sectional study of three groups of children: those with HO, congenital
hypopituitarism (CH), and simple obesity (SO).
Results: A total of 47 children (HO ⫽ 18, CH ⫽ 13, and SO ⫽ 16) had BMR measured, using indirect
calorimetry (Deltatrac II). A lower BMR was seen in the HO group, which remained even after
adjusting for lean mass. Physical activity, assessed using triaxial accelerometry, demonstrated
longer activity periods in the HO group, although the degree of activity was reduced. No significant
differences were seen in calorie intake.
Conclusion: Energy expenditure, rather than energy intake, has a greater role in the development
of obesity after cranial tumor therapy. Reductions in BMR and physical activity, leading to a positive
energy balance and weight gain despite an age-appropriate calorie intake, may contribute to
hypothalamic obesity. (J Clin Endocrinol Metab 93: 2588 –2593, 2008)
H
ypothalamic damage after cranial tumors, either as a direct
effect of the tumor itself or secondary to treatment, produces severe refractory obesity, known as hypothalamic obesity
(HO) (1, 2). The hypothalamus itself has a role in both appetite
regulation and energy expenditure, and damage results in inappropriate hypothalamic signaling and abnormal sympathetic
tone (3, 4).
The sympathetic nervous system contributes to all aspects of
energy expenditure, including basal metabolic rate (BMR) and
physical activity. Abnormal sympathetic tone due to hypothalamic damage may be a factor in producing a reduction in BMR,
because stimulation of the ventromedial nucleus of the hypothalamus (VMH) in rats leads to an increase in metabolism (5),
and hence, damage to the VMH will not result in a rise in BMR.
The adipocytokine leptin is also involved in the regulation of
BMR, with leptin infusions increasing BMR (6). Consequently,
leptin resistance and dysfunctional leptin receptors will also not
lead to the desired increase in BMR.
Damage to the VMH in animal studies has also been associated with hyperphagia, which would further exacerbate the
weight gain. Parents of children with HO also report increases in
appetite after diagnosis and subsequent management of cranial
tumors.
The aim of this study was to investigate the differences in
energy expenditure, both BMR and physical activity, and food
intake among children with HO, congenital hypopituitarism
(CH), and simple obesity (SO).
0021-972X/08/$15.00/0
Abbreviations: BMI, Body mass index; BMR, basal metabolic rate; CH, congenital hypopituitarism; HO, hypothalamic obesity; SDS, SD score; SO, simple obesity; VMH, ventromedial
nucleus of the hypothalamus.
Printed in U.S.A.
Copyright © 2008 by The Endocrine Society
Subjects and Methods
This was a cross-sectional study. Subjects were recruited through the
Endocrine and combined Endocrine-Oncology Brain Tumor and Die-
doi: 10.1210/jc.2007-2672 Received December 3, 2007. Accepted April 9, 2008.
First Published Online April 15, 2008
2588
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J Clin Endocrinol Metab. July 2008, 93(7):2588 –2593
J Clin Endocrinol Metab, July 2008, 93(7):2588 –2593
tetic clinics at the Birmingham Children’s Hospital, Birmingham, UK.
Informed consent was obtained and ethical approval for the study was
acquired from the South Birmingham Ethics Committee. All tumor patents were stable and post treatment for at least 2 yr.
Obesity was defined as a body mass index (BMI) greater than the
International Obesity Task Force proposed age- and sex-specific cutoff
points, corresponding to an adult BMI greater than 30 kg/m2 (7).
Three groups of children were studied and compared: 1) those with
HO, defined as obesity secondary to a hypothalamic lesion or hypothalamic damage as a result of surgery, radiotherapy, or both, and at least
one pituitary hormone deficiency was also used in the definition of HO;
2) those with CH, defined as children with at least one primary pituitary
hormone deficiency, without evidence of a cranial tumor; and 3) those
with SO, defined as obesity without any medical cause.
Fasting blood samples were taken in all subjects, and if the samples
were not analyzed immediately, they were separated and stored at ⫺20C.
Thyroid hormones were measured by an Abbott Axsym (Abbott Ltd
Diagnostics, Maidenhead, Berkshire, UK) using a microparticle enzyme
immunoassay method.
Dual energy x-ray absorptiometry scans
Dual energy x-ray absorptiometry scans were performed using a Lunar Prodigy scanner to assess body composition and body fat distribution. From the data, total bone mineral density, bone mineral content,
and bone area were calculated, as was fat mass index and fat-free mass
index. Normative data using over 1500 children between the ages 5–18
yr from Caucasian, South Asian, and Afro-Caribbean ethnic backgrounds from the Birmingham Children’s Hospital was used to calculate
SD scores SDS (8).
Energy expenditure
Basal metabolic rate was measured using Deltatrac II (Datex-Ohmeda, Louisville, KY). The Deltatrac was allowed to warm up to room
temperature and stabilize for at least half an hour before measurements
were recorded. The Deltatrac II was calibrated using Datex Ohmeda
gases (95% oxygen and 5% carbon dioxide). Measurements of oxygen
consumption in milliliters (VO2) per minute and carbon dioxide production in milliliters per minute (VCO2) were made in fasting subjects.
This involved subjects wearing a ventilated hood while supine in a bed.
Subjects remained quiet while watching television during the measurements. Measurements were recorded every minute for up to half an hour.
The first 10 measurements were not used in calculation of BMR or fat
oxidation to allow the subject to become accustomed to the ventilated
hood.
Physical activity
For accelerometry, triaxial accelerometers (RT3-Stayhealthy, Monrovia, CA) were worn for up to 7 d during waking hours. The accelerometers were programmed using height, weight, age, and gender for each
subject before use. Minutes where no activity was demonstrated were
excluded, usually while the patient was asleep (or not wearing the device), and therefore the number of active minutes and counts per minute
were calculated and extracted. Active minutes were defined as minutes
where activity is recorded above the BMR. The vector magnitude, which
is the composite measure of activity in all three planes, was also extracted. The degree of activity was determined by expressing the number
of counts per active minute.
Calorie intake
Energy intake was assessed using a food diary and food frequency
questionnaire. This involved the patient recording their daily food and
drink intake for 7 d and also how often certain foods were eaten. Calorie
intake was estimated, using the software Microdiet based on McCance
and Widdowson’s The Composition of Foods (9), by the Dietetic Department (Dr. Anita Macdonald, Chief Dietician, Birmingham Children’s Hospital). Data are expressed as total energy intake (kilocalories
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2589
per day) and also as a percentage of estimated average requirements using
United Kingdom standards (10). Total protein, fat, and carbohydrate
intake was also estimated and also expressed as a percentage of total
calorie intake.
Statistical analysis
This was performed using computer software SPSS version 12 (SPSS,
Chicago, IL). Where data were normally distributed, results are presented as mean ⫾ SE. For nonnormally distributed data, the median and
range are shown. Normally distributed data were compared between
groups using ANOVA. Statistical significance was taken as P ⬍ 0.05
using two-tailed probability tables.
Results
A total of 47 children (HO ⫽ 18, CH ⫽ 13, and SO ⫽ 16) had
BMR measured. Auxological data are shown in Table 1. The
SO group was significantly taller than the HO and CH groups.
Although the SO group was heavier than the HO and CH
group, this was only significant in the latter. No significant
differences were seen in BMI SDS between the groups. Tumor
diagnoses and treatment in the HO group are shown in Table
2. Pituitary hormone deficiencies in the HO and CH groups
are shown in Table 3.
BMR and metabolism
Significant differences between the groups were observed in
resting metabolic rate measured using indirect calorimetry (P ⫽
0.001). Mean BMR was lower in both the HO and CH groups
compared with the SO group (P ⬍ 0.01). No differences were
noted between HO and CH groups; means (SE) were for HO 1667
(108), CH 1535 (94), and SO 2150 (110) kcal/d.
Thyroid hormones
Differences were also seen in free T3 and free T4 levels between groups, with the SO group having higher free T3 and lower
free T4 levels, although free T3 was significant only when compared with the HO group, and free T4 significant only when
compared with the CH group (P ⬍ 0.01; Table 4) (T3 HO vs. CH,
P ⫽ 0.13; T4 HO vs. CH, P ⫽ 0.27).
Lean body mass
Because lean body mass and free T3 levels influence metabolism, BMR was adjusted for total lean mass, sex, and T3 levels
TABLE 1.
Auxological data
Total no.
Male no.
Age (yr)
Height (SDS)
Weight
(SDS)
BMI (SDS)
18
13
16
7
8
10
13.5 (6 –18)
8 (6 –18)
11 (6 –14)
0.17 (⫺3.1–2.6) ⫺0.12 (⫺3.3–3.6) 1.40 (0.2–3.2)a,b
2.51 (0.6 – 4.5)
1.94 (⫺1.8 –5.9) 3.255 (2.0 –5.1)b
HO
2.74 (2.0 – 4.9)
CH
2.44 (⫺0.2–5.2)
SO
3.205 (2.2– 4.7)
Data are presented as median (range) for nonnormally distributed variables.
a
P ⬍ 0.01 for difference between HO and SO.
b
P ⬍ 0.01 for difference between CH and SO.
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Shaikh et al.
TABLE 2.
Energy Expenditure and Hypothalamic Obesity
J Clin Endocrinol Metab, July 2008, 93(7):2588 –2593
Tumor diagnoses and treatment in HO group
Tumor
Total no. of
patients
Surgery
Chemotherapy
Radiotherapy
Glioma
Craniopharyngioma
Germinoma
Astrocytoma
Medulloblastoma
Retinoblastoma
5
5
3
3
1
1
4
5
2
3
1
1
2
1
1
1
0
0
4
4
3
3
1
1
and demonstrated significant differences (P ⬍ 0.001) (adjusted
means: HO 1619 vs. CH 1789 vs. SO 2028 kcal/24 h).
The relationship between BMR and lean body mass (Fig. 1)
illustrates that the HO group has a lower BMR compared with
the SO group. The BMR was more variable in the CH group,
initially being similar to the SO group, but as lean mass increases,
BMR approaches that of the HO group.
A significant relationship (Pearson’s correlation 0.461; P ⬍
0.01) was seen between free T3 and BMR, with no significance
between free T4 and BMR and between T4 and T3.
Physical activity
Accelerometer data were available on 35 subjects (HO ⫽ 18,
CH ⫽ 10, and SO ⫽ 7). Although more subjects participated,
data were missing either due to the device being lost by the individual or battery failure. From the raw data, the number of
active minutes and total minutes were extracted. The total vector
magnitude of activity was then expressed per active minute, giving the degree of activity when the subject was active.
Data were not normally distributed and were analyzed using
nonparametric tests and expressed as median (range).
Minutes of activity
No differences in the total number of minutes the accelerometer was worn was seen between the groups: HO 10,511
(8,749 –17,508), CH 10,575 (8,881–10,920), SO 10,816
(10,192–10,920). The number of active minutes and the percent activity (active minutes/total minutes ⫻ 100) was higher
in the HO group, although this was not statistically significant; active minutes were 4607 (863– 6027) for HO, 4227
(2594 –5003) for CH, and 4560 (2887–5013) for SO; percent
activity was 44.3% (9.7–55.2%) for HO, 38.8%
(23.8 – 46.3%) for CH, and 41.8% (26.4 – 45.9%) for SO.
Degree of activity
The degree of activity was determined by expressing the
amount of activity per active minute. The HO had the lowest
degree of activity HO 337.50 (147–554), CH 462 (288 – 630),
SO 383 (306 –587), and this remained even after adjusting for fat
mass, although it was only significantly lower compared with the
CH group, P ⬍ 0.05. Figure 2. The total amount of activity, as
determined by the vector magnitude, was also lower in the HO
group after adjusting for fat mass, but not statistically significant, HO 166256, CH 1910429, SO 1701653. A significant
association was seen between the degree of activity and fat mass,
P ⬍ 0.01, (Spearman Correlation ⫺0.601).
Calorie intake
Data on calorie consumption were available and suitable for
analysis in 44 patients (HO ⫽ 16, CH ⫽ 12, and SO ⫽ 16) and
were expressed as daily energy consumption (kilocalories per
day); daily protein, fat, and carbohydrate consumption in grams;
and also as a percentage of protein, fat, and carbohydrate compared with total energy consumption. Total energy consumption
was also expressed as a percentage of estimated average requirements of United Kingdom children (10).
Total energy intake
Energy intake was higher in the HO group, mean (SE) of 1980
(204) kcal/d, compared with the CH group, 1569 (103) kcal/d,
and SO group, 1782 (141) kcal/d, but this was not significant
(P ⫽ 0.22). Although age and sex are related to energy consumption, no differences were seen between groups, and no significant
differences were seen when energy consumption was adjusted for
age, weight, fat mass, or lean mass.
All three groups reported a lower percentage of energy intake
when compared with the estimated average requirements of
United Kingdom children, but again there was no difference between groups (P ⫽ 0.47), with mean (SE) of 91% (6.7%) for HO,
80% (5.1%) for CH, and 87% (3.6%) for SO .
Protein intake
Both HO and SO groups had a higher protein intake compared with the CH group, with mean (SE) of 68 (8.9) g/d for HO,
57 (6.1) g/d for CH, and 71 (6.5) g/d for SO, with the percentage
of energy intake from protein for the groups being mean (SE) of
TABLE 4.
TABLE 3. Percentage of pituitary hormone deficiencies in
HO and CH groups
Group
GH
TSH
ACTH
Sex steroid
therapy
HO (%)
CH (%)
83
100
94
100
56
77
28
8
Thyroid function
T4 (pmol/liter)
T3 (pmol/liter)
HO
CH
SO
14.59 (1.1)
4.01 (0.2)
15.41 (1.0)
4.75 (0.2)
12.59 (0.4)b
4.93 (0.3)a
Data are presented as mean (SE) for normally distributed variables.
a
P ⬍ 0.01 for difference between HO and SO.
b
P ⬍ 0.01 for difference between CH and SO.
J Clin Endocrinol Metab, July 2008, 93(7):2588 –2593
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Carbohydrate intake
The HO group had the highest carbohydrate intake compared with the other groups,
who had similar intakes. The means (SE) of the
HO, CH, and SO groups were 269 (37.4),
215 (16.0), and 221 (17.5) g/d, respectively.
The percentage of energy intake from carbohydrate was mean (SE) of 51.3% (2.05%) for
HO, 51.6% (2.30%) for CH, and 47.8%
(1.32%) for SO.
None of the differences in protein, fat, and
carbohydrate intake and percentage energy
intake from protein, fat, and carbohydrate
between the groups achieved statistical
significance.
Discussion
FIG. 1. Relationship between BMR and lean body mass.
13.9% (1.25%) for HO, 18.0% (2.74%) for CH, and 16.0%
(0.80%) for SO.
Fat intake
Both HO and SO groups had a higher fat and percentage of
energy from fat intake compared with the CH group, with fat
intake mean (SE) of 77.6 (7.12) g/d for HO, 58.2 (6.76) g/d for
CH, and 74.5 (7.56) g/d for SO and with percentage of energy
from fat mean (SE) of 35.6% (2.00%) for HO, 32.9% (2.39%)
for CH, and 36.2% (1.32%) for SO.
FIG. 2. Accelerometry: degree of activity per active minute.
This study has demonstrated reductions in
energy expenditure, particularly resting, in
children with hypothalamic damage compared with controls, with no differences in
calorie intake. This suggests that energy expenditure rather than energy intake has a greater influence on the
development of obesity after hypothalamic damage.
Energy intake and expenditure
BMR has been previously measured in only four patients with
HO and compared with obese controls, with no difference seen
(11). These data, however, were not adjusted for lean mass. Our
data, with a greater number of patients, has demonstrated a
significantly lower BMR after adjusting for lean mass in the HO
group. Lean body mass has been shown to be the major reason
for interindividual variation in BMR (12); other factors include
sympathetic nervous system activity (13) and thyroid hormones,
in particular T3 (14, 15).
Abnormal sympathetic tone due to hypothalamic damage
may be a factor in producing a reduction in BMR. Because stimulation of the VMH in rats leads to an increase in metabolism
(16), damage to the VMH will not result in a rise in BMR. Defective leptin signaling itself has been shown to reduce sympathetic tone in animal studies (16). Consequently, leptin resistance
and dysfunctional leptin receptors will not result in the desired
increase in BMR. VMH-lesioned animals have also been shown
to be hyperinsulinemic, and this has been suggested as a cause of
weight gain in patients with craniopharyngioma. In view of this
possible hyperinsulinemia, octreotide, which suppresses insulin
release, has been shown to reduce weight gain in patients (17);
however, our unpublished data have not demonstrated any differences in insulin levels.
T3 is the biologically active thyroid hormone and, from our
data, has a significant impact on BMR, with a good association
between free T3 and BMR. All children who were hypothyroid
in our study were on appropriate and adequate thyroid hormone
replacement therapy; free T4, however, which is routinely measured to assess thyroid function, does not influence BMR. Al-
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Shaikh et al.
Energy Expenditure and Hypothalamic Obesity
though a higher free T4 was observed in the HO group compared
with the SO group, there was a poor correlation between free T4
and BMR, even in those patients who did not require thyroid
hormone replacement therapy. A lower free T3 was seen in the
HO group and may be an explanation for the reduced BMR in
the HO group. Reductions in sympathetic tone have been shown
in rats to reduce T3 levels, and therefore it is possible that reduced
leptin activity via the sympathetic nervous system may also lead
to lower T3 levels (18, 19).
Several other factors might also explain the reduced BMR in
the HO group, such as inadequate thyroid hormone replacement
(T4), and in view of possible reduced conversion to T3, it may be
more appropriate to supplement these individuals with T3 rather
than T4. High-dose T3 has been used in three patients with HO,
resulting in a weight loss of between 4 and 14 kg (20). These
patients, two of whom were children, had normal serum free T4
levels but were supplemented with T3 leading to supraphysiological T3 levels. Despite these high levels, the individuals remained asymptomatic. Dextroamphetamine was shown to have
some benefit in five children in stabilizing weight gain (21). Other
therapeutic strategies affecting metabolic rate have not been successful and are not without major side effects.
Physical activity
Only one previous study has measured physical activity in
hypothalamically obese patients using accelerometry (22). Reduced physical activity as a cause of obesity has been previously
shown in childhood survivors of acute lymphoblastic leukemia
(23). Our study is similar to previous findings of reduced physical
activity in HO individuals. Despite being active for longer periods, HO patients in our study had a reduced degree of activity,
and their activity was not as intense per active minute compared
with the obese group, although not significantly lower. Accelerometry is not the same as physical activity expenditure; however, our study suggests that physical activity is reduced in hypothalamically obese patients. The reduced physical activity may
be explained by neurological and visual problems resulting from
the tumor and its subsequent treatment, because these will significantly reduce mobility. The obesity itself also has an influence
on the degree of physical activity, and our data demonstrate that
as fat mass increases, the degree of physical activity falls. This
may be due to physical activity becoming more difficult for the
individual due to increased body mass, which then further exacerbates the weight gain. Hypothalamic damage can also result
in abnormal sleep patterns, due to disturbed melatonin production producing daytime sleepiness and resulting in decreased
physical activity (24, 25). A recent study has suggested that inadequate sleep in normal children may contribute to childhood
obesity (26). The mechanism by which sleep deprivation leads to
obesity is thought to be due to the disruption of hormones, such
as ghrelin, insulin, and GH (27). Hypothalamic damage results
in disruption of these hormones, and sleep deprivation may exacerbate this further.
Energy intake
Hyperphagia and subsequent obesity is a well described feature after treatment for cranial tumors and thought to be due to
J Clin Endocrinol Metab, July 2008, 93(7):2588 –2593
damage to the appetite and satiety centers within the hypothalamus (28 –30). Previous studies, however, have shown no increase in energy intake in cranial tumor survivors but rather a
reduced intake compared with controls. A large number of individuals who participated in this study had food diaries that
were suitable for analysis. Our data have demonstrated a slightly
increased energy intake in the HO group compared with the
controls, although this was not statistically significant possibly
due to small patient numbers. The increased calories were mainly
derived from fat and carbohydrate. Although an increased energy intake was demonstrated in the HO group compared with
the other groups, this was still less than the estimated average
requirement and was not significantly different from the other
groups. We did not demonstrate hyperphagia, which may be due
to underreporting by individuals, because none of the groups
reported excessive energy intake, and the percentage of the estimated average requirement in all groups was less than 100%.
Therapies that reduce appetite, such as serotonergic agents,
have been used in one individual without success (31). In another
small study, sibutramine was shown to have some benefit in
terms of weight reduction in children with HO (32). Because
these agents act at a hypothalamic level, damaged and dysfunctional receptors in HO will not produce the desired effect. This
is probably why sibutramine also has little benefit in HO, although there are very few published data (2).
Summary
Energy expenditure appears to have a greater role in the etiology of HO than energy intake. A reduced BMR, either directly
due to hypothalamic dysfunction or indirectly due to suboptimal
active thyroid hormone metabolites, will result in a positive energy balance even in the presence of a normal recommended
calorie intake.
Acknowledgments
Special acknowledgment goes to the children who participated in this
study. We also acknowledge Dr. Nicola Crabtree and Dr. Nick Shaw
(Department of Endocrinology, Birmingham Children’s Hospital, Birmingham, UK) for their help with the DXA scans and body composition
data, Professor Asker Jekundrup and Michelle Venables (School of Sport
Sciences, University of Birmingham, UK) for their help with assessing
energy expenditure, and Dr. Anita Macdonald (Department of Dietetics,
Birmingham Children’s Hospital, Birmingham, UK) for her help with
analysis of the food diaries and questionnaires.
Address all correspondence and requests for reprints to: M. Guftar
Shaikh, Department of Endocrinology, Birmingham Children’s
Hospital, Birmingham, B4 6NH, United Kingdom. E-mail: guftar.
[email protected].
This work was supported by Novo Nordisk, Pfizer, Birmingham
Children’s Hospital Research and Development Department, and the
Ella Brown Foundation.
Author Statement: M.G.S. has received grant support from Novo
Nordisk and Pfizer Endocrine Care (2001–2005), together with lecture
fees from Merck Serono. J.M.W.K. has received lecture fees from Merck
Serono, NovoNordisk, Ferring, and Ipsen, and grant support from Ferring, Merck Serono, Ipsen, Pfizer, and NovoNordisk.
Author Disclosure Summary: M.G.S., R.G.G., and J.M.W.K. received grant support (September 2001 to March 2005) from Novo Nor-
J Clin Endocrinol Metab, July 2008, 93(7):2588 –2593
disk, Pfizer, Birmingham Children’s Hospital Research and Development Department and the Ella Brown Foundation.
Current address for R.G.G.: Children’s Brain Tumour Research Centre, Queen’s Medical Centre, Nottingham, UK.
jcem.endojournals.org
17.
18.
References
1. Lustig RH, Rose SR, Burghen GA, Velasquez-Mieyer P, Broome DC, Smith K,
Li H, Hudson MM, Heideman RL, Kun LE 1999 Hypothalamic obesity caused
by cranial insult in children: altered glucose and insulin dynamics and reversal
by a somatostatin agonist. J Pediatr 135(2 Pt 1):162–168
2. Pinkney JH, Daousi C, MacFarlane I 2005 Recent advances in the understanding and treatment of hypothalamic obesity in humans. In: Trends in obesity
research. New York, NY: Nova Publishers; 41– 66
3. Sahu A 2003 Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. Front Neuroendocrinol 24:225–253
4. Sainsbury A, Cooney GJ, Herzog H 2002 Hypothalamic regulation of energy
homeostasis. Best Pract Res Clin Endocrinol Metab 16:623– 637
5. Ruffin M, Nicolaidis S 1999 Electrical stimulation of the ventromedial hypothalamus enhances both fat utilization and metabolic rate that precede and
parallel the inhibition of feeding behavior. Brain Res 846:23–29
6. Ruffin M and Nicolaidis S 2000 Intracerebroventricular injection of murine
leptin enhances the postprandial metabolic rate in the rat. Brain Res 874:30 –36
7. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH 2000 Establishing a standard
definition for childhood overweight and obesity worldwide: international survey. BMJ 320:1240
8. Crabtree NJ, Oldroyd B, Truscott JG, Fordham JN, Kibirige M, Fewtrell M,
Gordon I, Shaw NJ 2004 UK paediatric reference data (GE Lunar Prodigy):
effects of ethnicity, gender and pubertal status. Osteoporos Int S6:15
9. Food Standards Agency and Institute of Food Research 2002 McCance and
Widdowson’s the Composition of Foods. 6th ed. Cambridge, UK: Royal Society of Chemistry
10. Department of Health 1991 Dietary reference values for the UK. Report on the
dietary reference values of the Committee on Medical Aspects of Food Policy.
London: HMSO
11. Bray GA and Gallagher Jr TF 1975 Manifestations of hypothalamic obesity in
man: a comprehensive investigation of eight patients and a review of the literature. Medicine (Baltimore) 54:301–330
12. Goran MI, Treuth MS 2001 Energy expenditure, physical activity, and obesity
in children. Pediatr Clin North Am 48:931–953
13. Welle S, Schwartz RG, Statt M 1991 Reduced metabolic rate during ␤-adrenergic blockade in humans. Metabolism 40:619 – 622
14. Silvestri E, Schiavo L, Lombardi A, Goglia F 2005 Thyroid hormones as molecular determinants of thermogenesis. Acta Physiol Scand 184:265–283
15. Onur S, Haas V, Bosy-Westphal A, Hauer M, Paul T, Nutzinger D, Klein H,
Muller MJ 2005 L-Tri-iodothyronine is a major determinant of resting energy
expenditure in underweight patients with anorexia nervosa and during weight
gain. Eur J Endocrinol 152:179 –184
16. Mark AL, Rahmouni K, Correia M, Haynes WG 2003 A leptin-sympathetic-
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
2593
leptin feedback loop: potential implications for regulation of arterial pressure
and body fat. Acta Physiol Scand 177:345–349
Lustig RH, Hinds PS, Ringwald-Smith K, Christensen RK, Kaste SC, Schreiber
RE, Rai SN, Lensing SY, Wu S, Xiong X 2003 Octreotide therapy of pediatric
hypothalamic obesity: a double-blind, placebo-controlled trial. J Clin Endocrinol Metab 88:2586 –2592
Cettour-Rose P, Burger AG, Meier CA, Visser TJ, Rohner-Jeanrenaud F 2002
Central stimulatory effect of leptin on T3 production is mediated by brown
adipose tissue type II deiodinase. Am J Physiol Endocrinol Metab 283:E980 –
E987
Sullo A, Brizzi G, Maffulli N 2004 Triiodothyronine deiodinating activity in
brown adipose tissue after short cold stimulation test in trained and untrained
rats. Physiol Res 53:69 –76
Fernandes JK, Klein MJ, Ater JL, Kuttesch JF, Vassilopoulou-Sellin R 2002
Triiodothyronine supplementation for hypothalamic obesity. Metabolism 51:
1381–1383
Mason PW, Krawiecki N, Meacham LR 2002 The use of dextroamphetamine
to treat obesity and hyperphagia in children treated for craniopharyngioma.
Arch Pediatr Adolesc Med 156:887– 892
Harz KJ, Muller HL, Waldeck E, Pudel V, Roth C 2003 Obesity in patients with
craniopharyngioma: assessment of food intake and movement counts indicating physical activity. J Clin Endocrinol Metab 88:5227–5231
Warner JT, Bell W, Webb DK, Gregory JW 1998 Daily energy expenditure and
physical activity in survivors of childhood malignancy. Pediatr Res 43:607–
613
Poretti A, Grotzer MA, Ribi K, Schonle E, Boltshauser E 2004 Outcome of
craniopharyngioma in children: long-term complications and quality of life.
Dev Med Child Neurol 46:220 –229
Muller HL, Handwerker G, Wollny B, Faldum A, Sorensen N 2002 Melatonin
secretion and increased daytime sleepiness in childhood craniopharyngioma
patients. J Clin Endocrinol Metab 87:3993–3996
Taheri, S 2006 The link between short sleep duration and obesity: we should
recommend more sleep to prevent obesity. Arch Dis Child 91:881– 884
Spiegel K, Knutson K, Leproult R, Tasali E, Van Cauter E 2005 Sleep loss: a
novel risk factor for insulin resistance and type 2 diabetes. J Appl Physiol
99:2008 –2019
Pinkney J, Wilding J, Williams G, MacFarlane I 2002 Hypothalamic obesity
in humans: what do we know and what can be done? Obes Rev 3:27–34
Roth C, Wilken B, Hanefeld F, Schroter W, Leonhardt U 1998 Hyperphagia
in children with craniopharyngioma is associated with hyperleptinaemia and
a failure in the downregulation of appetite. Eur J Endocrinol 138:89 –91
Skorzewska A, Lal S, Waserman J, Guyda H 1989 Abnormal food-seeking
behavior after surgery for craniopharyngioma. Neuropsychobiology
21:17–20
Jordaan GP, Roberts MC, Emsley RA 1996 Serotonergic agents in the treatment of hypothalamic obesity syndrome: a case report. Int J Eat Disord 20:
111–113
Marcus Claude, Norgen S, Danielsson P 2005 Sibutramine treatment of children with hypothalamic obesity and other aggravating syndromes. Horm Res
64(Suppl 1):269