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Reductions in Basal Metabolic Rate and Physical Activity Contribute to Hypothalamic Obesity

Departments of Endocrinology (M.G.S., J.M.W.K.) and Oncology (R.G.G.), Birmingham Children’s Hospital, Birmingham, B4 6NH, United Kingdom

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.shaikh{at}nhs.net.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Hypothalamic 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).

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This was a cross-sectional study. Subjects were recruited through the Endocrine and combined Endocrine-Oncology Brain Tumor and Dietetic 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 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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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.

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).

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.

View larger version (19K): [in this window] [in a new window]   FIG. 1. Relationship between BMR and lean body mass.

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 x 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).

View larger version (19K): [in this window] [in a new window]   FIG. 2. Accelerometry: degree of activity per active minute.

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 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.

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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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. Although 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 damage to the appetite and satiety centers within the hypothalamus (28, 29, 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.

	Footnotes

 
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 Nordisk, 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.

First Published Online April 15, 2008

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.

Received December 3, 2007.

Accepted April 9, 2008.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Shaikh, M. G. Articles by Kirk, J. M. W. Search for Related Content PubMed PubMed Citation Articles by Shaikh, M. G. Articles by Kirk, J. M. W. Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology Obesity