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Correlation of Plasma Orexin-A Levels with Body Mass Index, Body Composition, Resting Energy Expenditure, and Excessive...

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Title:
Correlation of Plasma Orexin-A Levels with Body Mass Index, Body Composition, Resting Energy Expenditure, and Excessive Daytime Sleepiness in Patients with Prader-Willi Syndrome and Early-Onset Obesity a Pilot Study
Physical Description:
1 online resource (22 p.)
Language:
english
Creator:
Gan, Mary Joyce
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Master's ( M.S.)
Degree Grantor:
University of Florida
Degree Disciplines:
Medical Sciences, Clinical Investigation (IDP)
Committee Chair:
Shorr, Ronald I
Committee Members:
Brantly, Mark Louis

Subjects

Subjects / Keywords:
obesity -- orexin-a -- prader-willi -- sleepiness
Clinical Investigation (IDP) -- Dissertations, Academic -- UF
Genre:
Medical Sciences thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Hypothalamic dysfunction in Prader-Willi syndrome (PWS) is evidenced by loss ofappetite control, narcolepsy-like symptoms, temperature dysregulation, highpain threshold, and hypothalamic-pituitary hormonal deficiencies. To date, nostudy has been able to fully explain the link between excessive daytimesleepiness and obesity in PWS, but the most consistent hypothesis suggestsprimary hypothalamic dysfunction. The hypothalamic hormone orexin protectsagainst obesity by increasing resting energy expenditure. Orexin deficiency, aknown cause of narcolepsy, may induce a predisposition to easy weight gain andexcessive daytime sleepiness observed in individuals with PWS and early-onsetobesity (EOO). Design and objective:This prospective study aimed to obtain preliminary data on the role of orexinin energy balance in the obese population. Methods:Plasma orexin levels were measured in 40 individuals with PWS (aged infancy to30 years), 13 individuals with EOO of unknown etiology (aged 2 to 18 years),and 31 sibling controls (aged infancy to 34 years). Individuals with PWS andEOO underwent dual-energy x-ray absorptiometry (DXA) to measure bodycomposition, indirect calorimetry to measure resting energy expenditure (REE),and overnight polysomnography and multiple sleep latency testing to measuredaytime sleepiness. Results:Three-way comparison of orexin levels among the 3 groups of participants showedno significant differences (P = 0.13). Among subjects with PWS, orexin levelscorrelated negatively with fat percentage (r = -0.35, P=0.051). Between PWS andcontrols, general linear regression predicted a change in orexin level forevery percentage change in body fat (P=0.042). Sibling controls trended toward a positive association while PWS trendedtoward a negative association.Conclusion: Although plasma orexin levels werenot significantly different between PWS, EOO, and sibling controls, plasmaorexin correlated negatively with body fat composition in individuals with PWS.Measurement of orexin levels in plasma may not be adequately sensitive toidentify pathology in individuals with PWS and EOO, and future studies mayrequire measurement of orexin levels in the cerebrospinal fluid.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Mary Joyce Gan.
Thesis:
Thesis (M.S.)--University of Florida, 2013.
Local:
Adviser: Shorr, Ronald I.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-08-31

Record Information

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Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2013
System ID:
UFE0045983:00001

MISSING IMAGE

Material Information

Title:
Correlation of Plasma Orexin-A Levels with Body Mass Index, Body Composition, Resting Energy Expenditure, and Excessive Daytime Sleepiness in Patients with Prader-Willi Syndrome and Early-Onset Obesity a Pilot Study
Physical Description:
1 online resource (22 p.)
Language:
english
Creator:
Gan, Mary Joyce
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Master's ( M.S.)
Degree Grantor:
University of Florida
Degree Disciplines:
Medical Sciences, Clinical Investigation (IDP)
Committee Chair:
Shorr, Ronald I
Committee Members:
Brantly, Mark Louis

Subjects

Subjects / Keywords:
obesity -- orexin-a -- prader-willi -- sleepiness
Clinical Investigation (IDP) -- Dissertations, Academic -- UF
Genre:
Medical Sciences thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Hypothalamic dysfunction in Prader-Willi syndrome (PWS) is evidenced by loss ofappetite control, narcolepsy-like symptoms, temperature dysregulation, highpain threshold, and hypothalamic-pituitary hormonal deficiencies. To date, nostudy has been able to fully explain the link between excessive daytimesleepiness and obesity in PWS, but the most consistent hypothesis suggestsprimary hypothalamic dysfunction. The hypothalamic hormone orexin protectsagainst obesity by increasing resting energy expenditure. Orexin deficiency, aknown cause of narcolepsy, may induce a predisposition to easy weight gain andexcessive daytime sleepiness observed in individuals with PWS and early-onsetobesity (EOO). Design and objective:This prospective study aimed to obtain preliminary data on the role of orexinin energy balance in the obese population. Methods:Plasma orexin levels were measured in 40 individuals with PWS (aged infancy to30 years), 13 individuals with EOO of unknown etiology (aged 2 to 18 years),and 31 sibling controls (aged infancy to 34 years). Individuals with PWS andEOO underwent dual-energy x-ray absorptiometry (DXA) to measure bodycomposition, indirect calorimetry to measure resting energy expenditure (REE),and overnight polysomnography and multiple sleep latency testing to measuredaytime sleepiness. Results:Three-way comparison of orexin levels among the 3 groups of participants showedno significant differences (P = 0.13). Among subjects with PWS, orexin levelscorrelated negatively with fat percentage (r = -0.35, P=0.051). Between PWS andcontrols, general linear regression predicted a change in orexin level forevery percentage change in body fat (P=0.042). Sibling controls trended toward a positive association while PWS trendedtoward a negative association.Conclusion: Although plasma orexin levels werenot significantly different between PWS, EOO, and sibling controls, plasmaorexin correlated negatively with body fat composition in individuals with PWS.Measurement of orexin levels in plasma may not be adequately sensitive toidentify pathology in individuals with PWS and EOO, and future studies mayrequire measurement of orexin levels in the cerebrospinal fluid.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Mary Joyce Gan.
Thesis:
Thesis (M.S.)--University of Florida, 2013.
Local:
Adviser: Shorr, Ronald I.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-08-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2013
System ID:
UFE0045983:00001


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1 CORRELATION OF PLASMA OREXIN A LEVELS WITH BODY MASS INDEX, BODY COMPOSITION, RESTING ENERGY EXPENDITURE, AND EXCESSIVE DAYTIME SLEEPINESS IN PATIENTS WITH PRADER WILLI SYNDROME AND EARLY ONSET OBESITY: A PILOT STUDY By MARY JOYCE DY GAN A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2013

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2 2013 Mary Joyce Dy Gan

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3 To Oscar, Odin, Olivia, Jorge, and Lourdes

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4 ACKNOWLEDGMENTS I thank my husband and children for waiting patiently and lovingly. I thank my mother and father for all that I am now. I thank the Foundation for Prader Willi Research, Sanford Burnham Research Institute, the Clinical and Translational Science Institute of the University of Florida, and all the study participants for their collaboration. This work was partially supported by grant 1UL1TR000064 from the National Center for Advancing Translational Science, National Institute of Health.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 6 ABSTRACT ................................ ................................ ................................ ..................... 7 INTRODUCTION ................................ ................................ ................................ ............. 9 CHAPTER 1 MATERIALS AND METHODS ................................ ................................ ................ 12 Subjects ................................ ................................ ................................ .................. 12 Sample and Data Coll ection ................................ ................................ ................... 12 Statistical Methods ................................ ................................ ................................ .. 13 2 RESULTS ................................ ................................ ................................ ............... 14 Correlation Analyses ................................ ................................ ............................... 14 Post hoc Analysis ................................ ................................ ................................ ... 14 3 DISCUSSION ................................ ................................ ................................ ......... 16 BIBLIOGRAPHY ................................ ................................ ................................ ........... 18 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 22

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6 LIST OF TABLES Table page 3 1 Gender distribution ................................ ................................ ............................. 15 3 2 Orexin levels ................................ ................................ ................................ ....... 15 3 3 Descri ptive statistics ................................ ................................ ........................... 15 3 4 Correlations with orexin by diagnosis ................................ ................................ 15

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7 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science CORRELATION OF PLASMA OREXIN A LEVELS WITH BODY MASS INDEX, BODY COMPOSITION, RESTING ENERGY EXPENDITURE, AND EXCESSIVE DAYTIME SLEEPINESS IN PATIENTS WITH PRADER WILLI SYNDROME AND EARLY ONSET OBESITY: A PILOT STUDY By Mary Joyce Dy Gan August 2013 Chair: Ronald I. Shorr Major: Medical Sci ence Clinical and Translational Science Background: Hypothalamic dysfunction in Prader Willi syndrome (PWS) is evidenced by loss of appetite control, narcolepsy like symptoms, temperature dysregulation high pain threshold, and hypothalamic pituitary hormonal deficiencies. To date, no study has been able to fully explain the link between excessive daytime sleepiness and obesity in PWS, but the most consistent hypothesis suggests primary hypothalamic dys function. The hypothalamic hormone orexin protects against obesity by increasing resting energy expenditure. Orexin deficiency, a known cause of narcolepsy, may induce a predisposition to easy weight gain and excessive daytime sleepiness observed in indivi duals with PWS and early onset obesity (EOO). Design and o bjective : This prospective study aimed to obtain preliminary data on the role of orexin in energy balance in the obese population. Methods: Plasma orexin levels were measured in 40 individuals with PWS (aged infancy to 30 years), 13 individuals with EOO of unknown etiology (aged 2 to 18 years), and 31 sibling controls (aged infancy to 34 years). Individuals with PWS and EOO underwent dual energy x ray absorptiometry (DXA) to measure body composition indirect calorimetry

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8 to measure resting energy expenditure (REE), and overnight polysomnography and multiple sleep latency testing to measure daytime sleepiness. Results: Three way comparison of orexin levels among the 3 groups of participants showed no significant differences ( P = 0.13). Among subjects with PWS, orexin levels correlated negatively with fat percentage (r = 0.35, P=0.051). Between PWS and controls, general linear regression predicted a change in orexin level for every percentage change in body fat (P=0.042). Sibling controls trended toward a positive association while PWS trended toward a negative association. Conclusion: Although plasma orexin levels were not significantly different between PWS, EOO, and sibling controls, plasma orexin correlated negatively with body fat composition in individuals with PWS. Measurement of orexin levels in plasma may not be adequately sensitive to identify pathology in indiv iduals with PWS and EOO, and future studies may require measurement of orexin levels in the cerebrospinal fluid.

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9 CHAPTER 1 INTRODUCTION In the United States, obesity affects approximately 12.5 million (17%) children and adolescents. 1 Hypothalamic dysfunction is associated with obesit y, as extensively described in the literature. 2 9 A well known human obesity syndrome is Prader Willi syndrome (PWS), characterized by features that suggest hypothalamic dysfun ction, including loss of appetite control, excessive daytime sleepiness (EDS), disordered thermoregulation, high pain threshold, and hypothalamic pituitary hormonal deficiencies (growth hormone, gonadotropins, thyroid stimulating hormone, and ad renocortico tropic hormone). 10 11 The estimated incidence of PWS is 1 in 25,000 births, while the estim ated prevalence is 1 in 50,000 12 The syndrome is due to loss of gene function in a critical region of chromosome 15. EDS in PWS is hypothesized to be due to hypothalamic dysfunction, since sleep disordered breathing does not consistently explain the prevalence and seve rity of daytime sleepiness. 13 14 Studies thus far have been unable to fully explain the link between obesity and EDS in PWS, but the most consistent hypothesis suggests primary hypothalamic dysfunctio n as an important contribu tor. 15 Orexin (from the Greek word orexis peptide hormone that regulates appetite, energy homeostasis, and the sleep wake cycle by binding and activating G protein coupled receptors expressed in the brain and the periphery 16 Direct evidence for the role of orexin in appetite regulation comes from behavioral effects of its administration to rodents When acutely injected into the rat central nervous system, orex in induces food consumption 17 19 On the other hand, when orexin signaling is disrupted by orexin receptor antagonists or anti bodies, food intake is

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10 reduced 20 Moreover, orexin plays an i mportant role in energy expenditure. Centrally injected orexin increases metabolic rate, as demonstrated b y increased oxygen consumption 21 Important ly, the effect on metabolic rate is more predominant than the effect on appetite stimulation. Rats injected intra paraventricularly with orexin, compared to rats injected with vehicle, demonstrated more weight loss without a signifi cant difference in food intake 22 Furthermore, mice with genetically ablated orexin neurons developed obesity despite a 30 % decrease in food co nsumption 23 suggesting decreased energy expenditure a s the cause of the weight gain 24 In humans, plasma orexin levels correlates with obesity. Adam, et al reported that plasma orexin levels correlated negatively with BMI in obese individuals 16 Consistent with this report, Baranowska, et al reported a strong correlation between low plas ma orexin and obesity in women 25 T ogether these findings suggest that orexin deficiency induces pathologic alterations that cause weight gain. A vast body of evidence indicates that orexin deficiency due to loss of orexin neurons or to abnormal orexin neurotransmission causes narcolepsy with cataplexy 26 32 In a report of one individual with PWS and hypersomnolence, cerebrospinal fluid (CSF) orexin concentration was low. 33 In another report of four patients with PWS, low CSF orexin levels co rrelated with severity of EDS 34 While orexin containing neurons have been shown to be absent from the hypothalamus of patients with narco lepsy with cataplexy 35 orexin neurons have not been previously studied in the hypot halamus of patients with PWS. The relationship of plasma orexin levels with these abnormalities has not yet been investigated.

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11 Sleep abnormalities are common in obese patients and in patients with PWS. Because obesity is often observed in patients with narcolepsy 36 37 and narcolepsy has been associated with low orexin levels, orexin deficiency is possibly involved in the development of obesity. The obesity epidemic compels healthcare professionals to be vigilant and up to date on potential novel treatments that may be able to reset energy balance. In the management of pediatric obesity, increasing energy expenditure is more rational than decreasing energy intake since child ren need to meet specific caloric requirements for somatic growth. Orexin is a promising therapeutic agent to increase energy expenditure. Given the potential implications of improved understanding of orexin physiology, we hypothesized that plasma orexin l evels are lower in the obese population (PWS and EOO) than in the non PWS and non EOO population. We also hypothesized that orexin deficiency is associated with high fat mass, low REE, and/or EDS. This study aimed to obtain preliminary data that may be use d for future clinical trials of orexin or its agonists and to ultimately find a therapeutic agent that may help address the problem of obesity.

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12 CHAPTER 2 MATERIALS AND METHODS Subjects The experimental group consisted of individuals with PWS or EOO. Incl usion criteria included coexistent sleep abnormalities or daytime sleepiness. Individuals with anatomic brain abnormalities (hypothalamic obesity) were excluded. The control group consisted of siblings of participants with PWS or EOO. Direct matching of si blings was not done due to lack of consistent availability of siblings. The study was approved by the Institutional Review Board of the University of Florida, and informed consent was obtained from each participant. Sample and Data Collection Participants with PWS or EOO were admitted to the clinical research center (CRC). Routine weight, height, and vital signs were measured. They each underwent dual energy X ray absorptiometry (DXA) scanning (GE Lunar Prodigy Advance) for body composition and each fasted beginning at 9 pm on the day of admission The next morning, they underwent indirect calorimetry testing (Parvo Medics TrueOne 2400 metabolic cart, Sandy, UT) for resting energy expenditure and blood draw for plasma orexin A levels. On a separate visit at the UF Shands Sleep Disorders Center, they underwent overnight polysomnography and multiple sleep latency testing (MSLT) the next day for evaluation for EDS. Overnight polysomnography served to ensure absence of an overt explanation for EDS. For measureme nt of plasma orexin A, 1 mL fasting blood samples were collected between 7 am and 8 am into 3.5 mL serum separating tubes and stored in a 80 C freezer before they were sent to the Diabetes and Obesity Research Center at Sanford Burnham Medical Research Institute in Orlando, FL for

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13 plasma orexin A immunoassay (Phoenix Pharmaceuticals, Inc.) Sibling controls underwent blood draw for plasma orexin A levels. De identified data from a PWS natural history study performed by two of the co authors (DJD, JLM) were included in data analysis. In this separate research study, individuals with PWS or EOO routinely visited the CRC for DXA scanning, indirect calorimetry, and fasting blood draw for measurement of several obesity related hormones. These participants previously gave consent for their stored blood samples to be used for research purposes. These blood samples were sent to the same research institut e for orexin A immunoassay. DXA and calorimetry data were de identified and included for data analysis. Statistical Methods Because the EOO group was much smaller and heavily skewed by gender, comparative analysis was restricted to PWS versus sibling contr ols. We compared PWS to sibling controls using Satterthwaite corrected two sided t test. Within each diagnostic group, using Pearson correlation coefficients, we also tested for correlations between orexin and body mass index (BMI, kg/m2) for participants > 19 years old, BMI SDS for participants 2 19 years old, body fat percentage, and resting energy expenditure (kcal/kg/day). Because limited MSLT data were available, statistical correlation with orexin was not undertaken but was described. P value <0.05 wa s considered statistically significant. Post hoc analysis between PWS and sibling controls was undertaken. We compared the least squares slope of orexin and body fat percentage by a general linear model. The dependent variable was orexin level, while independent variables were group, fat percentage, and interaction between group and fat percentage.

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14 CHAPTER 3 RESULTS A total of 84 participants were included in the study. Forty had PWS (48%), 13 had EOO (15%), and 31 (37%) were sibling controls. Females comprised 44%. Median age was 5 years (range i nfancy to 34 years). Gender distribution was skewed in the EOO group, precluding this group from inclusion into data analysis (Table 3 1). Three way comparison of orexin levels among the 3 groups of participan ts showed no significant differences ( P = 0.13). Satterthwaite corrected two sided T test for orexin levels between PWS and sibling controls also showed no significant difference ( P = 0.81) (Table 3 2). Between PWS and sibling controls, means and SD for BM I (for subjects >19 years old), BMI SDS (for subjects 2 19 years), fat composition, and resting energy expenditure differed significantly (Table 3 3). Correlation Analyses Among individuals with PWS, orexin levels correlated negatively with body fat percen tage (r = 0.35, p = 0.051). Although not statistically significant, orexin correlated negatively with REE (r = 0.17, p = 0.4), inconsistent with previous findings that orexin increases energy expenditure. BMI, BMI SDS, and REE did not show significant c orrelations with orexin (Table 3 4). Post hoc Analysis We conducted a general linear model with orexin as the dependent variable and group (PWS vs sibling controls), fat percentage, and interaction between group and fat percentage as independent variables We found a significant interaction and estimated that the difference in average change in orexin level per unit of fat percentage is 1.76

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15 pg/mL (SE 0.86) higher in controls than in PWS (P=0.042). Sibling controls tended toward a positive association wh ile PWS trended toward a negative association. Due to a limited number of participants that underwent MSLT, we did not include MSLT data in our statistical analysis. Nevertheless, on review of sleep latency data by age group and diagnosis (PWS or EOO), w e found that most participants with PWS fulfilled American Academy of Sleep Medicine (AASM) criteria for eit her narcolepsy or hypersomnia. 38 Table 3 1. Gender distribution: Females/N (%) PWS EOO Controls Gender 19/40 (48%) 2/13 (15%) 16/31 (52%) Table 3 2. Orexin levels. Entries are Mean (SD) [N] PWS EOO Controls Orexin 22.6 (15.8) [40] 33.7 (18.1) [13] 23.6 (19.1) [31] Table 3 3. Descriptive s tatistics: Means and SD by g roup. Entries are M ean (SD) [N] PWS [N=40] Controls [N=31] P v alue (2 sided) BMI SD 2.01 (2.74) [28] 0.79 (1.01) [21] 0.037 Fat 31.7 (15.7) [32] 17.3 (5.00) [19] <0.001 REE 1017 (355) [26] 796 (233) [12] 0.029 Age 8.0 (7.4) [40] 6.6 (7.1) [31] 0.46 BMI 23.4 (11.0) [39] 19.0 (4.7) [29] 0.030 Table 3 4. Correlations with o rexin by d iagnosis. Entries are Pearson r (P Value, two sided) [N] PWS Controls BMI SD 0.07 (0.73) [28] 0.18 (0.44) [21] Fat 0.35 (0.051) [32] 0.33 (0.17) [19] REE 0.17 (0.40) [26] 0.055 (0.87) [12] Age 0.06 (0.73) [40] 0.10 (0.59) [31] BMI 0.005 (0.98) [39] 0.13 (0.50) [29]

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16 CHAPTER 4 DISCUSSION This is the first clinical study to demonstrate the relationship between plasma orexin A levels and energy balance in individuals with PWS and EOO. Although previous studies have measured orexin levels in spi nal fluid in patients with PWS 34 and in plasma in individuals with ob esity 16 and metabolic syndrome 39 no previous study has attempted to investigate whether orexin levels in spinal fluid correlate with that in plasma. Our study was limited by this knowledge gap regarding correlation between spinal fluid plasma concentration. This pilot study was designed to obtain preliminary data on plasma orexin A levels in the obese population. Future studies are necessary to fill this knowledge gap. Given that most of our participants with PWS had EDS, we expected that ore xin levels would be lower than in EOO and sibling controls. We found that orexin levels were 11 pg/mL higher in EOO than in PWS (P=0.049), possibly indicating orexin resistance in the EOO group instead of orexin deficiency. This finding is consistent with previous reports of significantly higher plasma orexin A in individuals with metabolic synd rome than in controls. 39 Notably, our EOO cohort was heavily skewed by male gender (11 males, 2 females). Possibly consistent with our finding, Baranowska, et al reported significantly lower plasma orexin A concentrations in obese women compa red with lean controls. 25 Further investigation is warranted to determine whether estrogen and testosterone affect plasma orexin concentrations. Our results show that plasma orexin concentrations correlated positively with resting energy expenditure, cons istent with previously published data. In the EOO group, a significant positive correlation existed between orexin levels and REE (r = 0.75,

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17 P=0.01). Orexin promotes resistance to obesity by increasing energy expenditure 40 and/or spontaneous physical activity 41 The effect on energy expenditure is more potent than the e ffect on appetite stimulation. 41 In the PWS group, we found that orexin levels correlated negatively with body fat percentage (r = 0.3 5, p = 0.051). This is consistent with findings from Adam, et al that plasma orexin is lower and plasma leptin is higher in obese individuals. In addition, Bronsky and colleagues observed that plasma orexin increased in obese children af ter weight loss 42 While increased fat mass in PWS is well kn own to be due to growth hormone deficiency, further studies are necessary to explain if orexin signaling in the periphery influences body fat composition. The well known effects of orexin on energy balance and wakefulness appear to be more complicated tha n originally described, with additional effects on energy expenditure and other hypothalamic funct ions such as thermoregulation. 43 Future studies can be designed to investigate the role of orexin in brown adipose tissue thermogenesis in increasing energy expenditure. Additionally, it is interesting and worthwhile to design clinical trials to compare the effects of orexin agonists wit h modafinil and placebo on daytime sleep abnormalities.

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18 BIBLIOGRAPHY 1. Ogden CL, Carroll MD, Curtin LR, Lamb MM, Flegal KM. Prevalence of high body mass index in US children and adolescents, 2007 2008. Jama. Jan 20 2010;303(3):242 249. 2. Williams LM. Hypothalamic dysfunction in obesity. Proc Nutr Soc. Nov 2012;71(4):521 533. 3. Chew HB, Ngu LH, Keng WT. Rapid onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD): a case with additional featur es and review of the literature. BMJ Case Rep. 2011;2011. 4. Abaci A, Catli G, Bayram E, et al. A case of rapid onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor: ROHHADNET syndrome. Endocr Pract. Jan Feb 2013;19(1):e12 16. 5. Ize Ludlow D, Gray JA, Sperling MA, et al. Rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation presenting in childhood. Pediatrics. Jul 2007;120(1):e179 188. 6. Velloso LA, Torsoni MA, Araujo EP. Hypothalamic dysfunction in obesity. Rev Neurosci. 2009;20(5 6):441 449. 7. Weaver JU, Noonan K, Kopelman PG. An association between hypothalamic pituitary dysfunction and peripheral endocrine function in extreme obesity. Clin Endocrinol (Ox f). Jul 1991;35(1):97 102. 8. Rand CM, Patwari PP, Rodikova EA, et al. Rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation: analysis of hypothalamic and autonomic candidate genes. Pediatr Res. Oct 2011;70(4):375 378. 9. van de Sande Lee S, Velloso LA. [Hypothalamic dysfunction in obesity]. Arq Bras Endocrinol Metabol. Aug 2012;56(6):341 350. 10. Elena G, Bruna C, Benedetta M, Stefania DC, Giuseppe C. Prader willi syndrome: clinical aspects. J Obes. 2012;2012:47394 1. 11. Jin DK. Systematic review of the clinical and genetic aspects of Prader Willi syndrome. Korean J Pediatr. Feb 2011;54(2):55 63. 12. Whittington JE, Holland AJ, Webb T, Butler J, Clarke D, Boer H. Population prevalence and estimated birth incidence a nd mortality rate for people with Prader Willi syndrome in one UK Health Region. J Med Genet. Nov 2001;38(11):792 798.

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19 13. Vela Bueno A, Kales A, Soldatos CR, et al. Sleep in the Prader Willi syndrome. Clinical and polygraphic findings. Arch Neurol. Mar 19 84;41(3):294 296. 14. Hertz G, Cataletto M, Feinsilver SH, Angulo M. Sleep and breathing patterns in patients with Prader Willi syndrome (PWS): effects of age and gender. Sleep. Jun 1993;16(4):366 371. 15. Bruni O, Verrillo E, Novelli L, Ferri R. Prader Wi lli syndrome: sorting out the relationships between obesity, hypersomnia, and sleep apnea. Curr Opin Pulm Med. Nov 2010;16(6):568 573. 16. Adam JA, Menheere PP, van Dielen FM, Soeters PB, Buurman WA, Greve JW. Decreased plasma orexin A levels in obese indi viduals. Int J Obes Relat Metab Disord. Feb 2002;26(2):274 276. 17. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein coupled receptors that regulate feeding behavior. Cell. Feb 20 1998;92(4):573 585. 18. Haynes AC, Jackson B, Overend P, et al. Effects of single and chronic intracerebroventricular administration of the orexins on feeding in the rat. Peptides. 1999;20(9):1099 1105. 19. Willie JT, Chemelli RM, Sinton CM, Yanagisawa M. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci. 2001;24:429 458. 20. Haynes AC, Jackson B, Chapman H, et al. A selective orexin 1 receptor antagonist reduces food consumption in male and female rats. Regul Pept. Dec 22 2000;96(1 2):45 51. 21. Lubkin M, Stricker Krongrad A. Independent feeding and metabolic actions of orexins in mice. Biochem Biophys Res Commun. Dec 18 1998;253(2):241 245. 22. Novak CM, Levine JA. Daily intraparaventricular orexin A treatment induc es weight loss in rats. Obesity (Silver Spring). Aug 2009;17(8):1493 1498. 23. Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron. May 2001;30(2):345 354. 24. Sellayah D, Bharaj P, Sikder D. Orexin is required for brown adipose tissue development, differentiation, and function. Cell Metabolism. Oct 5 2011;14(4):478 490. 25. Baranowska B, Wolinska Witort E, Martynska L, Chmielowska M, Baranowska Bik A. Plasma orexin A, orexi n B, leptin, neuropeptide Y (NPY) and insulin in obese women. Neuro Endocrinol Lett. Aug 2005;26(4):293 296.

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20 26. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. Jan 1 2000;355(9197):39 40. 2 7. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. Sep 2000;27(3):469 474. 28. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulatio n. Cell. Aug 20 1999;98(4):437 451. 29. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. Aug 6 1999;98(3):365 376. 30. Kanbayashi T, Inoue Y, Chiba S, et al. CSF hy pocretin 1 (orexin A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia. J Sleep Res. Mar 2002;11(1):91 93. 31. Tsukamoto H, Ishikawa T, Fujii Y, Fukumizu M, Sugai K, Kanbayashi T. Undetectable levels of CSF hypocretin 1 (o rexin A) in two prepubertal boys with narcolepsy. Neuropediatrics. Feb 2002;33(1):51 52. 32. De la Herran Arita AK, Guerra Crespo M, Drucker Colin R. Narcolepsy and orexins: an example of progress in sleep research. Front Neurol. 2011;2:26. 33. Mignot E, L ammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. Oct 2002;59(10):1553 1562. 34. Nevsimalova S, Vankova J, Stepanova I, Seemanova E, Mignot E, Nishino S. H ypocretin deficiency in Prader Willi syndrome. Eur J Neurol. Jan 2005;12(1):70 72. 35. Zeitzer JM, Nishino S, Mignot E. The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends Pharmacol Sci. Jul 2006;27(7):368 37 4. 36. Kok SW, Overeem S, Visscher TL, et al. Hypocretin deficiency in narcoleptic humans is associated with abdominal obesity. Obes Res. Sep 2003;11(9):1147 1154. 37. Dahmen N, Bierbrauer J, Kasten M. Increased prevalence of obesity in narcoleptic patients and relatives. Eur Arch Psychiatry Clin Neurosci. 2001;251(2):85 89. 38. AASM. International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd ed. Westchester, Illinois2005.

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22 BIOGRAPHICAL SKETCH Mary Joyce Dy Gan obtained her professional degree in medicine from the University of the Philippines in 1995. She completed two 3 year residencies in pediatrics, one in Manila, Philippines (2003) and the other one at Florida State University in Pen sacola, FL (2010) From there, she moved to the University of Florida to obtain fellowship training in pediatric endocrinology (2013) as well as a master s degree in medical sciences with a concentration in clinical and translational science (2013).