A Personalized Program of Physical Activity and Diet for Hypothalamic Obesity
A Personalized Program of Physical Activity and Diet for Hypothalamic Obesity
Hypothalamic obesity (HO) is an obesity secondary to an alteration of the functioning of the
 hypothalamus, the central organ of energy homeostasis. The causes of OH are related to an
 hypothalamic lesion (eg craniopharyngioma) or to genetic diseases (ex: Prader-Willi
 syndrome). OH, which accounts for about 5 to 10% of obesity, is a complex handicap
 characterized by severe obesity associated with eating disorders, cognitive and behavioral
 disorders and sometimes a visual deficit, with a major impact on quality of life, morbidity
 and mortality. There is currently no specific treatment of HO. Management is essentially
 behavioral, based on daily support of eating behavior and physical activities (PA). OH is
 characterized by an intense and almost permanent hunger felt, a satiety disorder and an
 obsessive interest in food. The food education of the entourage is essential, the advise
 concern the control of the access to food and the setting up of a precise food frame on the
 quantities, with low energetic density, and schedules. OH is characterized by obesity with
 lean mass deficit. PA must therefore be regular, adapted to the disability and personalized
 to take into account cognitive deficits and behavioral disorders. Although the supervision of
 meals and daily PA is now recognized as fundamental in the care of these patients (National
 Program of Diagnosis and Care established by the French "Haute Autorité de Santé"), few
 studies have evaluated the effectiveness of programs with personalized support on global
 health. The investigators hypothesize that a personalized 4-month individual home-based
 counseling program on dietary counseling and PA can be effective to modify behaviors such as
 diet and PAs with an impact on changing weight and quality of life. The 16-week program
 includes a dietetic component (initial assessment with dietary care plan followed by a
 30-minute telephone interview every month with dietician) and a PA component (two 1-hour
 individualized sessions, performed at home and supervised by a PA educator). Before and after
 the program, the investigators will evaluate habitual PA with an accelerometer, feeding
 behavior, physical functioning, weight change, body composition, quality of life and will
 constitute a biobank of serums, adipose tissues and stools. If the effectiveness of this
 program is demonstrated this will help to find ways to sustain this support by the
 institutions, to train professionals in the complex accompaniment of these patients. Finally
 this program set up as part of a rare disease can show the benefits in other populations of
 more common pathology (common severe obesity, intellectual disability, behavioral disorders).
Hypothalamic obesity (HO) is defined as obesity secondary to impaired functioning of the
 hypothalamus nuclei, the central organ of energy and weight homeostasis. Among the causes of
 OH, there are those related to a hypothalamic lesion (lesional) such as craniopharyngioma
 (CP) or inflammatory (sarcoidosis, tuberculosis etc ..) and those called genetic, with gene
 abnormalities involved in the central regulation of energy homeostasis. The genetic causes of
 obesity can be either "monogenic" by mutation of genes involved in the leptin / melanocortin
 pathway, or "syndromic", defined by the association of obesity and other clinical signs
 (syndrome), such as Prader-Willi syndrome (PWS). PWS, which has a frequency of 1/15000
 births, is one of the most well-known obesity-related syndromes. It is characterized by
 muscle hypotonia at birth, severe hyperphagia and dietary impulsivity, dysmorphic features,
 and intellectual disability with cognitive-behavioral abnormalities.

 Although HO has various origins, it has a common phenotype with the presence of severe
 obesity, having a heavy impact on the morbidity and mortality. Obesity is multifactorial,
 associated with an increase in energy intake, a decrease in energy expenditure and an
 alteration of peripheral metabolism. First, impaired functioning of the hypothalamic nuclei
 leads to resistance to leptin and other hormones involved in the energy balance (GLP1,
 ghrelin etc.) leading to an increase in hunger and a lack of satiety responsible for
 hyperphagia. An alteration of the cognitive control of food intake and a hyper activation of
 the reward system have also been described in PWS, which can explain episodes of uncontrolled
 food impulsivity (food theft) and a high sensitivity to external stimuli in particular
 visualization of food. As such, it is a particularly interesting model for studying
 hyperphagia and alterations in the control of food intake. It should be noted that eating
 disorders vary from one individual to another but can also fluctuate for the same individual
 depending on the psychological state of the patients and their daily activities. The
 involvement of the autonomic nervous system leads to a decrease in the sympathetic tone
 responsible for a fall in resting energy expenditure. Indeed, there is a positive correlation
 between autonomic nervous system activity, basal metabolism, and spontaneous physical
 activity. In addition, endocrine deficits, present in HO, not or insufficiently substituted,
 such as gonadotropic, thyrotropic or somatotropic insufficiency have also a negative impact
 on resting energy expenditure. The total energy expenditure is also lowered by the low
 spontaneous physical activity (PA) of the patients in relation to the hypotonia described in
 these patients and a reduction of the spontaneous activation of the movements. In addition,
 sleep disorders (OSA, narcolepsy, daytime hypersomnolence) are common in patients with OH and
 may increase exercise fatiguability and difficulties for patients to do PA. Finally, visual
 disturbances (reduction of severe visual acuity by amputation of the visual field) associated
 with optic chiasm involvement in lesion-induced HO or induced by craniopharyngioma tumor
 resection, are also a limitation for PA and increase sedentary lifestyle. The absence of PA
 and the increase in sedentary lifestyle are associated with abnormal body composition with an
 increase in body fat at the expense of muscle mass . This is especially important in patients
 with PWS associated with developmental muscle hypotonia].

 People with HO have often cognitive deficits, learning difficulties and social skills
 disorders. These are constant in the PWS but also in the lesional cause. All these factors
 lead to altering the quality of life. Thus, an impairment of quality of life has been
 demonstrated in 185 obese patients with craniopharyngioma in childhood. In our cohort of HO
 subjects, mood disorders assessed by the HAD score are common: 91% for lesional HO 50% for
 genetic HO and this is correlated with BMI. The Kendall-Taylor study shows that, in children
 with craniopharyngioma, the quality of life score depends on the age at diagnosis, the
 presence of somatotropic deficiency and BMI. At present, there is no specific treatment of
 HO. Drug treatments have been proposed such as melatonin, somatostatin analogue or
 sympathomimetics but with limited effects on weight and feeding behavior, resulting in no
 prescribing recommendations given the lack of randomized studies with sufficient patient
 samples. Sibutramine tested in patients with lesional or genetic HO, withdrawn from the
 market in France since 2010 for potentially deleterious effects on the cardiovascular system.
 GLP 1 analogues are also an interesting therapeutic approach in patients with
 craniopharyngioma with some efficacy on weight , but are currently reserved for diabetic
 patients. Regarding bariatric surgery, the HAS recommends that "the indication must be
 exceptional and discussed on a case by case basis". A meta-analysis of the results of
 bariatric surgery in 21 subjects with craniopharyngioma showed a weight loss at 1 year of
 15.1 kg, in the same average as the obese general population operated. Nevertheless the
 subjects were selected (absence of important behavioral disorders) and the results concern
 only the short term. In genetic HO, especially PWS, the results of bariatric surgery should
 be used with caution. In terms of weight loss, the results are not as good, with medium-term
 weight regain, persistence of hyperphagia despite the reduction of the gastric pouch, and an
 increased risk of morbidity and mortality. Management is essentially behavioral, based on
 daily support of eating behavior and PA. Food management requires from a very young age for
 these patients, a permanent food control, to fight against primary impulsivity of central
 origin, can be a cause of frustration and behavioral disorders. Indeed, the genetic syndrome
 is characterized by intense and permanent hunger, a lack of satiety and an obsession for
 food. The affected patients are completely overwhelmed by this addictive behavior. It is
 extremely difficult or impossible for the child as for the adult with this syndrome to
 control his dietary intake. The entourage must therefore control access to food at home and
 abroad. This requires constant supervision. An early education of food in the family is
 essential because today it there is no possible and sustainable autonomy regarding diet for
 these patients. There is a strong need for coherence for caregivers to avoid unnecessary
 discussions and arguments. It is necessary to inform, prevent, associate the family and
 friendly entourage so that there is a coherence with the line of conduct chosen by all.
 Patients can not feel the signals that would allow them to have a meal like other people, so
 it is recommended to put in place a precise food frame on quantities and schedules, a low
 energy density food setting while providing sufficient food volume. A strict framework
 reassures and secures the patient because he has benchmarks. This is to reassure the person
 himself, to do everything possible to limit the temptations that are a source of tantrums and
 frustration. By respecting meal schedules and their composition ("food security"), by
 diverting patients' thinking, by occupying them, we can improve the food obsession of
 patients with HO. This specific and personalized dietary management is therefore necessary
 and essential. Physical activities are also a basic component of treating common obesity and
 its complications. It has a favorable effect on weight control, especially on the prevention
 of weight gain. In addition, PA has important beneficial effects on body composition.
 Regardless of weight loss, PA decreases total body fat and visceral abdominal fat. It also
 limits the loss of muscle mass during weight loss. Beyond its effects on weight control and
 body composition, PA is beneficially associated with many health parameters and decreases the
 risk of developing the major complications of obesity (type 2 diabetes and cardiovascular
 diseases). PA is also associated with an increase in quality of life. Finally, PA improves
 physical capacity that is often greatly diminished in obese subjects. Obesity is associated,
 on the one hand, with a decrease in cardiorespiratory fitness, muscular strength, functional
 capacity (observed for example during the 6-minute walk test) and, on the other hand,
 impaired balance and locomotion. Studies in patients with HO showed that patients had a low
 level of PA. Only one study measured PA level in the PWS. PA was measured using
 accelerometers in 28 young adults with moderate obesity. Only 25% of men and 15% of women
 achieved the minimum level of recommended PA and the average daily duration of moderate to
 high intensity AP was 14 minutes. Two studies measured PA level using accelerometers or
 pedometers in patients with craniopharyngioma. PA level was lower than that seen in normal
 weight subjects. In addition, the functional capacity of HO subjects appears to be impaired.
 For example, muscle strength, balance, and locomotion were assessed in 5 studies of 12 to 19
 young adults with PWS and massive obesity. Muscle strength was significantly reduced compared
 to normal weight subjects, but also compared to control obese subjects. The balance was also
 altered, increasing the risk of falling. Finally, these patients adopted a different walking
 pattern (decreased walking speed and step length, increased double support time). Grolla et
 al. showed that a 4-week program, repeated 4 times a year, combining a low-calorie diet and a
 sustained program of PA (up to 7 hours of activities per day, such as walking, exercise bike
 , carpet exercises) reduced BMI of 2.5 kg / m2 and body fat by 2.5 kg in patients with PWS.
 Two other studies evaluated the effect of a PA program combining an initial stay of 2 weeks
 and a home-based training program for 6 months. During the initial 2 weeks, patients
 participated in 4 sessions per week, supervised by trained staff, during which they performed
 strength training and endurance exercises. During the following 6 months at home, patients
 autonomously performed 3 sessions per week of muscle strengthening. This program resulted in
 improved biomechanical parameters of the ankle and knee during walking. Other measured
 parameters (muscle strength, balance) were unchanged. Another study followed patients with
 PWS for 7 years during which patients regularly participated in rehabilitation programs
 combining PA, dietary management and physiotherapy. The results showed an improvement in the
 biomechanical parameters of gait. Thus, the management of HO should be comprehensive,
 residing in the control of the environmental risk factors of weight gain: management of
 hyperphagia by regular and personalized nutritional and dietary monitoring and appropriate
 medico-social support (educator, informed parents). Compulsive eating behavior can be reduced
 in a structured environment, with support and stimulation of other interests (especially
 physical activities and activities). In addition, a daily PA is essential to compensate for
 the decreased basic metabolism (see above). If support by PA and food management is now
 recognized as a fundamental element of the care of patients suffering from HO (National
 Program of Diagnosis and Care established by the HAS (Haute Autorité de Santé) http: //
 www.has-sante.fr/portail/upload/docs/application/pdf/2012-06/ald_hors_liste_-_pnds_on_the_syn
 drome_de_prader-willi.pdf), no study has evaluated the effectiveness of a personalized
 support program, framed and at home, focusing on dietary counseling, control of eating
 behavior and PA, on dietary behavior, patients' health status, physical activity volume and
 functional capacity, the evolution of weight and quality of life.

 The hypothesis of the investigators is that a personalized home-based support program for
 dietary advice and PA for 4 months helps to change weight changes through behavioral changes
 such as increasing habitual physical activity, improving eating behavior, functional capacity
 and quality of life.
Inclusion Criteria:

 -  Male or female subject aged 18 to 60

 -  BMI ≥ 30kg / m² or MG ≥ 35% of total weight in men / 40% of total weight in women

 -  "Hypothalamic" obesity, defined as obesity with hyperphagia, and cognitive or
 neuropsychological disorders

 -  Entourage present (family or educator)

 -  Treatments not modified for at least 2 months (growth hormone, gonadotropic /
 thyrotropic / corticotropic substitution, Minirin, psychotropic drugs, etc.)

 -  Affiliation to a social security scheme

 Exclusion Criteria:

 -  Introduction of new treatments in the 2 months preceding inclusion that can modify the
 feeding behavior (GLP1 analogues, Topiramate, psychotropic drugs, etc.).

 -  Decompensation of a cardiorespiratory or psychiatric pathology in the 3 months
 preceding the inclusion.

 -  Subject in a situation that, in the opinion of the investigator, could interfere with
 his / her optimal participation in the study (eg severe behavioral disorders) or
 constitute a particular risk for the patient (eg severe cardiorespiratory pathology).

 -  Contraindication to the physical activity discovered during the first evaluation
 (electrocardiogram abnormalities, abnormal stress test, abnormal cardiac
 echocardiography or effort scintigraphy, etc.).

 -  Subject in exclusion period after participation in another clinical trial.

 -  Pregnancy, breastfeeding.

 -  Interruption of more than 15 days of the foreseeable monitoring protocol (leave etc
 ..).