Development Of Hypothalamic Obesity Research Articles

FRI066 Treatment History And Comorbidities Reported By Patients With Hypothalamic Obesity Treated With Setmelanotide In A Phase 2 Trial

Abstract Disclosure: C.L. Roth: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. A.H. Shoemaker: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc., Saniona. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. M. Gottschalk: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. J. Miller: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. G. Yuan: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. S. Malhotra: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. C. Scimia: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. M.J. Abuzzahab: Consulting Fee; Self; Pfizer, Inc., Consynance, Rhythm Pharmaceuticals, Inc., Endo Pharmaceuticals. Background: Hypothalamic obesity (HO) is an acquired form of severe obesity that can occur following surgical resection or radiotherapy of brain tumors. Multiple factors associated with the development of HO—including degree of hypothalamic damage from tumor treatment, comorbidities (eg, pituitary deficiencies), polypharmacy used to treat comorbidities, and unique pathophysiology—confer treatment challenges; HO is often unresponsive to lifestyle modifications and traditional obesity pharmacotherapies. In a Phase 2, 16-week trial of setmelanotide in patients with HO, 16 of 18 patients (88.9% [90% confidence interval, 69.0%-98.0%]; P<0.0001) achieved ≥5% body mass index (BMI) reduction from baseline, with a mean percent BMI change of −15.4% in patients adhering to treatment (n=17). We assessed patient histories (ie, tumor treatments, prior attempts to lose weight, and comorbidities) reported in the trial to further characterize this patient population. Methods: Patients aged ≥6 to ≤40 years with documented evidence of HO were enrolled in an open-label Phase 2 trial (NCT04725240) and received setmelanotide once daily for 16 weeks. The primary endpoint was the proportion of patients with ≥5% BMI reduction from baseline at Week 16. Tumor treatments, prior attempts to lose weight, and comorbidities are summarized narratively. Results: Eighteen patients with HO (age range, 6-24 years) were treated with setmelanotide. HO was diagnosed in patients following treatment of craniopharyngioma (n=14), hamartoma (n=3), or juvenile pilocytic astrocytoma (n=1). Six patients (33.3%) had tumor recurrence and/or multiple tumor treatments. Thirteen patients (72.2%) reported prior lifestyle modifications (ie, calorie restriction [n=4], low-carbohydrate diet [n=6], dietary tracking/modification [n=4], food access restriction [n=1], personal training [n=1]) and/or pharmacotherapy use (ie, exenatide [n=3], semaglutide [n=1], liraglutide [n=2], metformin [n=2], methylphenidate [n=2], dextroamphetamine [n=1], lisdexamfetamine [n=2], naltrexone [n=3], oxytocin [n=3], phentermine [n=1]) without substantial benefit. Comorbidities occurring in ≥25% of patients were diabetes insipidus (n=14), hypothyroidism (n=14), growth hormone deficiency (n=11), adrenal insufficiency (n=10), hypogonadism (n=8), pan/hypopituitarism (n=8), psychiatric disorders (n=8), vision problems (n=6), gastrointestinal symptoms (n=6), obstructive sleep apnea (n=5), and hypothalamic-pituitary disorder (n=3). All patients adhering to treatment (n=17, including those with pituitary deficiencies and common comorbidities)) experienced BMI reductions with setmelanotide. Conclusions: Despite complex medical histories, hypothalamic damage, and various prior failed interventions, setmelanotide reduced BMI in patients with HO in a Phase 2 trial. Presentation: Friday, June 16, 2023

Transition From Diencephalic Syndrome to Hypothalamic Obesity in Children With Suprasellar Low Grade Glioma: A Case Series.

BackgroundChildren with suprasellar low grade glioma (LGG) frequently develop problems to maintain their body weight within the normal range, due to hypothalamic dysfunction. Hypothalamic damage may result in the diencephalic syndrome (DS), characterized by underweight or failure to thrive, but also in hypothalamic obesity (HO). Children with LGG presenting with DS at young age often develop HO later in life. The underlying pathophysiology for this change in body mass index (BMI) is not understood. Previous hypotheses have focused on the tumor or its treatment as the underlying cause. To better understand its etiology, we aimed to relate changes in BMI over time in children with suprasellar LGG presenting with DS to age, tumor progression, treatment, and endocrine function. We hypothesize that the development of HO in children with LGG presenting with DS is related to maturation status of the hypothalamus at time of injury and thus age.MethodsIn this retrospective case series, all cases diagnosed in the Netherlands with suprasellar located LGG, currently treated or followed, with a history of DS developing into HO were included.ResultsIn total, 10 children were included. Median age at LGG diagnosis was 1.5 years (range 0.4–5.5), median BMI SDS was −2.64. The children developed overweight at a median age of 4.5 years (2.2–9.8). The median total difference in BMI SDS between underweight and obesity was +5.75 SDS (4.5–8.7). No association could be found between transition of DS to HO and onset of a pituitary disorder (present in 70.0%), surgery, chemotherapy, or tumor behavior. Two had developed central precocious puberty (CPP), both while having underweight or normal weight.ConclusionThe shift from DS to HO in children with hypothalamic LGG may be associated with age and not to tumor behavior, treatment characteristics or pituitary function. The development of CPP in these children seems not to be related to obesity. Our findings may indicate that the clinical picture of hypothalamic dysfunction reflects the maturation state of the hypothalamus at time of lesioning. Future prospective studies are needed to better understand underlying causative mechanisms of the morbid changes in body weight.

Pathophysiology and Individualized Treatment of Hypothalamic Obesity Following Craniopharyngioma and Other Suprasellar Tumors: A Systematic Review.

The development of hypothalamic obesity (HO) following craniopharyngioma (CP) and other suprasellar tumors leads to reduced patient quality of life. No treatment algorithms are currently available for management of HO. Depending on which hypothalamic nuclei are destroyed, the pathophysiologic mechanisms and clinical symptoms that contribute to HO differ among patients. Herein, we review the contribution of the hypothalamus to the pathophysiologic mechanisms and symptoms underlying CP-associated HO. Additionally, we performed a systematic search of MEDLINE and Embase to identify all intervention studies for weight management in patients with CP or other suprasellar tumors published until September 2017. The search yielded 1866 publications, of which 40 were included. Of these 40 studies, we identified four modalities for intervention (i.e., lifestyle, dietary, pharmacotherapeutic, or surgical) within six clinical domains (i.e., psychosocial disorders, hyperphagia, sleep disturbances, decreased energy expenditure, hyperinsulinemia, and hypopituitarism). We used the findings from our systematic review, in addition to current knowledge on the pathophysiology of HO, to develop an evidence-based treatment algorithm for patients with HO caused by CP or other suprasellar tumors. Although the individual effects of the HO interventions were modest, beneficial individual effects may be achieved when the pathophysiologic background and correct clinical domain are considered. These two aspects can be combined in an individualized treatment algorithm with a stepwise approach for each clinical domain. Recently elucidated targets for HO intervention were also explored to improve future management of HO for patients with CP and other suprasellar tumors.

The development of hypothalamic obesity in craniopharyngioma patients: A risk factor analysis in a well-defined cohort.

Hypothalamic obesity (HO) is a major concern in patients treated for craniopharyngioma (CP). The influence of degree of resection on development of HO, event-free survival (EFS), and neuroendocrine sequelae is an issue of debate. A retrospective cohortconsisting of all CP patients treated between 2002 and 2012 in two university hospitals was identified. Multivariable logistic regression was used to study the associations between preoperative BMI, age at diagnosis, tumor volume, performed surgical resection, and presence of HO at follow-up. Thirty-five patients (21 children and 14 adults) were included. Median follow-up time was 35.6 months (4.1-114.7). Four patients were obese at diagnosis. HO was present in 19 (54.3%) patients at last follow-up of whom eight were morbidly obese. Thirteen (37.1%) patients underwent partial resection (PR) and 22 (62.9%) gross total resection (GTR). GTR was related to HO (OR 9.19, 95% CI 1.43-59.01), but for morbid HO, obesity at diagnosis was the only risk factor (OR 12.92, 95% CI 1.05-158.73). EFS in patients after GTR was 86%, compared to 42% after PR (log-rank 9.2, P=0.003). Adjuvant radiotherapy after PR improved EFS (log-rank 8.2, P=0.004). Panhypopituitarism, present in 15 patients, was mainly seen after GTR. HO is less frequent after PR than after GTR, but PR cannot always prevent the development of morbid obesity in patients with obesity at diagnosis. PR reduces the occurrence of panhypopituitarism. When developing a treatment algorithm, all these factors should be considered.

A Review of Childhood and Adolescent Craniopharyngiomas With Particular Attention to Hypothalamic Obesity

BackgroundAlthough craniopharyngiomas are considered “benign” neoplasms by the World Health Organization classification, these tumors may create significant morbidity and mortality in patients. Hypothalamic obesity is a frequent complication of craniopharyngiomas and is refractory to current management options. Patients/MethodsWe reviewed 24 cases of craniopharyngiomas treated from 1992 to 2010 in patients <18 years of age regarding clinical presentation, neuroimaging, recurrence, morbidity, and mortality, with particular attention to hypothalamic obesity. ResultsOur cohort conformed to published data in regard to neuroimaging characteristics, and clinical findings in the areas of endocrine, visual, neurological, neurobehavioral, and hypothalamic domains. At last follow-up, 53% of our patients were overweight (8%) or obese (46%). Only 25% of our patients had a healthy body mass index. Contrasting these data with body mass indices at diagnosis, where 21% of patients were overweight and 17% were obese, we found that there was a significant trend towards obesity over time. A significant portion of our mortality appears to be related to complications of obesity. The Native American population in Arizona appears to have a statistically greater incidence of obesity in childhood. Despite our small sample size, 75% of our Native Americans were obese at last follow-up and accounted for 50% of the mortality. ConclusionHypothalamic obesity is a significant complication of craniopharyngiomas associated with increased mortality. The development of hypothalamic obesity is influenced by premorbid obesity, genetics, and therapy received, specifically radiation. Because of the intractability of hypothalamic obesity, improved understanding of neuroendocrine mechanisms, genomics, and newer antiobesity medications will be necessary to curb this significant complication.

Pathophysiology and clinical characteristics of hypothalamic obesity in children and adolescents.

The hypothalamus plays a key role in the regulation of body weight by balancing the intake of food, energy expenditure, and body fat stores, as evidenced by the fact that most monogenic syndromes of morbid obesity result from mutations in genes expressed in the hypothalamus. Hypothalamic obesity is a result of impairment in the hypothalamic regulatory centers of body weight and energy expenditure, and is caused by structural damage to the hypothalamus, radiotherapy, Prader-Willi syndrome, and mutations in the LEP, LEPR, POMC, MC4R and CART genes. The pathophysiology includes loss of sensitivity to afferent peripheral humoral signals, such as leptin, dysregulated insulin secretion, and impaired activity of the sympathetic nervous system. Dysregulation of 11β-hydroxysteroid dehydrogenase 1 activity and melatonin may also have a role in the development of hypothalamic obesity. Intervention of this complex entity requires simultaneous targeting of several mechanisms that are deranged in patients with hypothalamic obesity. Despite a great deal of theoretical understanding, effective treatment for hypothalamic obesity has not yet been developed. Therefore, understanding the mechanisms that control food intake and energy homeostasis and pathophysiology of hypothalamic obesity can be the cornerstone of the development of new treatments options. Early identification of patients at-risk can relieve the severity of weight gain by the provision of dietary and behavioral modification, and antiobesity medication. This review summarizes recent advances of the pathophysiology, endocrine characteristics, and treatment strategies of hypothalamic obesity.

Diencepephalic syndrome before diagnosis of childhood craniopharyngioma – Results of German multicenter studies on 485 long-term survivors after childhood craniopharyngioma

Background: Childhood craniopharyngiomas (CP) are rare intracranial embryogenic malformations of the sellar region arising from remnants of Rathke's pouch. Hypothalamic involvement of craniopharyngioma (HI) resulting in pathological patterns of eating behaviour and obesity are known to have major impact on prognosis and quality of life in surviving patients. HI of sellar masses is also associated with disturbances of satiety regulation leading to a failure to thrive, weight loss and even cachexia known as diencephalic syndrome (DS). The rate of DS and the outcome of CP patients with DS is unknown. Methods: 485 CP patients have been recruited in the German multicenter studies HIT-ENDO and KRANIOPHARYNGEOM 2000/2007. 21 CP patients (4.3%) presented with a BMISDS < -2 SDS at the time of diagnosis. In 4 of 21 cases low BMI could be explained by prematurity or congenital heart failure. 11 patients presented with DS due to proven hypothalamic involvement (HI). 3 patients presented without HI and in 3 patients HI was not evaluable. We compared weight development since birth at standardized time points (based on the German health survey “Vorsorgeuntersuchungen”) in cohorts of CP patients presenting DS, normal weight or obesity (BMISDS >3SDS) at time of diagnosis. Results: Weight development was disturbed in DS patients already in early childhood. Crossing of the weight percentile occurred in most cases during the first or second year of life. In contrast, the development of hypothalamic obesity is related closely to time of CP diagnosis. Conclusion: DS is a rare congenital clinical manifestation of CP with a high risk for delayed diagnosis and treatment.

MELATONIN SECRETION AND HYPERSOMNIA IN CHILDREN AND ADOLESCENTS AFTER CRANIOPHARYNGIOMA RESECTION

Craniopharyngioma is a rare embryonic tumor of the chiasm-sellar region with low malignancy rate but high frequency of recurrence. In spite of the favorable outcome and satisfactory results of treatment the patients quality of life worsens due to complications associated with anatomic localization of craniopharyngioma close to the optic nerve, optic chiasm, hypophysis and hypothalamus. The development of hypothalamic obesity is observed in 25–60% of children and adolescents after surgical treatment of craniopharyngioma, which is usually accompanied with significant disturbances of circadian rhythm and has the most important influence on patients quality of life.

The role of leptin, soluble leptin receptor, resistin, and insulin secretory dynamics in the pathogenesis of hypothalamic obesity in children

In this study, we have investigated the role of leptin, soluble leptin receptor(sOb-R), resistin, and insulin secretory dynamics in the development of hypothalamic obesity. Children who had hypothalamo-pituitary tumor were divided into two groups. First group included obese-overweight (hypothalamic obese = HOB group, n = 23) and second group included non-obese children (hypothalamic non-obese = HNOB group, n = 16). Exogenously obese-overweight children (OB group, n = 22) were included as controls. Basal and second-hour serum glucose and insulin in oral glucose tolerance test (OGTT), basal serum leptin, sOb-R, resistin levels, and homeostasis model assessment (HOMA) indexes were compared between the groups. Age, sex, and pubertal status were similar in study groups. Median and interquartile ranges of body mass index (BMI) z scores were similar in HOB and OB groups (2.0 (1.5-2.1) and 2.1 (1.8-2.3), respectively). Serum leptin levels corrected for BMI were highest and total leptin/sOb-R ratios (free leptin index (FLI)) tended to be higher in HOB than HNOB and OB groups, indicating leptin resistance (leptin/BMI, 4.0 (1.6-5.2), 1.5 (0.8-3.1), and 2.5 (1.8-3.5); FLI, 2.0 (0.8-3.5), 0.6 (0.3-1.2), and 1.5 (1-2.3) in HOB, HNOB, and OB groups; respectively). Serum resistin levels were similar in groups (2.6 (1.9-3.1), 2.8 (1.7-3.4), and 3.0 (2.2-3.5) ng/ml in HOB, HNOB, and OB groups, respectively). Basal serum glucose, basal and second-hour insulin levels in OGTT, and HOMA index were higher in OB group than the HOB and HNOB groups, indicating insulin resistance in simple obesity; however, increment of insulin to same glycemic load in OGTT was highest in the HOB group indicating insulin dysregulation (p < 0.05). Hypothalamic obesity seems to be related to both dysregulated afferent (leptin) and efferent (insulin) neural outputs through the autonomic nervous system resulting in energy storage as fat.

Development of hypothalamic obesity in growing rats

Administration of monosodium glutamate to neonate rats causes hypothalamic lesions in the region of the nucleus arcuatus and the eminentia mediana, followed by massive accumulation of triglycerides, diminished secretion of growth hormone, reduced body length and organ weights and diminished number of adipocytes (hypoplastic-hypertrophic obesity). Locomotor activity of obese animals is reduced by about 50%. Food intake is increased by about 10% during growth and development of obesity but decreased beneath the level of that in control animals in the stationary phase of obesity. Hyperinsulinemia coupled with insulin resistance develops in the stationary phase of obesity, i.e. when adipocyte diameter has reached approximately 100 microns. The effects of reduced secretion of growth hormone are considered to be a main factor of fat accumulation in this type of obesity.

Hypothalamic hyperinsulinemia and obesity: role of adrenal glucocorticoids.

The effects of adrenalectomy on the obesity and hyperinsulinemia induced by ventromedial hypothalamic (VMH) lesions were studied in female rats. Plasma insulin and glucose levels were assayed after a 4-h fast and 17 min after the initiation of a meal (6 ml sweetened milk in 7 min). The development of hypothalamic obesity was prevented by prior adrenalectomy and restored by administration of corticosterone. Adrenalectomy abolished both the basal and postabsorptive hyperinsulinemia observed in sham-adrenalectomized rats with VMH lesions. Corticosterone treatment of adrenalectomized animals enhanced both basal and postabsorptive insulin levels, but adrenalectomized rats with VMH lesions were hyperinsulinemic compared with animals with sham lesions only under the postabsorptive condition. Postabsorptive glucose levels were unaffected by either the lesion or adrenal ablation. The results support our previous conclusion that postabsorptive hyperinsulinemia is of greater importance than is basal hyperinsulinemia in the pathogenesis of hypothalamic obesity. Although the results are consistent with a stimulatory role of corticosterone on food intake mediating the postabsorptive hyperinsulinemia, a primary effect on CNS loci involved with the regulation of insulin secretion is also possible.

Hypothalamic obesity : The autonomic hypothesis and the lateral hypothalamus.

Several lines of evidence support the hypothesis that derangements in the function of the autonomic nervous system play an important role in the development of hypothalamic obesity. Vagotomy below the diaphragm reverses the syndrome. In diabetic rats cured of their diabetes with transplants of fetal pancreatic tissue beneath the renal capsule, ventromedial hypothalamic (VMH) lesions do not produce the characteristic rise in food intake nor do they significantly increase serum insulin. These observations indicate that the hyperinsulinaemia following VMH lesions is the result of neural connections rather than from a circulating humoral factor released following VMH injury. The smaller salivary glands, reduced level of glucagon and impaired mobilization of fatty acids during stress in VMH lesioned rats point to reduced activity of the sympathetic nervous system. The impaired mobilization of fat from retroperitoneal depots in VMH lesioned rats during fasting is similar to the effect of sympathetic denervation of the retroperitoneal fat pad. Similarly, unilateral sympathectomy caused an increased weight gain in rats almost as much as unilateral VMH lesions but significantly less than in bilaterally lesioned rats. These studies with fasting and feeding implicate the VMH in the control of the sympathetic nervous system. When atropine and epinephrine were given to VMH lesioned rats, there was a significant depression in basal and glucose-stimulated levels of insulin. Finally when VMH lesions were placed after lateral hypothalamic lesions, the effect of the VMH lesions did not seem to be reduced, suggesting that the two effects are independent. A model dealing with the effects of VMH lesions is presented in an attempt to integrate these findings.

Adipose tissue lipoprotein lipase activity in rats with obesity-inducing hypothalamic knife cuts

Three experiments examined the effects of obesity-inducing parasagittal hypothalamic knife cuts on adipose tissue lipoprotein lipase (LPL) activity in female rats. Knife cuts induced a 4-fold increase in adipose tissue LPL activity. Knife-cut rats with controlled insulin levels were hyperphagic but showed no increase in adipose tissue LPL activity or body weight gain. Prevention of the hyperphagia by food restriction also blocked the changes in LPL activity and weight gain. Finally, exogenous insulin treatment increased adipose tissue LPL activity in the absence of hyperphagia in neurologically-intact rats. We conclude that increased adipose tissue LPL activity may play a permissive role in the development of hypothalamic obesity, with the increase in enzyme activity being secondary to knife-cut-induced hyperinsulinemia.

Effect of transplantation of pancreas on development of hypothalamic obesity

HYPOTHALAMIC obesity is a syndrome of hyperphagia and obesity that follows destruction of the ventromedial region of the hypothalamus. This syndrome is associated with loss of normal nocturnal rise in food intake and with several endocrine changes of which increased concentrations of insulin are the most important. It remains to be settled, however, whether the hyperphagia or hyperinsulinaemia is the primary factor in the development of hypothalamic obesity. The aim of the present experiment was to distinguish between these possibilities by freeing the insulin-secreting islets of Langerhans from neural control. This was done by implanting foetal pancreatic tissue under the kidney capsule of diabetic rats. This experiment prevented the characteristic hyperphagia and obesity seen in the control animals with normally innervated pancreatic tissue. Obesity can be produced by several experimental procedures1. Among the most widely studied is the one due to damage to the ventromedial region of the hypothalamus2,3. For many years, hypothalamic obesity was ascribed to the destruction of a ‘satiety centre’ which was thought to coincide anatomically with the ventromedial nucleus of the hypothalamus4. Ablation of this ‘satiety centre’ was believed to remove the inhibitory influences from a primary feeding centre in the lateral hypothalamus and allow excess feeding. Recent investigations have suggested, however, that this interpretation may be incorrect5,6, and alternative hypotheses have been proposed. One of these suggests that the increase in food intake and obesity are both secondary to the rise in insulin levels which follow ventromedial hypothalamic (VMH) injury. The present studies were designed to critically examine this hypothesis.

Role of the incretory function of the pancreatic islets in the mechanisms of development of hypothalamic obesity

Administration of alloxan, which injures the β cells and depresses insulin secretion, to animals with experimental hypothalamic obesity prevented any further increase in body weight despite an excessive food intake by the animals. It is concluded that the most important mechanism of development of obesity following injury to the ventromedial hypothalamic nuclei is the hypersecretion of insulin caused by such injury.

Development of hypothalamic obesity in the male golden hamster (Mesocricetus auratus) as a function of food preference

When fed a preferred diet, male hamsters with lesions of the ventromedial hypothalamus gained reliably more weight than control animals. There were no reliable differences in weight gain between lesioned and control groups when the diet was nonpreferred. In addition, lesioned hamsters differed from control animals in nest-building behavior and open-field activity, independent of weight differences. The groups could not be differentiated on the basis of reactivity to capture and handling. It was suggested that hypothalamic obesity in the male golden hamster is due, at least in part, to dietary preferences. Other behavioral changes resulting from lesions of the ventromedial hypothalamus may only be peripherally related to food-motivated behaviors and may be a function of the species-typical behaviors of the particular species studied.