Ann Pediatr Endocrinol Metab.  2013 Dec;18(4):161-167. 10.6065/apem.2013.18.4.161.

Pathophysiology and clinical characteristics of hypothalamic obesity in children and adolescents

• Kim JH
• Choi JH

• KMID: 2266349
• DOI: http://doi.org/10.6065/apem.2013.18.4.161

Abstract

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 11beta-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.

Keyword

Hypothalamus; Insulin; Leptin; Obesity

MeSH Terms

11-beta-Hydroxysteroid Dehydrogenases
Adipose Tissue
Adolescent*
Body Weight
Child*
Eating
Energy Metabolism
Homeostasis
Humans
Hypothalamus
Insulin
Leptin
Melatonin
Obesity*
Obesity, Morbid
Prader-Willi Syndrome
Pro-Opiomelanocortin
Radiotherapy
Sympathetic Nervous System
Weight Gain
11-beta-Hydroxysteroid Dehydrogenases
Insulin
Leptin
Melatonin
Pro-Opiomelanocortin

Reference

1. Daousi C, Dunn AJ, Foy PM, MacFarlane IA, Pinkney JH. Endocrine and neuroanatomic features associated with weight gain and obesity in adult patients with hypothalamic damage. Am J Med. 2005; 118:45–50. PMID: 15639209.

2. Rutter MM, Rose SR. Long-term endocrine sequelae of childhood cancer. Curr Opin Pediatr. 2007; 19:480–487. PMID: 17630615.

3. Geffner M, Lundberg M, Koltowska-Haggstrom M, Abs R, Verhelst J, Erfurth EM, et al. Changes in height, weight, and body mass index in children with craniopharyngioma after three years of growth hormone therapy: analysis of KIGS (Pfizer International Growth Database). J Clin Endocrinol Metab. 2004; 89:5435–5440. PMID: 15531494.

4. Deepak D, Furlong NJ, Wilding JP, MacFarlane IA. Cardiovascular disease, hypertension, dyslipidaemia and obesity in patients with hypothalamic-pituitary disease. Postgrad Med J. 2007; 83:277–280. PMID: 17403957.

5. Moraes JC, Coope A, Morari J, Cintra DE, Roman EA, Pauli JR, et al. High-fat diet induces apoptosis of hypothalamic neurons. PLoS One. 2009; 4:e5045. PMID: 19340313.

6. Hochberg I, Hochberg Z. Hypothalamic obesity. Endocr Dev. 2010; 17:185–196. PMID: 19955767.

7. Coll AP, Farooqi IS, Challis BG, Yeo GS, O'Rahilly S. Proopiomelanocortin and energy balance: insights from human and murine genetics. J Clin Endocrinol Metab. 2004; 89:2557–2562. PMID: 15181023.

8. Lu XY, Barsh GS, Akil H, Watson SJ. Interaction between alpha-melanocyte-stimulating hormone and corticotropin-releasing hormone in the regulation of feeding and hypothalamo-pituitary-adrenal responses. J Neurosci. 2003; 23:7863–7872. PMID: 12944516.

9. Woods SC, DAlessio DA. Central control of body weight and appetite. J Clin Endocrinol Metab. 2008; 93(11 Suppl 1):S37–S50. PMID: 18987269.

10. Lustig RH, Post SR, Srivannaboon K, Rose SR, Danish RK, Burghen GA, et al. Risk factors for the development of obesity in children surviving brain tumors. J Clin Endocrinol Metab. 2003; 88:611–616. PMID: 12574189.

11. Muller HL, Emser A, Faldum A, Bruhnken G, Etavard-Gorris N, Gebhardt U, et al. Longitudinal study on growth and body mass index before and after diagnosis of childhood craniopharyngioma. J Clin Endocrinol Metab. 2004; 89:3298–3305. PMID: 15240606.

12. Luque RM, Kineman RD. Impact of obesity on the growth hormone axis: evidence for a direct inhibitory effect of hyperinsulinemia on pituitary function. Endocrinology. 2006; 147:2754–2763. PMID: 16513828.

13. Hochberg I, Hochberg Z. Expanding the definition of hypothalamic obesity. Obes Rev. 2010; 11:709–721. PMID: 20233310.

14. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet. 1999; 36:437–446. PMID: 10874630.

15. Bougneres P, Pantalone L, Linglart A, Rothenbuhler A, Le Stunff C. Endocrine manifestations of the rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor syndrome in childhood. J Clin Endocrinol Metab. 2008; 93:3971–3980. PMID: 18628522.

16. Haqq AM, Farooqi IS, O'Rahilly S, Stadler DD, Rosenfeld RG, Pratt KL, et al. Serum ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome. J Clin Endocrinol Metab. 2003; 88:174–178. PMID: 12519848.

17. Kanumakala S, Greaves R, Pedreira CC, Donath S, Warne GL, Zacharin MR, et al. Fasting ghrelin levels are not elevated in children with hypothalamic obesity. J Clin Endocrinol Metab. 2005; 90:2691–2695. PMID: 15769982.

18. Goldstone AP, Patterson M, Kalingag N, Ghatei MA, Brynes AE, Bloom SR, et al. Fasting and postprandial hyperghrelinemia in Prader-Willi syndrome is partially explained by hypoinsulinemia, and is not due to peptide YY3-36 deficiency or seen in hypothalamic obesity due to craniopharyngioma. J Clin Endocrinol Metab. 2005; 90:2681–2690. PMID: 15687345.

19. Hoybye C, Barkeling B, Espelund U, Petersson M, Thoren M. Peptides associated with hyperphagia in adults with Prader-Willi syndrome before and during GH treatment. Growth Horm IGF Res. 2003; 13:322–327. PMID: 14624765.

20. Sahoo T, del Gaudio D, German JR, Shinawi M, Peters SU, Person RE, et al. Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat Genet. 2008; 40:719–721. PMID: 18500341.

21. Zimmermann U, Kraus T, Himmerich H, Schuld A, Pollmacher T. Epidemiology, implications and mechanisms underlying drug-induced weight gain in psychiatric patients. J Psychiatr Res. 2003; 37:193–220. PMID: 12650740.

22. Bergman RN, Ader M. Atypical antipsychotics and glucose homeostasis. J Clin Psychiatry. 2005; 66:504–514. PMID: 15816794.

23. Gothelf D, Falk B, Singer P, Kairi M, Phillip M, Zigel L, et al. Weight gain associated with increased food intake and low habitual activity levels in male adolescent schizophrenic inpatients treated with olanzapine. Am J Psychiatry. 2002; 159:1055–1057. PMID: 12042200.

24. Melkersson KI, Hulting AL, Brismar KE. Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry. 2000; 61:742–749. PMID: 11078035.

25. Skorzewska A, Lal S, Waserman J, Guyda H. Abnormal food-seeking behavior after surgery for craniopharyngioma. Neuropsychobiology. 1989; 21:17–20. PMID: 2812293.

26. Goldstone AP. Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab. 2004; 15:12–20. PMID: 14693421.

27. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, ORahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003; 348:1085–1095. PMID: 12646665.

28. Dekkers OM, Biermasz NR, Smit JW, Groot LE, Roelfsema F, Romijn JA, et al. Quality of life in treated adult craniopharyngioma patients. Eur J Endocrinol. 2006; 154:483–489. PMID: 16498063.

29. Snow A, Gozal E, Malhotra A, Tiosano D, Perlman R, Vega C, et al. Severe hypersomnolence after pituitary/hypothalamic surgery in adolescents: clinical characteristics and potential mechanisms. Pediatrics. 2002; 110:e74. PMID: 12456941.

30. Bittel DC, Butler MG. Prader-Willi syndrome: clinical genetics, cytogenetics and molecular biology. Expert Rev Mol Med. 2005; 7:1–20. PMID: 16038620.

31. Shaikh MG, Grundy RG, Kirk JM. Hyperleptinaemia rather than fasting hyperinsulinaemia is associated with obesity following hypothalamic damage in children. Eur J Endocrinol. 2008; 159:791–797. PMID: 18819946.

32. Farooqi IS, O'Rahilly S. Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr. 2009; 89:980S–984S. PMID: 19211814.

33. Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998; 392:398–401. PMID: 9537324.

34. Guran T, Turan S, Bereket A, Akcay T, Unluguzel G, Bas F, et al. The role of leptin, soluble leptin receptor, resistin, and insulin secretory dynamics in the pathogenesis of hypothalamic obesity in children. Eur J Pediatr. 2009; 168:1043–1048. PMID: 19043735.

35. Lustig RH, Rose SR, Burghen GA, Velasquez-Mieyer P, Broome DC, Smith K, et al. Hypothalamic obesity caused by cranial insult in children: altered glucose and insulin dynamics and reversal by a somatostatin agonist. J Pediatr. 1999; 135(2 Pt 1):162–168. PMID: 10431109.

36. Srinivasan S, Ogle GD, Garnett SP, Briody JN, Lee JW, Cowell CT. Features of the metabolic syndrome after childhood craniopharyngioma. J Clin Endocrinol Metab. 2004; 89:81–86. PMID: 14715831.

37. Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY, et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature. 2007; 449:228–232. PMID: 17728716.

38. Phillip M, Moran O, Lazar L. Growth without growth hormone. J Pediatr Endocrinol Metab. 2002; 15(Suppl 5):1267–1272. PMID: 12510977.

39. Bucher H, Zapf J, Torresani T, Prader A, Froesch ER, Illig R. Insulin-like growth factors I and II, prolactin, and insulin in 19 growth hormone-deficient children with excessive, normal, or decreased longitudinal growth after operation for craniopharyngioma. N Engl J Med. 1983; 309:1142–1146. PMID: 6353237.

40. Roth CL, Hunneman DH, Gebhardt U, Stoffel-Wagner B, Reinehr T, Muller HL. Reduced sympathetic metabolites in urine of obese patients with craniopharyngioma. Pediatr Res. 2007; 61:496–501. PMID: 17515878.

41. Schofl C, Schleth A, Berger D, Terkamp C, von zur Muhlen A, Brabant G. Sympathoadrenal counterregulation in patients with hypothalamic craniopharyngioma. J Clin Endocrinol Metab. 2002; 87:624–629. PMID: 11836295.

42. Dun SL, Brailoiu GC, Yang J, Chang JK, Dun NJ. Cocaine- and amphetamine-regulated transcript peptide and sympatho-adrenal axis. Peptides. 2006; 27:1949–1955. PMID: 16707193.

43. Tiosano D, Eisentein I, Militianu D, Chrousos GP, Hochberg Z. 11 beta-Hydroxysteroid dehydrogenase activity in hypothalamic obesity. J Clin Endocrinol Metab. 2003; 88:379–384. PMID: 12519880.

44. Manley PE, McKendrick K, McGillicudy M, Chi SN, Kieran MW, Cohen LE, et al. Sleep dysfunction in long term survivors of craniopharyngioma. J Neurooncol. 2012; 108:543–549. PMID: 22528788.

45. Muller HL, Handwerker G, Wollny B, Faldum A, Sorensen N. Melatonin secretion and increased daytime sleepiness in childhood craniopharyngioma patients. J Clin Endocrinol Metab. 2002; 87:3993–3996. PMID: 12161549.

46. Mason PW, Krawiecki N, Meacham LR. The use of dextroamphetamine to treat obesity and hyperphagia in children treated for craniopharyngioma. Arch Pediatr Adolesc Med. 2002; 156:887–892. PMID: 12197795.

47. Ismail D, O'Connell MA, Zacharin MR. Dexamphetamine use for management of obesity and hypersomnolence following hypothalamic injury. J Pediatr Endocrinol Metab. 2006; 19:129–134. PMID: 16562585.

48. Greenway FL, Bray GA. Treatment of hypothalamic obesity with caffeine and ephedrine. Endocr Pract. 2008; 14:697–703. PMID: 18996788.

49. Lustig RH, Hinds PS, Ringwald-Smith K, Christensen RK, Kaste SC, Schreiber RE, et al. Octreotide therapy of pediatric hypothalamic obesity: a double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2003; 88:2586–2592. PMID: 12788859.

50. Cettour-Rose P, Burger AG, Meier CA, Visser TJ, Rohner-Jeanrenaud F. Central stimulatory effect of leptin on T3 production is mediated by brown adipose tissue type II deiodinase. Am J Physiol Endocrinol Metab. 2002; 283:E980–E987. PMID: 12376325.

51. Fernandes JK, Klein MJ, Ater JL, Kuttesch JF, Vassilopoulou-Sellin R. Triiodothyronine supplementation for hypothalamic obesity. Metabolism. 2002; 51:1381–1383. PMID: 12404183.

52. Danielsson P, Janson A, Norgren S, Marcus C. Impact sibutramine therapy in children with hypothalamic obesity or obesity with aggravating syndromes. J Clin Endocrinol Metab. 2007; 92:4101–4106. PMID: 17726084.

53. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006; 368:1696–1705. PMID: 17098089.

54. Simmons JH, Shoemaker AH, Roth CL. Treatment with glucagon-like Peptide-1 agonist exendin-4 in a patient with hypothalamic obesity secondary to intracranial tumor. Horm Res Paediatr. 2012; 78:54–58. PMID: 22831918.

55. Zoicas F, Droste M, Mayr B, Buchfelder M, Schofl C. GLP-1 analogues as a new treatment option for hypothalamic obesity in adults: report of nine cases. Eur J Endocrinol. 2013; 168:699–706. PMID: 23392214.

56. Muller HL, Gebhardt U, Wessel V, Schroder S, Kolb R, Sorensen N, et al. First experiences with laparoscopic adjustable gastric banding (LAGB) in the treatment of patients with childhood craniopharyngioma and morbid obesity. Klin Padiatr. 2007; 219:323–325. PMID: 18050042.

57. Inge TH, Pfluger P, Zeller M, Rose SR, Burget L, Sundararajan S, et al. Gastric bypass surgery for treatment of hypothalamic obesity after craniopharyngioma therapy. Nat Clin Pract Endocrinol Metab. 2007; 3:606–609. PMID: 17643131.