Nutrition and Growth

Editor(s): Shamir R. (Tel Aviv) 
Turck D. (Lille) 
Phillip M. (Tel Aviv) 
Table of Contents
Vol. 106, 2013
Section title: Paper

Treatment Options for Children with Monogenic Forms of Obesity

Hainerová I.A. · Lebl J.
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Mutations in genes involved in energy balance regulation within the central nervous system lead to monogenic forms of obesities. Individuals with these mutations are characterized by early-onset obesity and in some cases by endocrine abnormalities. Carriers of leptin gene mutations are able to normalize their body weight after daily subcutaneous leptin administration. Pharmacotherapy targeting the specific-gene deficiencies has not clinically been tested in other monogenic obesities. Mutations in the melanocortin 4 receptor gene (MC4R) represent the most common monogenic cause of human obesity. Several treatment options have been investigated in subjects with MC4R mutations. Few studies showed that an intensive life-style intervention induces similar weight reduction in MC4R mutation carriers in comparison to MC4R mutation noncarriers. However, long-term body weight maintenance is hardly ever achieved in MC4R mutation carriers. Sibutramine, serotonin and noradrenalin reuptake inhibitor, in MC4R mutation carriers induced weight reduction and improved cardiometabolic health risks. This result was also found in our homozygous MC4R mutation carrier. In vitro studies of melanocortin agonists efficiently activate mutated MC4R with impaired endogenous agonist functional response and thus, further research in the development of drugs for MC4R mutations is needed. An administration of intranasal adrenocorticotropic hormone was not shown to be effective in subjects with pro-opiomelanocortin gene mutations. Bariatric surgery has also been performed in few of MC4R mutation carriers. After gastric banding, lower body weight reduction and worse improvement of metabolic complications was found in MC4R mutation carriers versus noncarriers. However, preliminary results suggest that diversionary operations as gastric bypass represent a suitable method also for MC4R mutation carriers. In conclusion, the management of monogenic obesities still remains a challenge.

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  1. Hetherington MM, Cecil JE: Gene-environment interactions in obesity. Forum Nutr 2010;63:195-203
  2. Stunkard AJ, Sorensen TI, Hanis C, Teasdale TW, Chakraborty R, Schull WJ, Schulsinger F: An adoption study of human obesity. N Engl J Med 1986;23314:193-198
  3. Stunkard AJ, Harris JR, Pedersen NL, McClearn GE: The body mass index of twins who have been reared apart. N Engl J Med 1990;322:1483-1487
  4. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-432
  5. O'Rahilly S, Farooqi IS: Human obesity as a heritable disorder of the central control of energy balance. Int J Obes (Lond) 2008;32:S55-S61
  6. Hainer V, Stunkard AJ: Kunesová M, Parízková J, Stich V, Allison DB: Intrapair resemblance in very low calorie diet-induced weight loss in female obese identical twins. Int J Obes Relat Metab Disord 2000;24:1051-1057
  7. Mann T, Tomiyama AJ, Westling E, Lew AM, Samuels B, Chatman J: Medicare's search for effective obesity treatments: diets are not the answer. Am Psychol 2007;62:220-233
  8. Miller WC: How effective are traditional dietary and exercise interventions for weight loss?. Med Sci Sports Exerc 1999;31:1129-1134
  9. Tadross JA, le Roux CW: The mechanisms of weight loss after bariatric surgery. Int J Obes (Lond) 2009;33:S28-S32
  10. Inge TH, Xanthakos SA, Zeller MH: Bariatric surgery for pediatric extreme obesity: now or later?. Int J Obes (Lond) 2007;31:1-14
  11. Krebs NF, Jacobson MS: American Academy of Pediatrics Committee on Nutrition: Prevention of pediatric overweight and obesity. Pediatrics 2003;112:424-430
  12. Farooqi IS, O'Rahilly S: Mutations in ligands and receptors of the leptin-melanocortin pathway that lead to obesity. Nat Clin Pract Endocrinol Metab 2008;4:569-577
  13. Bochukova EG, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K, Saeed S, Hamilton-Shield J, Clayton-Smith J, O'Rahilly S, Hurles ME, Farooqi IS: Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 2010;463:666-670
  14. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S: Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903-908
  15. Galgani JE, Greenway FL, Caglayan S, Wong ML, Licinio J, Ravussin E: Leptin replacement prevents weight loss-induced metabolic adaptation in congenital leptin-deficient patients. J Clin Endocrinol Metab 2010;95:851-855
  16. Andreev VP, Paz-Filho G, Wong ML, Licinio J: Deconvolution of insulin secretion, insulin hepatic extraction post-hepatic delivery rates and sensitivity during 24-hour standardized meals: time course of glucose homeostasis in leptin replacement treatment. Horm Metab Res 2009;41:142-151
  17. Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML: Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 2004;101:4531-4536
  18. Santoro N, Perrone L, Cirillo G, Raimondo P, Amato A, Coppola F, Santarpia M, D'Aniello A, Miraglia Del Giudice E: Weight loss in obese children carrying the proopiomelanocortin R236G variant. J Endocrinol Invest 2006;29:226-230
  19. Krude H, Biebermann H, Schnabel D, Tansek MZ, Theunissen P, Mullis PE, Grüters A: Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab 2003;88:4633-4640
  20. Hinney A, Bettecken T, Tarnow P, Brumm H, Reichwald K, Lichtner P, Scherag A, Nguyen TT, Schlumberger P, Rief W, Vollmert C, Illig T, Wichmann HE, Schäfer H, Platzer M, Biebermann H, Meitinger T, Hebebrand J: Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative popu lation-based sample and obese adults from Germany. J Clin Endocrinol Metab 2006;91:1761-1769
  21. Roubert P, Dubern B, Plas P, Lubrano-Berthelier C, Alihi R, Auger F, Deoliveira DB, Dong JZ, Basdevant A, Thurieau C, Clement K: Novel pharmacological MC4R agonists can efficiently activate mutated MC4R from obese patient with impaired endogenous agonist response. J Endocrinol 2010;207:177-1783
  22. Rene P, Le Gouill C, Pogozheva ID, Lee G, Mosberg HI, Farooqi IS, Valenzano KJ, Bouvier M: Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity. J Pharmacol Exp Ther 2010;335:520-532
  23. Hainerová I, Larsen LH, Holst B, Finková M, Hainer V, Lebl J, Hansen T, Pedersen O: Melanocortin 4 receptor mutations in obese Czech children: studies of prevalence, phenotype development, weight reduction response, and functional analysis. J Clin Endocrinol Metab 2007;92:3689-3696
  24. Reinehr T, Hebebrand J, Friedel S, Toschke AM, Brumm H, Biebermann H, Hinney A: Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene. Obesity (Silver Springs) 2009;17:382-389
  25. 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
  26. Hainerová IA, Zamrazilová H, Sedláčková D, Hainer V: Hypogonadotropic hypogonadism in a homozygous MC4R mutation carrier and the effect of sibutramine treatment on body weight and obesity-related health risks. Obes Facts 2011;4:324-328
  27. Potoczna N, Branson R, Kral JG, Piec G, Steffen R, Ricklin T, Hoehe MR, Lentes KU, Horber FF: Gene variants and binge eating as predictors of comorbidity and outcome of treatment in severe obesity. J Gastrointest Surg 2004;8:971-981
  28. Aslan IR, Campos GM, Calton MA, Evans DS, Merriman RB, Vaisse C: Weight loss after roux-en-Y gastric bypass in obese patients heterozygous for MC4R mutations. Obes Surg 2011;21:930-934
  29. Aslan IR, Ranadive SA, Ersoy BA, Rogers SJ, Lustig RH, Vaisse C: Bariatric surgery in a patient with complete MC4R deficiency. Int J Obes (Lond) 2011;35:457-461
  30. Choquet H, Meyre D: Genomic insights into early-onset obesity. Genome Med 2010;2:36

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