Childhood obesity is a worldwide epidemic which is affecting children at increasingly younger ages. In this project we will compare children with a well-defined genetic origin of obesity with those with obesity of unknown origin to test the hypothesis that obesity itself, independent of genetic mechanism, compromises neural development. Prader-Willi syndrome (PWS) is a contiguous gene defect that results in a well-defined pattern of early-onset childhood obesity. Environmental manipulations (i.e. parental vigilance) can markedly reduce the extent of the obesity in PWS, and potentially protect cognitive function. Therefore, PWS is an excellent model for elucidating the relative contributions of genetics and obesity to brain development. A group of children with early-onset morbid obesity of unknown origin (EMO) will serve as a comparison group to further evaluate our hypothesis that obesity, regardless of the etiology, compromises brain development. Excess adipose tissue results in abnormal levels of a variety of hormones and cytokines. We have recently found that individuals in both these groups (EMO and PWS) had premature development of white matter lesions in the brain, in contrast to their normal weight control siblings (Miller et al, 2006). In this project we will perform qualitative and quantitative measurements of brain MRIs to compare (1) individuals with PWS who become obese early in childhood with (2) individuals with PWS who remain normal weight during early childhood, and (3) children with EMO, and (4) normal weight sibling controls from both groups to test our hypothesis that the abnormal hormonal and metabolic milieu present with early-onset obesity compromises neural development. In this grant we are seeking evidence of a connection between early-onset obesity and brain damage in groups with a different etiology and degree of obesity. This study will provide invaluable information regarding a possible consequence of childhood obesity - damage to the developing brain. Individuals with PWS represent a small fraction of children with early childhood obesity, but will help differentiate the effects of obesity from the effects of genetics, as the group with EMO likely have [sic] a variety of different etiologies for becoming obese. As childhood obesity is an epidemic, the results of this study will have important implications regarding early intervention for children with obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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University of Florida
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United States
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Heymsfield, Steven B; Avena, Nicole M; Baier, Leslie et al. (2014) Hyperphagia: current concepts and future directions proceedings of the 2nd international conference on hyperphagia. Obesity (Silver Spring) 22 Suppl 1:S1-S17
Zhang, Yi; Zhao, Heng; Qiu, Siyou et al. (2013) Altered functional brain networks in Prader-Willi syndrome. NMR Biomed 26:622-9
Miller, J L; Lynn, C H; Shuster, J et al. (2013) A reduced-energy intake, well-balanced diet improves weight control in children with Prader-Willi syndrome. J Hum Nutr Diet 26:2-9
Deal, Cheri L; Tony, Michele; Hoybye, Charlotte et al. (2013) GrowthHormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. J Clin Endocrinol Metab 98:E1072-87
Bonnefond, Amelie; Raimondo, Anne; Stutzmann, Fanny et al. (2013) Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features. J Clin Invest 123:3037-41
Miller, Jennifer L; Linville, Tiffany D; Dykens, Elisabeth M (2013) Effects of metformin in children and adolescents with Prader-Willi syndrome and early-onset morbid obesity: a pilot study. J Pediatr Endocrinol Metab :1-7
Miller, Jennifer L; Lynn, Christy H; Shuster, Jonathan et al. (2011) Carnitine and coenzyme Q10 levels in individuals with Prader-Willi syndrome. Am J Med Genet A 155A:569-73
Miller, Jennifer L; Lynn, Christy H; Driscoll, Danielle C et al. (2011) Nutritional phases in Prader-Willi syndrome. Am J Med Genet A 155A:1040-9
Miller, Jennifer L; Shuster, Jonathan; Theriaque, Douglas et al. (2009) Sleep disordered breathing in infants with Prader-Willi syndrome during the first 6 weeks of growth hormone therapy: a pilot study. J Clin Sleep Med 5:448-53