Prader-Willi syndrome (PWS) is a genetic disease characterized by an insatiable appetite and a variety of behavioral dysregulations. It is known that the brain, and particularly a region of the brain called the hypothalamus, is important to regulating appetite and body weight. We also know that many key physiological processes, including appetite regulation, are established during the perinatal period — that time just prior to and soon after birth – and that hormonal conditions in the babies are key in these processes. Notably, babies with PWS display abnormally elevated levels of the gut-hormone ghrelin and we recently found in our lab that this hormone has marked effects on hypothalamic development. The goal of this research project is to determine, using a mouse model for PWS, whether the elevated levels of ghrelin observed in babies with PWS disrupt the normal development of brain circuits involved in appetite regulation. The results of these experiments promise to provide new insight into the mechanism by which alteration of the early life hormonal environment that occurs in children with PWS, leads to perturbations of neurodevelop-mental events and may result to hyperphagia and obesity in later life. The knowledge we gain from this project may also help determine therapeutic interventions to reduce metabolic and neurological problems associated with PWS.
Research Outcomes:
Wired for eating: how is an active feeding circuitry established in the postnatal brain? Muscatelli F, Bouret SGC. Current Opinions in Neurobiology. Volume 52: 165-171, 2018.
Sex and gender differences in developmental programming of metabolism. Dearden L, Bouret SG, Ozanne SE. Molecular Metabolism. 15: 8–19, 2018.
A Transcriptomic Signature of the Hypothalamic Response to Fasting and BDNF Deficiency in Prader-Willi Syndrome. Bochukova EG, Lawler K, Croizier S, Keogh JM, Patel N, Strohbehn G, Lo KK, Humphrey J, Hokken-Koelega A, Damen L, Donze S, Bouret SG, Plagnol V, Farooqi IS. Cell Reports. 2018 Mar 27; 22(13): 3401–3408.
Loss of Magel2 Impairs the Development of Hypothalamic Anorexigenic Circuits. Maillard J, Park S, Croizier S, Vanacker C, Cook JH, Prevot V, Tauber M, Bouret SG. Human Molecular Genetics. 2016 Aug 1;25(15):3208-3215.
Obesity Impairs the Action of the Neuroendocrine Ghrelin System. Zigman JM, Bouret SG, Andrews ZB. Trends Endocrinol Metab. 2016 Jan;27(1):54-63.
Neonatal ghrelin programs development of hypothalamic feeding circuits. Steculorum SM, Collden G, Coupe B, Croizier S, Lockie S, Andrews ZB, Jarosch F, Klussmann S, Bouret SG. Journal of Clinical Investigation. 2015 Feb 2;125(2):846-58.
Gene-Environment Interactions Controlling Energy and Glucose Homeostasis and the Developmental Origins of Obesity. Bouret S, Levin BE, Ozanne SE. Physiol Rev. 2015 Jan;95(1):47-82.
Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin. Collden G, Balland E, Parkash J, Caron E, Langlet F, Prevot V, Bouret SG. Mol Met. 2015 Jan 4(1):15–24.
Development of the hypothalamic melanocortin system. Coupe B, Bouret SG. Frontiers in Endocrinology (Lausanne). 2013;4:38.
Funded Year:
2012
Awarded to:
Sebastien Bouret, PhD
Amount:
$50,000
Institution:
Children's Hospital of Los Angeles
