OR53-1 The basic helix-loop-helix transcription factor Ngn3 regulates the development and function of Pomc/Cart neurons in the hypothalamic arcuate nucleus

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR53-Transcriptional Regulators & Epigenetic Control
Basic/Translational
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:15 AM
Room 133 (Moscone Center)
Siew-Lan Ang*1, Michelle Pelling1, Suzanne Claxton1, Georg Mellitzer2, Caitlin Collin3, Nicoletta Kessaris4, William Richardson4, Gerard Gradwohl2 and Neal Anthwal1
1National Institute of Medical Research, London, United Kingdom, 2IGBMC, Illkirch-Graffenstaden, France, 3IGBMC, Illkirch-Graffenstaden, 4Wolfson Institute for Biomedical Research, London
Obesity is a major, increasingly prevalent health problem affecting modern societies. Despite substantial progress in understanding the neurobiology of energy homeostasis, little is known regarding how brain systems designed to promote weight stability are altered in common forms of obesity. The hypothalamus of the CNS is the major regulator in energy homeostasis. The most commonly studied diet regulators are the appetite stimulator neuropeptide Y (NPY) and appetite suppressor proopiomelanocortin (POMC), produced mainly in the arcuate (ARC) nucleus. Despite the importance of POMC and NPY neurons, little is known about the molecular mechanisms regulating their specification during development and their maintenance in adults.

The basic helix loop helix transcription factor Neurogenin 3 (Ngn3) has critical roles in all the major organs in regulating energy balance, such as pancreas, gut and brain. Here, we demonstrate that early embryonic hypothalamic inactivation of Ngn3 in mice results in rapid post-weaning obesity that is associated with hyperphagia and reduced energy expenditure. This obesity is caused by loss of expression of Pomc in Pomc/Cart neurons in the arcuate nucleus, indicating an incomplete specification of anorexigenic first order neurons. Furthermore, following the onset of obesity both the arcuate and ventromedial hypothalamic nuclei become insensitive to peripheral leptin treatment. This conditional mouse mutant therefore represents a novel model system for obesity associated with over feeding and under activity, and sheds new light on the role of Ngn3 in regulating the specification of hypothalamic neurons controlling energy balance.

Nothing to Disclose: SLA, MP, SC, GM, CC, NK, WR, GG, NA

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Medical Research Council, UK
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