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This version published online on October 9, 2003
Endocrinology, doi:10.1210/en.2003-0946
A more recent version of this article appeared on January 1, 2004
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Submitted on July 25, 2003
Accepted on September 30, 2003

Generation of a phenotypic array of hypothalamic neuronal cell models to study complex neuroendocrine disorders

Denise D. Belsham1*, Fang Cai1, Hong Cui1, Simon R. Smukler1, Anne Marie F. Salapatek1, and Lulzim Shkreta1

1 Departments of Physiology, Obstetrics and Gyneacology, and Medicine, University of Toronto and Division of Cellular and Molecular Biology, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada M5S 1A8

* To whom correspondence should be addressed. E-mail: d.belsham{at}utoronto.ca.

Knowledge of how the brain achieves its diverse central control of basic physiology is severely limited by the virtual absence of appropriate cell models. Isolation of clonal populations of unique peptideurgic neurons from the hypothalamus will facilitate these studies. Herein we describe the mass immortalization of mouse primary hypothalamic cells in monolayer culture, resulting in the generation of a vast representation of hypothalamic cell types. Subcloning of the heterogeneous cell populations resulted in the establishment of 38 representative clonal neuronal cell lines, of which 16 have been further characterized by analysis of 28 neuroendocrine markers. These cell lines represent the first available models to study the regulation of neuropeptides associated with the control of feeding behavior, including neuropeptide Y, ghrelin, urocortin, proopiomelanocortin, melanin-concentrating hormone, neurotensin, proglucagon, and growth hormone-releasing hormone. Importantly, a representative cell line responds appropriately to leptin stimulation and results in the repression of neuropeptide Y gene expression. These cell models can be used for detailed molecular analysis of neuropeptide gene regulation and signal transduction events involved in the direct hormonal control of unique hypothalamic neurons, not yet possible in the whole brain. Such studies may contribute information necessary for the strategic design of therapeutic interventions for complex neuroendocrine disorders, such as obesity.




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