This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Recent work in the Cowley lab, and other laboratories, has demonstrated that a neuronal circuit within the hypothalamus functions as a common pathway for many signals of energy state. Aspects of this work also demonstrated that this hypothalamic circuitry was the target through which fenfluramine acted to cause weight loss, and that this pathway is necessary for fenfluramine induced weight loss. Although fenfluramine is no longer used as a weight control agent, other safer drugs act in a similar manner to fenfluramine. Clinical data, and detailed study of the neuronal circuitry, has suggested several drug combinations that may act synergistically to activate the hypothalamic circuits that control body weight. In particular, it is hypothesized that blocking auto-inhibition of these circuits will allow them to remain active and responsive to weight control drugs. The work outlined in this proposal will assess the effects of three different classes of drug combination on the activity of hypothalamic neurons, and on food intake and body weight in mice and rats.
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