GENETICS OF NEUROPEPTIDE Y FUNCTION

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DESCRIPTION (applicant's abstract): Neuropeptide Y (NPY) has been implicated in the regulation of appetite and energy balance because (a) centrally administered NPY stimulates robust feeding, (b) NPY mRNA and protein levels rise in the arcuate nucleus of the hypothalamus under conditions of reduced energy balance, as well as in ob/ob mice that lack leptin and consequently become hyperphagic. Moreover, intervention of NPY signaling by administering anti-sense oligonucleotides, antibodies or NPY receptor antagonists generally inhibits feeding. Thus, it was a surprise that knock-out mice unable to make NPY had normal body weight regulation. The genetic results clearly indicate that NPY is not essential for feeding under the conditions examined, but they do not address the question of whether NPY is acutely involved in regulation of appetite. It is possible that chronic absence of NPY triggers compensatory mechanisms. This proposal aims to use genetic techniques to explore several potential forms of compensation. The specific aims address the following questions: (1) Does agouti related protein (AgRP) compensate for NPY deficiency?, (2) Do the neurons that make NPY and AgRP in the arcuate nucleus produce other neuromodulators that may compensate for NPY deficiency?, and (3) Does acute inactivation of NPY gene expression in the adult affect appetite and energy balance? The first aim will be addressed by generating mice in which both NPY and AgRP genes are inactivated. If AgRP compensates for NPY, then these mice should be lean. The second aim relies on genetic ablation of the neurons that make NPY and AgRP. If those neurons are important for energy balance, then those mice should be lean. The last aim is addressed by creating mice with a NPY gene that can be inactivated at will. Inactivation of NPY expression in the adult may have transient or chronic effects on regulation of appetite and energy balance. These genetic experiments should help rationalize the current disparate results obtained by permanent NPY gene silencing and by acute intervention of NPY signaling.