The prevalence of obese and overweight humans has increased dramatically. The type 2 diabetes and cardiovascular disease comorbidities of obesity focus attention squarely on the need to developm effective treatments. Targets for those treatments come from basic science research. The central nervous sytem controls energy intake and energy expenditure but knowledge of the specific circuits and neurochemicals mediating control remains quite limited. The proposed experiments will yield data that will contribute to defining the neural circuits that control energy expenditure driven by (1) melanocortin receptor (MCR) activation and (2) oral contact with food. As such, this proposal is relevant to clinical drug development and to public health. Mutations in the MC4R gene are the most common monogenetic cause of human obesity. Animals with MC4R mutations overeat and expend less energy.
The aims of this proposal are shaped by preliminary data from oral-fed neurologically intact, and gavage-fed intact and chronic decerebrate rats (neural connections from forebrain are eliminated). Those data suggest two hypotheses - that forebrain processing mediates the increased sympathetic tone seen with oral nutrient maintenance and that oral maintenance is necessary for the triggering of energetic responses by brainstem MCR stimiulation in intact animals - and that caudal brainstem nuclei bearing MCRs are the site of action for sympathetically mediated expenditure responses. The experiments: (1) determine whether the increase in sympathetic tone seen with oral nutrient delivery (versus matched gastric nutrient delivery) is necessary for MCR-triggered, sympathetic nervous system mediated energy expenditure responses, (2) define the contribution of specific MCR bearing nuclei in the caudal brainstem to MCR triggered energy expenditure and (3) define the forebrain nuclei that process oral sensory input, increase sympathetic tone and thereby """"""""gate"""""""" the energetic effect of MCR signaling in the caudal brainstem. Measurement of heart rate, core and brown adipose tissue temperature, and actiivty will be made in oral- and gavage-fed intact and decerebrate rats, in rats with intraparenchymal cannula aimed at caudal brainstem nuclei (raphe pallidus, rostral ventrolateral lateral medulla and nucleus tractus solitarius), and in rats with cytotoxic lesions of the paraventricular nucleus.
