Opiates and endogenous opioid peptides beta-endorphin, enkephalins and dynorphins primarily signal rewarding aspects of food consumption and are relatively unimportant in mediating feeding responses to metabolic demands. Classical pharmacological experiments have defined the contribution of various opioid receptor subtypes to the control of breeding but re limited in their power to distinguish among effects of the endogenous peptide ligands themselves. Moreover, beta-endorphin is synthesized together with melanocortin peptides from pro-opiomelanocortin (POMC) and probably is consecrated with melanocortins at many, if not all, POMC neuron terminals. There is abundant evidence for opposing and cooperative actions of beta-endorphin and melanocortins in several homeostatic brain functions, further complicating our understanding of the functional position of POMC neurons in hypothalamic circuits regulating the balance between caloric intake and energy expenditure. Our laboratory has initiated a genetic approach to investigate the physiological actions of individual endogenous opioid peptides, and the postulated interactions between opioids and melanocortins on feeding and metabolism. We will use beta-endorphin deficient mice previous generated in our lab, other existing spontaneous and induced mutants, and newly developed POMC mutants as physiological model systems to address the following specific hypotheses: 1.) The unusual growth pattern and resulting moderate obesity of beta-endorphin-deficient male mice, and wild-type male mice cross-fostered to beta-endorphin- deficient damns, is due to a combination of genetically determined factors contributed from both the mutant dams and the mutant offspring. Experimental approaches will include evaluations of relevant neuroendocrine circuits, maternal behavior, quantify and quality of mil from nursing dams, food intake, metabolic rates, and histology of adipocytes in white fat pads. 2.) Adult beta-endorphin- and enkephalin-deficient mice will exhibit altered food preferences and diminished motivation for eating because of decreased rewarding properties of food. These studies will use two existing strains of opioid-deficient mice and double homozygote mutant crosses between the strains for comparative analyses of food intake, food preference, macronutrient selection, and metabolic rate. Studies will be conducted in both food-deprived and sated mice to differentiate responses based on metabolic demands from rewarding properties of preferred reward. Two-bottle free choice drinking studies will be used to quantitate intake and preferences for sweet or salty liquid and aversion for quinine-laced water. 3.) POMC-derived beta-endorphin and melanocortins have coordinated actions on weight homeostasis. The major experimental models will be crosses between the beta-endorphin mutan6ts and melanocortin-receptor (MCR) knockout mice. We predict that the double homozygous beta- endorphin/MCR-4 KO mice will exhibit an additive or synergistic phenotype leading to more profound obesity in adults. Additionally, a new series of bigenic mouse mutants will be produce based on Cre-loxP recombination strategies that will carry spatially and/or temporally restricted null alleles for the POMC gene. Developmental, feeding and metabolic status of these various mouse models will be compared to each other and to the spontaneous Agamma yellow, obese mutant.
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