The primary aim of the research project would be to establish the identity of a pituitary factor in the genetically obese mouse (ob/ob) which has been shown to rapidly stimulate insulin secretion in vitro using a perfusion system of the intact pituitary gland in series with isolated pancreatic islets, and to establish whether this factor is associated with the hyperinsulinemia encountered in the ob/ob mice and in other forms of experimental obesity. Experiments will be carried out with physiological concentrations of pituitary hormones and with known ACTH related peptides, to see whether they stimulate the effect of the perfused gland. When the nature of the factor has been established it is planned to use an immunoassay technique to measure the concentration in the pituitary and perfusates from obese and lean mice. The role of the hypothalamus in the control of the insulin releasing factor from the pituitary will also be studied in vitro in obese and lean mice. This is of interest in view of the two hypotheses that have been advanced as to the primary defect in the ob/ob mice: a hypothalamic lesion and hypersecretion of insulin. These two hypotheses could be inter-related through the pituitary effect on insulin secretion. The mechanism of stimulation of insulin secretion by the pituitary factor will be investigated and compared with other insulin secretagogues, the aim being to explain the lack of response of islets from obese mice which have been shown to be hyperactive in their response to glucose stimulation of insulin secretion compared with lean mouse islets.