Our long-term objectives continue to be elucidation of mechanisms controlling spontaneous food intake (SFI) to ameliorate DFI abnormalitie occurring in nutritionally ill humans. To this end, we developed and used an Automated Computerized Rat Eater Meter (ACREM) that allows determinations of food intake and feeding patterns in a wide variety of experimental conditions using TPN, constituting a reproducible clinicall relevant standard. We studied SFI changes in response to metabolic perturbations induced by initiating, varying, or ceasing TPN and more recently, we added in-vivo lateral hypothalamic-dopaminergic (LHA-DA) an ventromedial-serotonergic (VMH-SER) microdialysis to our study methods. Data from these studies and others suggest exploitation of information in a systematic investigation directed toward ameliorating morbid obesity. Our hypotheses is that chronic enhancement of either dopaminergic functioning cells in LHA or of serotonergic functioning cells in VMH leads to a chronic decrease in SFI and progressive weight reduction. In this work we will determine if 1) the obese Zucker rat (animal model for human morbid obesity) has quantitatively similar but qualitatively different LHA-DA or VMH-SER responses to eating, as compared to the nonobese lean age-matched Zucker controls; 2) increasing LHA-DA and/or VMH-SER levels of obese Zuckers by continuous intra-hypothalamic infusions leads to decreased SFI; and 3) intra-hypothalamic implants of fetal brain cells (dopamine-rich into LHA and/or serotonin-rich into VMH into obese Zuckers will induce chronic increases in LHA-DA and VMH-SER function. This is verified by a) decreases in SFI documented by ACREM, b) in vivo microdialysis of LHA-and VMH fetal implant, c) subsequent long-term reductions in body weight and changes in body composition measured by serial in vivo bioelectrical impedance analysis, and d) reversal of decreasing SFI, body weight gain, and body composition changes by chronic infusion of DA and SER antagonists sufficiently to ameliorate morbid obesity. Based on our pilot studies which indicate that DA and SER hypothalamic implants are a) viable, as tested by immunohistochemistry and electrophysiological studies of implanted fetal cells and b) functionin by their inducing a decrease in SFI which initially slows body weight gain, then gradually decreases body weight to approach that of age- matched lean Zucker controls and associated body composition changes, we believe that the therapeutic approach to morbid obesity set forth in thi proposal is physiological and provides effective, long-lasting treatment of morbid obesity; and thus a greater likelihood of success than any approach thus far.
Showing the most recent 10 out of 44 publications
