Eliot Stellar - US grants

The long-term objective of this proposal is to apply information gained from laboratory studies of the variables that control food intake to the treatment of obesity. We plan four types of studies. 1) We will study the microstructure of eating behavior in the laboratory by electromyographic recording of chews from the masseter muscle. These studies will show how chews, one of the biological units of eating behavior, determine the rate of food intake. We will evaluate the effect of major variables such as palatability of food on chewing patterns and how chewing patterns can be modified to change ingestion rate. 2) The EMG recording of chews will also be also be used to validate an intraoral sensor which we are developing for ambulatory monitoring of chews in the natural environment. We will use ambulatory monitoring of chews to study daily meal patterns in lean and obese subjects and in patients during treatment for obesity. Analysis of these meal patterns will help us to understand how meal size and meal frequency are controlled and will help us to identify problem eating patterns in obese patients. 3) We will continue laboratory studies to examine the variables that contribute to the different eating patterns between lean and obese women that we have observed previously. We will also test whether behavioral changes that are advocated by treatment programs for obesity, such as slowing the rate of ingestion, actually help people to eat less. 4) We will draw on a battery of tests that differentiate the eating behavior of lean and obese people to monitor the progress of patients before, during, and after treatment for obesity. We will examine whether our behavioral measures are related to other physiological and psychological measures on the patients (e.g. resting energy expenditure and scores on the Stunkard-Messick Eating Inventory). We will determine whether our behavioral measures help predict the outcome of treatment and whether certain behavioral changes can either promote or interfere with weight loss. We will also test whether weight loss causes changes in the behavioral measures. Given the fact that most of the people will lose weight regain all or much of it, it is extremely important to optimize the treatment of obesity by tailor-making weight loss regimens to individual patients. This we hope to do on the basis of the data we collect in laboratory tests and in ambulatory monitoring of daily eating patterns by objective means. We also hope to monitor compliance to treatment regimens with ambulatory recording of food intake. It may also be possible in the future to use this system to signal obese patients when they eat too fast, too much, and too often.

The purpose of the proposed studies is to determine the behavioral and biological bases of the effects of cholecystokinin octapeptide (CCK-8) on the rat's responses to food. The behavioral basis will be investigated by using appetitive as well as consummatory measures of motivated behavior. The appetitive measure is the running speed to very small food rewards in a meter-long runway, where postingestional effects are negligible. The consummatory measure is the amount of food ingested in a one-hour intake test in the animal's home cage. The consummatory measure gets at the satiety effects of CCK and the appetitive measure at the effects of CCK on taste-responsiveness taste reward, and the incentive value of foods. The biological basis will be investigated by pursuing our previous findings that exogenous CCK has both peripheral (intraperitoneal or i.p.) and central (intracerebroventricular or ICV) effects on satiation and on food rewards (1,2). To explore these effects further, prefeeding will be combined with peripheral or central CCK administration, testing the hypothesis that the effective dose in each route of administration will be lowered by prefeeding and a second hypothesis that subthreshold i.p. and ICV CCK doses will be additive and thus effective when given together. To explore the neural substrate, the locus of ICV injection will be varied from the anterior ventricles (third and lateral) to the fourth ventricle. In addition, specific sites in the brain will be investigated by lesioning those sites and by direct injection of CCK or the CCK-blocker, proglumide, in order to determine whether central (and where appropriate, peripheral) effects of CCK may be enhanced or diminished. In the study of the satiating effect of CCK, food-deprived rats will be used and the sites to be explored will include the area postrema (AP) and the paraventricular nuclei (PVN). In the study of the effects of CCK on taste reward and incentive effectiveness, food-satiated rats will be used to investigate sites in the limbic taste pathway, including the rostral region of the nucleus of the solitary tract (rostral NTS), the parabrachial nuclei (PBN) in the pontine taste area, the lateral hypothalamus (LH), and the central nucleus of the amygdala (CNA). By elucidating CCK's effects on both appetitive and consummatory aspects of the motivation toward food we will contribute to the theory of motivation, and also gain a better understanding of the behavioral and biological processes that go awry in the eating disorders.

This is an application for a NEUROSCIENCE WORK GROUP IN MENTAL HEALTH that will bring together eleven senior investigators for collaborative research on the neurohormonal mechanisms of salt appetite in the rat. Recent behavioral-endocrinological research has demonstrated that salt appetite is an hormonally induced behavior. It is aroused by the synergistic action in the brain of angiotensin and aldosterone which are also the hormones of renal sodium conservation. The Work Group will combine behavioral- endocrinological methods with state-of-the-art biological techniques (cytosol receptor analysis, membrane pharmacology, microiontophoresis and electrophysiology, and cellular biochemistry) in a broad-ranging reductionist analysis of the neural mechanisms by which angiotensin and aldosterone act to arouse a specific motivated behavior that depends for its expression on a single sensory channel (the salt taste). Six Projects are proposed. They are closely integrated around the central question: What is the cellular and molecular nature of the neural mechanism by which angiotensin and associated hormones (aldosterone and atrial natriuretic hormone) mobilize salt. appetite?

Small doses of systemic mineralocorticoid (DOCA or aldosterone) combined with infusions of low doses of angiotensin II into the cerebral ventricles of the sodium replete rat induce a rapid, reliable, and robust appetite for salt, and the salt appetite of the sodium deplete rat is suppressed by interference with the cerebral actions of angiotensin II with drugs that prevent its synthesis or block its receptors. These findings support the hypothesis that excess sodium intake is provoked by a synergy of action in the brain of the two hormones of renal sodium conservation - angiotensin II (Ang II) and aldosterone (ALDO). Endogenous Ang I, Ang II, and ALDO will be measured by radioimmune assay in the sodium deficient, the adrenalectomized, and the drug or hormone treated rat to evaluate the hypothesis directly. Blockade of synthesis of endogenous Ang II with orally self-administered captopril (Squibb) will test the idea that in the adrenalectomized rat, in which angiotensin must act without aldosterone, the appetite for salt is completely dependent on angiotensin. The role of endogenous ALDO will be evaluated in the intact rat by varying the salt content of its diet and by using a new mineralocorticoid receptor blocker (RU 28318) that is potent and specific. Renin-angiotensin systems exist both in the periphery and in the brain. Their potencies for arousal of salt appetite by synergy with ALDO will be compared by contrasting the results of intravenous infusion of Ang II or of competitive antagonists of Ang II with those already obtained with intracranial infusion of the same agents. In addition, the neurological mechanisms that may mediate the synergistic effect of the hormones will be studied with emphasis on the circumventricular organs, as will the effects of the synergy treatment and the excess salt intake that it produces on the rat's blood pressure. The ontogeny of the appetite will be studied in newborn rats, and its phylogeny will be studied in the pigeon. Excess salt intake is implicated in the etiology of hypertensive disease. An understanding of its hormonal causes could lead to rational chemical therapies and to reductions of salt intake in humans at risk for hypertension.