Neil F. Shay - US grants

Dietary zinc may ultimately become complexed with any of an estimated 200 different zinc-binding proteins. Until recently, the site or sites where zinc deficiency alters cellular function and compromises the regulation of appetite has not been known. In our label we have made several novel findings that allow us to present hypotheses regarding the integrity of the appetite-regulating functions of the hypothalamus. We believe that reduced zinc status alters the cellular physiology of appetite-regulating neuropeptides, causing the loss of appetite we refer to as zinc deficiency- induced anorexia. We believe that zinc deficiency is a cause or accelerating factor in anorexia nervosa and other loss of appetite syndromes. Our broad hypotheses are: (1) Reduced zinc status suppresses the synthesis and/or processing of appetite-stimulating neuropeptide Y (NPY), reducing the normal drive for food intake mediated by NPY. (2) Alterations in levels of growth hormone releasing hormone (GRF) are observed when zinc deficient rats are repleted with normal levels of zinc and regain normal appetite. Our preliminary data supports these hypotheses are: Neuropeptide Y gene expression is reduced significantly in zinc deficient rats Zinc deficient rats consume reduced amounts of only carbohydrate when allowed to self-select from macronutrient diets; carbohydrate intake is known to be driven by NPY Injections of NPY into the hypothalamus of a zinc deficient rat will restore food intake to normal levels Zinc-deficient rats that are repleted with zinc are characterized by a surge in specific protein intake that correlates with a transient increase in GRF levels The normal diurnal food preference cycle (for rats) of carbohydrate preference early in the dark cycle and increased preference for protein and fat later in the dark phase is disrupted by zinc deficiency. Our research plan will utilize molecular-based methods to characterize the integrity of the hypothalamus as a function of zinc status. This includes measurements of gene expression, peptide levels, processing of peptides, and receptor studies. ln-vivo infusion and withdrawal of brain chemicals will be performed utilizing brain cannulation methodology. The proposed experiments address a critical, unexplored area between appetite-regulation and zinc status. The project utilizes an array of molecular-based methods to investigate an unexplained problem in nutritional science recognized for over 30 years, zinc deficiency-induced anorexia. A strength of this proposal includes the interdisciplinary team of collaborators assembled with extremely wide.ranging areas of expertise. The proposed studies are needed to understand and treat appetite-related disorders.

DESCRIPTION (provided by applicant): This application is for partial funding for the 2003 FASEB Summer Conference on "Molecular Mechanisms of Regulation by Dietary Constituents." The conference will be held from August 16-21, 2003 at Snowmass Colorado. This conference is a sequel to a very successful 2001 summer conference on the impact of diet on gene expression. The goals of this conference are to stress the recent advances of Molecular Genetics and their impact on nutritional research and to increase the interaction between nutrition scientists and molecular geneticists who are not well acquainted with nutritional research. Given that dietary constituents have a tremendous impact on human health, it is important to study the cellular and molecular targets of their action. This meeting aims to expand the interface of Molecular Genetics and Nutrition and to thereby increase the interactive research capacity of these two fields. All sessions will bring cutting edge work in molecular genetics as it relates to critical questions in nutritional research. A special emphasis provides sessions describing modem molecular tools such as yeast genetics, functional genomics and proteomics, and other molecular methods. The conference will provide a forum for the development of new research projects among the participants involving molecular-based research related to nutritional problems. We are encouraging participation of trainees, new, and women scientists. There will be 8 major oral sessions plus a plenary lecture. Poster presentations will be scheduled for two afternoons. All major sessions are organized around the central themes of molecular regulation: transcriptional regulation by lipids, carbohydrates and amino acids, transcriptional control by nuclear receptors, translational control, nutrients as signaling molecules in regulating gene expression, and regulation of glucose and lipid homestasis. Special sessions will allow oral presentations to be selected from submitted abstracts to allow the meeting to provide increased breadth and to include additional short talks highlighting the newest molecular tools used in nutrition research. The aim of this conference is to fill a void in the field by unifying scientists with common conceptual and methodological approaches to problems related to nutrition and health.

DESCRIPTION (provided by applicant): This project will investigate potential interactions between phytochemical-containing soy extracts and the prescription phamaceuticals, the statins. Statins are a pharmaceutical approach to reducing blood cholesterol levels, and soy supplements are an alternative, botanical approach to to reduce blood cholesterol levels. The long term goal of this research project is to enable individuals and physicians to include soy supplement products as a complementary treatment in addition to prescibing statin intake to reduce blood cholesterol levels. Currently, physicians typically advocate that individuals first use diet to try to reduce cholesterol levels. When a low-fat diet does not reduce cholesterol levels, then physicians will prescribe a cholesterol-lowering drug. Soy has been of interest since it is know that intake of soy reduces cholesterol levels. Nutrition researchers suspect a number of properties of soy may contribute to its cholesterol-lowering effect. Soy also has a second property, it can enhace the 'cytochrome P450' detoxification system of the liver. The P450 proteins enhance metabolism of organic compounds that enables them to be more easily excreted from the body. P450 proteins metabolize the category of cholesterol-lowering drugs called statins. This project will help determine how soy lowers cholesterol and which liver P450s are activated by soy. It appears that these two actions may simultaneously help and hinder the ability of an individual to lower their cholesterol levels while taking statins. This project will help provide critical information that could enhance the effectiveness of statins, help further lower an individual's cholesterol levels, and perhaps reduce the cost of routine drug therapy often required for those with elevated cholesterol levels. In the future, it may be possible to determine and chemically separate the different components of soy that reduce cholesterol and activate the P450 proteins. If this could be done, it is possible that a specific soy extract product could be produced that has a singular effect that helps lower blood cholesterol levels.