Nutrition

Dr. Cynthia Thomson, PhD, RD, is a Professor and Director of the Canyon Ranch Center for Prevention and Health Promotion in the Mel and Enid Zuckerman College of Public Health at the University of Arizona. Dr. Thomson holds joint appointments in the College of Agriculture and Life Sciences and the College of Medicine. Her research emphasis includes dietary intervention in breast and ovarian cancer survivors, as well as behavioral interventions for weight control and metabolic regulation. Dr. Thomson received her Ph.D. from the Interdisciplinary Program in Nutritional Sciences, University of Arizona and completed NCI-sponsored post-doctoral training at the University of Arizona Cancer Center with a focus on diet and cancer prevention.

Monica Schmidt is an Associate Professor in the School of Plant Sciences in the College of Agricultural and Life Sciences at the University of Arizona. Dr. Schmidt’s research interests are in both functional foods and functional genomics. Her research aims at applying molecular biology and genetic techniques to help alleviate current major agricultural problems. As soybean is a global commodity, much of her research focuses on soybean seed traits. Current research is investigating cellular mechanisms to strengthen the metabolic engineering efforts to fortify crops with nutraceutical carotenoids. Since soybean oil is a large component of the American diet, Dr. Schmidt is also investigating means to engineer a more healthy oil composition. Other functional food projects aim at the suppression of deleterious compounds in crops, such as toxins produced from contaminating fungus, in maize and peanuts. She uses techniques of plant biotechnology in over a dozen crops to investigate gene function, at a cellular and entire plant level. Dr. Schmidt has worked with both domestic and international collaborators on value-added traits in seeds of legumes for over a decade and is one of the few academic laboratories that can routinely transform soybean. She has been involved with a number of innovations in tissue culture / transformation techniques (for example, maturation media for soybean, novel gene expression cassette system) and her research on seed manipulation has resulted in a start-up company and patents. Keywords: plant biotechnology, functional foods, soybean, maize

CURRENT AND FUTURE RESEARCH PLANS Renquist lab research can be broken into 4 foci that target the pathophysiologies of obesity (insulin resistance, hypertension, and cancer) or aim to better understand energy balance (food intake and energy expenditure) to combat the obesity epidemic. 1) Metabolic Syndrome: Excess hepatic lipid accumulation, common in obesity, is directly related to the incidence and severity of Type II Diabetes Mellitus and hypertension. Hepatic lipid accumulation depolarizes the hepatocyte. To understand the role of hepatocyte membrane potential in mediating the pathophysiologies of obesity, we use tissue specific knockout, pharmacological, and mouse models with adenovirus induced ion channel expression. Through this research we have found that obesity changes hepatocyte neurotransmitter release to affect activity of the hepatic vagal afferent nerve. This research has been supported by competitive grants from the Arizona Biomedical Research Commission and The American Heart Association. Primary hypothesis: Hepatic membrane potential is communicated through the peripheral nervous system to affect serum glucoregulatory hormones, peripheral tissue glucose uptake, and blood pressure. 2) Targeted cell ablation. In two grants funded by Found Animals Foundation, we have focused on inducing permanent sterility by selectively delivering a GnRH targeted toxin to GnRH receptive gonadotropes (A strategy developed by Terry Nett, CSU). The cancer field is demanding delivery systems that improve ligand or antibody directed therapeutics. Many cancers (e.g. breast, ovarian, melanoma, pancreatic, and colorectal) express GnRH receptors. Thus, effective GnRH-targeted toxins can also be directed to target cancer. Two issues have limited the application of GnRH targeted toxins. First, the potential for effects in ‘non-targeted’ GnRH expressing cells. Second, the endosomal sequestration of internalized toxins. By separately targeting an endosome disrupter with one G-protein coupled receptor (GPCR) ligand and the toxin with another GPCR ligand, we eliminate both limitations. By using this modification of the delivery system to maximize endosome escape, we have increased in vitro efficacy more than 1,000,000,000 times. This improvement in efficacy helped our research team to secure a DoD grant aimed applying this strategy to prostate cancer. Importantly, GnRH targeted doxorubicin has recently been approved by the FDA for treatment of cancer. We fully expect that our targeted endosome disrupters would enhance the efficacy of this FDA approved treatment while improving specificity and decreasing the potential for side effects. Primary hypothesis: Optimizing GnRH-toxin conjugates to enhance endosome escape will allow for selective ablation of target cells encouraging the development of improved ligand directed chemotherapeutics and an injectable sterilant 3) Control of food intake and milk production. Understanding the mechanisms that regulate food intake under differing environmental conditions provides opportunities to pharmacologically manipulate phagic drive to treat obesity. Heat stress depresses food intake dependent on histamine signaling. My lab aims to understand how the neuroendocrine/endocrine suppression of visceral blood flow, a physiological adaptation to encourage heat loss by increasing cutaneous blood flow, depresses phagic drive. This USDA NIFA funded project is focused on the dairy cow as our target species, but we employ mouse models and see this as an opportunity to better understand the control of food intake. We use mice that lack histamine receptors to focus on the role of central nervous system histamine signaling in the control of blood flow to the digestive tract and mammary gland. Therapeutics aimed at suppressing visceral blood flow may have application in addressing the obesity epidemic. Primary hypothesis: A decrease in blood flow to the digestive tract and mammary gland is responsible for a decrease in food intake and milk production common to heat stress. 4) Energy Expenditure. I developed an assay to measure the metabolic rate of embryonic zebrafish for application in drug and gene discovery. Since joining the University of Arizona, I have secured funding from USDA Western Regional Aquaculture Center and USDA NIFA funding to apply this assay to identify fish that are genetically superior for growth. We further showed that by measuring the metabolic rate of skeletal muscle biopsies from adult fish, we could identify the fish that were more feed efficient. Skeletal muscle biopsies from adult feed efficient fish were less metabolically active. Recently, we have initiated studies using tissue biopsies from homeothermic mice. This research will allow us to assess the tissue specific response to physiological perturbations (e.g. exercise, diet, obesity, fasting). Since insulin and leptin both increase energy expenditure, we expect that assays performed in tissue explant from homeotherms may allow for screening of insulin and leptin sensitizers in a more physiologically relevant model. We further propose this this assay could be a tool to assess insulin or leptin resistance and drug response in patient biopsies. Primary hypothesis: This assay designed for high throughput metabolic rate determination may be applied to improve growth and feed efficiency in production animals, improve drug development and gene discovery in biomedical models, or personalize medicine for patients. Keywords: Obesity, Metabolic Syndrome, Cancer

Sean W. Limesand, PhD, is an Associate Professor in the School of Animal and Comparative Biomedical Sciences at the University of Arizona in the College of Agriculture and Life Sciences. He is also a member of the UA’s BIO5 Institute and Department of Obstetrics and Gynecology. Dr. Limesand is nationally and internationally recognized for his work studying fetal endocrinology and metabolism in pregnancy and in pregnancies compromised by pathology such as intrauterine growth restriction and diabetes. His research is focused on defining developmental consequences resulting from a compromised intrauterine environment. Specifically, he is focused on fetal adaptations in insulin secretion and action that when altered in utero create lifelong metabolic complications. Dr. Limesand has lead the charge on prenatal origins of –cell dysfunction as the Principal Investigator for a number of federal and foundation grant awards and published more than 40 peer-reviewed articles on topics related to this research. Keywords: Diabetes, Pregnancy, Perinatal Biology

Janet L. Funk, MD, FACP, is a Professor of Medicine at the University of Arizona College of Medicine. Dr. Funk leads a federally-funded research team that is focused on identifying new treatments for chronic diseases that have strong inflammatory components, including metabolic bone diseases, such as arthritis, bone tumors and osteoporosis, and cardiovascular diseases, including diabetes. Recent studies have focused on the use of medicinal plants that have historically been used to treat inflammatory conditions, such as arthritis. By understanding whether and how these plants work in blocking inflammatory pathways in the body, we are striving to harness the power of nature and the wisdom of our ancestors to indentify new treatments for diseases that are common in our modern society. Discoveries we have made at the lab bench have allowed us to move forward into the clinics, building upon the old to discover the new.

An overwhelming obesogenic environment, the backdrop to a globally-expanding western lifestyle, has led to a ‘diabesity’ pandemic that represents a costly and urgent global health crisis. The success of gastric bypass surgery and gut-derived diabetes/obesity treatments highlight the major role of the gastrointestinal (GI) tract in metabolic diseases. My research aims to better understand the complex intestinal signaling mechanisms involved in the regulation of energy and glucose homeostasis in physiological and pathophysiological states. My work to date has focused on elucidating how nutrients are sensed by the gut, and how changes in these mechanisms lead to a reduction in food intake and/or a reduction in endogenous hepatic glucose production via a gut-brain neuronal axis. More specifically, my work focused on alterations in intestinal detection of fats and carbohydrates and paracrine gut peptide signaling (CCK and GLP-1) during high-fat feeding, the influence of the gut microbiota on these pathways, and how these contribute to the development of obesity and diabetes. As such, I plan to continue to decipher this complex interaction between gut-sensing mechanisms and the gut microbiota, as a better understanding of these pathways are crucial for the development of successful, gut-targeted therapeutic options in the treatment of metabolic diseases. Given the rapid rise of obesity/diabetes in only several generations, obesity cannot be attributed to genomic alterations, but more likely results from a complex set of interactions between genetic risk factors and environmental changes. Importantly, studies suggest the development of adult phenotypes (obesity and diabetes) results from early, transient environmental interactions, coined ‘early life programming,’ which has been partly attributed to epigenetic changes. Gut microbiota development is also crucial during this time, and differing modes of development (i.e. maternal microbiota, type of delivery, breastfeeding vs. formula feeding, etc.) can lead to later metabolic dysfunctions. Therefore, using animals models prone to the development of obesity and/or diabetes from polygenetic inheritance and transgenerational, epigenetic, changes in gene activity, I am studying how varying environmental factors (diet, housing, exercise, pre/post-natal environment, etc.) result in differential effects on the gut microbiota, intestinal nutrient sensing, and whole body energy and glucose homeostasis. A better understanding of how early changes in the gut microbiota can impact the development of metabolic regulation, and vice versa, is vital for developing successful strategies to curb diabetes and obesity.