Obesity

Jennifer H Stern

Assistant Professor, Medicine
Assistant Professor, Physiology
Member of the Graduate Faculty
Assistant Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(520) 626-5842

Research Interest

Stern lab research aims to understand the role of glucagon signaling in the pathogenesis of obesity, type II diabetes mellitus, and aging. Glucagon Signaling in Obesity and Type II Diabetes: Insulin resistance and elevated insulin are key to the metabolic disturbances in type II diabetes mellitus (T2DM). Yet, elevated glucagon, common to diabetes, may be equally important in the metabolic abnormalities in T2DM. Dr. Stern has shown that nutritional state differentially affects glucagon secretion in obesity. In turn, the glucagon:insulin ratio is dysregulated in obesity. Current Stern lab research aims to understand the metabolic consequences of a dysregulated glucagon response to fasting and re-feeding. Glucagon Signaling and Aging: More than 25% of the U.S. population greater than 65 years old has Type II diabetes mellitus, representing the highest prevalence of diabetes of any age group. Most research aimed at understanding the consequences of obesity in aging have focused on insulin and downstream signaling cascades, overlooking a potential role for glucagon. Given that many prominent diabetes treatments target glucagon or glucagon signaling pathways, it is essential to understand the role of glucagon in aging. Stern lab research examines 1) the tissue specific effects of glucagon signaling, 2) the role of glucagon signaling in obesity-accelerated aging, and 3) the role of glucagon signaling in healthspan extension promoted by calorie restriction. This work will close a significant gap in our understanding of how glucagon alters aging, while allowing us to assess the potential risks associated with inhibition of glucagon signaling. Other Stern Lab Research Foci: Sleep disturbance and metabolic dysfunction Obesity related cancer development and progression

Benjamin J Renquist

Associate Professor, Animal and Comparative Biomedical Sciences
Associate Professor, Nutritional Sciences
Associate Professor, Physiological Sciences - GIDP
Associate Professor, BIO5 Institute
Department Affiliations
Contact
(520) 626-5793

Work Summary

Renquist Lab Research aims to address the causes and consequent diseases of obesity. To this end we have research focused on 1) type 2 diabetes and obesity associated hypertension, 2) development of effective, ligand-directed, chemotherapeutic for cancer, and 3) central nervous system control of visceral blood flow and food intake.

Research Interest

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

Melanie D Hingle

Associate Professor, Nutritional Sciences
Associate Professor, Public Health
Member of the Graduate Faculty
Associate Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(520) 621-3087

Work Summary

Melanie Hingle's work focuses on understanding determinants of energy balance behaviors (i.e. how and why behaviors are initiated and sustained), and identifying contributors to the success of interventions (i.e. when, where, and how interventions should be delivered) are critical steps toward developing programs that effectively change behavior, thereby mitigating unhealthy weight gain and promoting optimal health. Current projects include: Determinants of metabolic risk, and amelioration of risk, in pediatric cancer survivors, Guided imagery intervention delivered via a mobile software application to increase healthy eating and physical activity in weight-concerned women smokers, and Family-focused diabetes prevention program delivered in partnership with the YMCA.

Research Interest

Identify and understand determinants of behavioral, weight-related, and metabolic outcomes in children, adolescents, and families, including how and why so-called “obesogenic behaviors” (unhealthy dietary habits, sedentary behaviors) are initiated and sustained. Develop and test novel approaches to motivate healthy lifestyle changes in children, adolescents, and families, including development, testing, and assessment of face-to-face and mobile device-based interventions.

Janet L Funk

Professor, Medicine
Professor, Nutritional Sciences
Professor, Cancer Biology - GIDP
Professor, Physiological Sciences - GIDP
Clinical Instructor, Pharmacy Practice-Science
Member of the Graduate Faculty
Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(520) 626-3242

Work Summary

Janet Funk's work includes a focus on metastatic breast cancer that spans the research spectrum from bench to bedside, translational arthritis studies of the pharmacokinetics and safety of turmeric, and collaborative endocrinological studies evaluating the effects of obesity and insulin resistance on bone development in Hispanic girls, as well as effects of obesity on breast cancer risk in older women.

Research Interest

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.