GloP1r - A New Frontier in Exercise and Nutrition

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1 Central Florida Research Update Ayala, Julio, PhD, Sanford-Burnham Medical Research Institute, Orlando, Florida Anorectic Mechanisms of Glp1r Agonists Obesity Jan 1, 2014 Dec 31, 2018 Integrated Physiology, Integrated Physiology\GLP- 1, GIP, and Other Gut Hormones, Integrated Physiology\Regulation of Food Intake Glucagon-like peptide-1 (Glp1) is a hormone that stimulates insulin secretion. As such, this hormone is targeted by drugs used to treat diabetes, a disease characterized by impaired insulin secretion. Glp1 has also reduces food intake and weight, suggesting that Glp1-based drugs could be used to treat obesity. One class of Glp1-based drugs called Glp1 analogs reduces food intake and weight. Interestingly, another class of Glp1-based drugs called DPP4 inhibitors has no effect on food intake or weight. This is intriguing since both classes of drugs activate a receptor for Glp1, the Glp1r. The purpose of this application is to understand why two classes of drugs that target the Glp1r have different effects on food intake and weight. When drugs bind to receptors like the Glp1r, they set in motion a series of steps inside cells that carry out the actions of those drugs. The hypothesis tested here is that the nature of the steps activated by the Glp1r depends on the drug that binds to it. The idea is that Glp1 analogs set in motion a series of steps that are different from those that are set in motion by DPP4 inhibitors. Importantly, the series of steps activated by Glp1 analogs ultimately lead to a greater reduction of food intake and weight. If the series of steps that lead to a greater reduction of food intake are identified, then drugs can be designed to specifically target those steps. This provides a new avenue for designing drugs to treat obesity.

2 Cusi, Kenneth, MD, University of Florida, Gainesville, Florida Nonalcoholic Fatty Liver Disease (NAFLD) in African-Americans with T2DM: Role of Screening and Early Intervention Clinical Science and Epidemiology Type 2 Diabetes Nov 1, 2013 Oct 31, 2014 Epidemiology, Insulin Action, Insulin Action\Insulin Resistance, Obesity, Obesity\Clinical Treatment Nonalcoholic fatty liver disease (NAFLD) is common condition associated with obesity and type 2 diabetes mellitus (T2DM) but it is largely overlooked by patients and doctors. Its clinical spectrum ranges from simple fat accumulation to severe liver inflammation (nonalcoholic steatohepatitis [NASH]). It affects ~30-40% of the general population but ~60-% of obese subjects and as many as 70-80% of patients with T2DM where it carries a worse prognosis causing diabetes to be harder to control and increasing the risk of cardiovascular disease. My goal is to establish the best treatment strategy for these patients based on a better understanding of the disease. The next critical step, and the objective of this application, is to study subjects at significant risk of NASH because they are prone to obesity and T2DM, such as African- Americans. They have been poorly represented in prior studies but still are at significant risk of the disease. The central hypothesis is that obese African-Americans with T2DM are at a significant risk of NASH, but that reversal is feasible with appropriate lifestyle intervention. To this end we propose to: 1) Assess the prevalence of NAFLD/NASH by screening for liver fat with the gold-standard magnetic resonance and spectroscopy technique; 2) Establish their metabolic and molecular profile and compare it with that of other ethnic groups; 3) Compare two lifestyle interventions in their ability to reduce hepatic steatosis by MRS (primary endpoint), improve liver histology (2º endpoint) and improve metabolic/molecular variables.

3 Brusko, Todd, PhD, University of Florida, Gainesville, Florida Influence of IL-12 and IL-18 on Immunoregulation and Type 1 Diabetes Pathogenesis Basic Science Type 1 Diabetes Jul 1, 2013 Jun 30, 2016 Immunology Avoidance of infection and autoimmunity relies on a series of carefully orchestrated events within the immune system. When these processes fail, a variety of autoimmune disorders can arise, including type 1 diabetes (T1D) which occurs when insulin producing pancreatic beta cells are destroyed. One key constituent charged with the responsibility to control such processes are a unique white blood cell referred to as Helper T (Th) cell. A number of studies suggests that Th cells from patients with T1D exhibit a remarkable loss of immune regulation. We believe the reason for this loss of control resides, in part, in the abnormal production of inflammatory products of immune sentinel cells, referred to as antigen presenting cells that produce the factors IL-12 and IL-18. In this application, we are proposing to determine how these factors (cytokines) are controlled during the development of T1D. Moreover, we will determine how they influence the populations of Th cells that either drive the destruction of pancreatic beta cells, or control these immune responses through the activity of regulatory T cells. Additionally, we seek to identify the genetic basis for the aforementioned defects. The successful completion of these aims is expected to better identify individuals at risk for T1D who may go on to develop the disease. Additionally, we expect to identify specific opportunities to target these cytokines and intervene in the disease process, potentially halting T1D progression or setting the stage for beta cell replacement therapies.

4 Alman, Amy, PhD, University of South Florida, Tampa, Florida Epicardial Fat and Inflammatory Mediators in the Excess Risk of Coronary Artery Calcification Among Women with Type 1 Diabetes Clinical Science and Epidemiology Type 1 Diabetes Jul 1, 2013 Jun 30, 2016 Epidemiology, Obesity, Obesity\Pathogenesis Women with type 1 diabetes are at increased risk of cardiovascular disease, but the mechanisms are not well understood. The recognition that fat tissues in different parts of the body may function differently is leading to new areas of research on how different areas of fat can increase the risk of cardiovascular disease. This may play an important role in the excess risk of cardiovascular disease experienced by women with type 1 diabetes for the following reasons: 1) fat is distributed differently in women compared to men (pear-shaped versus apple-shaped), 2) fat tissues have been shown to play a role in insulin resistance and to increase inflammation and these have been associated with cardiovascular disease, and 3) different fat tissues have different effects on cardiovascular disease risk. These observations have led to the hypothesis for this project: that epicardial fat, a type of fat that surrounds the coronary arteries in the heart, plays a role in the increased risk of cardiovascular disease seen in women with type 1 diabetes. Cardiovascular disease is a significant cause of morbidity and mortality in those with diabetes. Understanding the risk factors better can help to identify those at greater risk and lead to new targeted interventions and treatments. Reductions in epicardial fat have been demonstrated with changes in diet and exercise, so this work can lead to significant improvements in the long-term health of those with type 1 diabetes.

5 Sparks, Lauren, PhD, Adventist Health System/ Florida Hospital, Orlando, Florida Exercise Resistance in Type 2 Diabetes Junior Faculty Type 2 Diabetes Jul 1, 2013 Jun 30, 2016 Exercise, Exercise\Human, Exercise\Regulation of Muscle Metabolism, Gene Chips and Microarrays By 2050 the number of people with diagnosed diabetes in the United States will reach 29 million. Increased sedentary behavior, coupled with early onset of type 2 diabetes (T2D), has popularized exercise interventions as an investigative tool of the health benefits associated with physical activity and as a feasible lifestyle modification. We know that exercise benefits most, but not all, individuals with insulin resistance (IR) and T2D. The beneficial effects are well studied, but why some individuals do not respond favorably to exercise is largely unexplored. Few studies have sought to unravel the potential mechanisms for this so called "exercise resistance". The goal of this proposal is to identify those individuals with T2D that do not respond favorably to exercise and investigate the underlying mechanisms which predict this lack of response. These findings will change how we prescribe exercise as a treatment and prevention for T2D. This work is innovative both in its translational approach of combining human and cell/laboratory models and in its cutting-edge methodologies in the clinic and at the bench. We will provide definitive results on the effects of endurance training on muscle metabolism in individuals with T2D and how these responses (or lack thereof) can be predicted by the patterns of genes in their muscle tissue and cells. This research will move the field forward and has the potential to shift the paradigm, allowing exercise interventions to be targeted to those individuals most likely to benefit and identify novel approaches to treat those who do not.

6 Collins, Sheila, PhD, Sanford-Burnham Medical Research Institute, Orlando, Florida Adipocyte 'Browning' and Body Fat Reduction by Cardiac Natriuretic Peptides Basic Science Obesity Jan 1, 2013 Dec 31, 2015 Adipocytes, Exercise, Exercise\Regulation of Muscle Metabolism, Obesity, Obesity\Animal Models Obesity is an epidemic in the US with annual costs exceeding $100 billion/yr, making it a public health and economic crisis. Lifestyle and behavioral approaches have modest and transient effect while approved therapies targeting appetite or fat absorption have poor tolerability or safety concerns. Drugs that act by increasing energy expenditure would be valuable. We recently discovered that the heart hormones ANP and BNP best known for their regulation of blood pressure can cause energy-storing fat cells to take on characteristics of so-called 'brown fat cells'. These cells are able to consume calories because they contain a specialized protein called 'uncoupling protein'. The ability of ANP and BNP to promote this 'browning' of fat cells depends upon the relative levels of two 'receptors' that they interact with on cells: one called NPRA promotes the signals for 'browning' while the other called NPRC sweeps up ANP and BNP and removes them from circulation. In this project we will test the idea that when levels of the NPRC protein are eliminated from fat cells in an animal, the 'browning' of the fat cells will burn excess calories and protect the animal from diet-induced obesity. We will also test the possibility that the skeletal muscles also respond to ANP and BNP to also increase calorie burning. We will use mice that lack the NPRC or not for these diet studies and we will also culture the muscle and fat cells to specifically understand their responses to ANP and BNP.

7 Sautin, Yuri, PhD, University of Florida, Gainesville, Florida Prodiabetic Role of Purine Degradation via Xanthine Oxidoreductase Basic Science Insulin Resistance/Prediabetes Jul 1, 2012 Jun 30, 2015 Adipocytes, Integrated Physiology, Integrated Physiology\Insulin Resistance, Signal Transduction (Non- Insulin Action), Signal Transduction (Non-Insulin Action)\Transcriptional Regulation Obesity and more complex condition metabolic syndrome, which are currently epidemic in our country have been linked with the increase in consumption of sugars, especially added sugars containing fructose, such as sucrose and high fructose corn syrup (HFCS). These studies should help elucidate the novel mechanisms by which initial steps of the metabolism of consumed fructose mediate metabolic syndrome including activation of pathways of fat accumulation, inflammation and oxidative stress that drive both obesity and insulin resistance and lead in many cases to the development of type 2 diabetes. This will provide insights into mechanisms, which make fructose-containing sugars more dangerous for the development of the prodiabetic conditions. In addition, they will be useful for developing new therapeutic approaches for the prevention and treatment of obesity and metabolic syndrome.