1997 — 2006 |
Seeley, Randy J. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulatory Responses to Positive Energy Balance @ University of Cincinnati
DESCRIPTION (provided by applicant): The incidence of obesity has reached epidemic proportions, is a major health burden, and costs the U.S. billions of dollars in health care and lost productivity. Failure to develop effective treatments for obesity is in large part due to a lack of clear understanding as to how food intake and energy balance are regulated by the CNS. Thus, research to determine the processes by which food intake and energy balance are controlled is likely to have a major impact on public health, but the research to date has been imbalanced. For whereas considerable effort has been devoted to understanding the neurochemical response to negative energy balance, relatively little attention has been devoted to the inverse situation of positive energy balance. This oversight is significant since obesity is necessarily associated with periods of positive energy balance and therefore can be considered as a failure of the body weight regulatory system to respond appropriately to positive energy balance. Thus studying the responses to positive energy balance may provide valuable clues concerning the etiology of obesity. Moreover, the regulatory responses to positive energy balance represent the recruitment of endogenous systems that produce reduced food intake, increased energy expenditure and significant weight loss. Finding potential ways to mimic or trigger these endogenous regulatory response systems could provide unique insights and therapeutic strategies for the treatment of obesity. The current proposal seeks to identify critical aspects of this response system. When animals are force-fed calories in excess of caloric need (involuntary overfeeding), their spontaneous food intake drops to near zero and they gain body weight. Additionally, for some time after the overfeeding regimen is terminated, spontaneous food intake remains low until body weight has returned to control levels. Our data indicate that this regulatory response to positive energy balance is mediated by the CNS melanocortin system. We propose assessing several hypotheses concerning how the CNS melanocortin system orchestrates the response to positive energy balance. First, we will determine the critical population of melanocortin receptors that mediate the reduced food intake and increased energy expenditure that follow a period of positive energy balance. Second, we will determine the critical inputs into the melanocortin system that signal positive energy balance. Finally, we will evaluate the unique effects of an endogenous melanocortin receptor antagonist that counteracts the normal response to positive energy balance. The information from this proposal will be critical to a complete picture of how energy balance is regulated and how disorders of energy balance such as obesity may be treated.
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1 |
1998 — 2000 |
Seeley, Randy J. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cns Mediation of Visceral Illness @ University of Cincinnati
Visceral illness refers to the nausea, dimunition of appetite and reduced food intake that contributes significantly to the morbidity and mortality of a wide range of clinical problems including cancer, AIDS, ingestion of toxins, and chemotherapy. Visceral illness can be modeled experimentally in animals using toxic doses of lithium chloride (LiCi). Although the syndrome of LiCi induces visceral illness is well characterized, the neurochemical systems that mediate the effects of this agent in the central nervous system are largely unknown and unexplored. We have recently accumulated evidence to support a role of for the brain-gut peptide glucagon-like-peptide-1 (7-36) amide (GLP-1) in mediating the effects of LiCi-induced visceral illness in the CNS. GLP-1 is a product of preproglucagon made in intestinal mucosal cells and in discrete population of neurons in the caudal brainstem. These neurons project primarily to the hypothalamus and GLP-1 receptors have been identified both in the hypothalamus and in the caudal brainstem. A variety of behavioral, physiological and neural effects of LiCi can be reproduced by administration of GLP-1 into the third cerebral ventricle. Additionally, some markers of LiCi-induced visceral illness are blocked by administration of a potent GLP-1 receptor antagonist into the CNS. These data have led to the guiding hypothesis of this proposal: the effects of LiCi induced toxicity, and perhaps other forms of visceral illness, are mediated by activation of CNS GLP-1 receptors. To test this hypothesis, we propose to 1) Assess whether a receptor antagonist for GLP-1 can ameliorate the effects of peripheral LiCi on a broad spectrum of markers of visceral illness in the rodent. 2) Assess the effect of LiCi on these markers of visceral illness in transgenic mice with null mutation of the GLP-1 receptor. 3) Localize the GLP-1 receptor population that signals GLP-1 and LiCi-induced visceral illness. 4) Identify the source of GLP-1(peripheral vs CNS) involved in transmitting LiCi induced visceral illness. 5) Assess whether the effects of other causes of visceral illness are transmitted by GLP-1 in the CNS. The experiments outlined in this proposal are critical to our understanding of the neural systems that are responsible for visceral illness. Understanding these systems is and important first step in devising therapeutic strategies for the many and varied clinical situations complicated by visceral illness.
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1 |
2001 — 2005 |
Seeley, Randy J. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cns Glp-1: Multiple Roles in Ingestion and Adiposity @ University of Cincinnati
Disorders of food intake, either under consumption by patients with wasting illness or over-consumption in ever-growing rates of obesity, are major health burdens and cost the U.S. billions of dollars in additional health care and lost productivity. Failure to develop effective treatments for these conditions is in large part due to a lack of clear understanding as to how food intake is regulated. Thus, research to explain the processes by which ingestive behavior is controlled is likely to have a major impact on the health of the population. Glucagon-like-peptide-1-(7-36) amide (GLP-1) is an intestinal hormone that has important effects on insulin secretion and glucose metabolism. GLP-1 is also produced in the Central Nervous System (CNS), exclusively in a discrete group of neurons in the caudal brainstem. A single receptor, specific for GLP-1, is expressed in pancreatic beta-cells and by neurons in specific regions of the brain including the hypothalamus, amygdala and caudal brainstem. The neuroanatomical distribution of the central GLP-1 system suggests a role as a relay center for transmitting visceral information to higher centers and there is emerging data indicating that signaling through the central GLP-1 receptor is involved in several aspects of the regulation of food intake. The central hypothesis of this proposal is that signaling through the CNS GLP-1 system is common to the non- homeostatic, meal, and adiposity regulating influences on food intake. The first specific aim will evaluate the hypothesis that signaling through the CNS GLP-1 receptor is a common mechanism through which diverse noxious stimuli activate the response to visceral illness. The second specific aim will use mouse experiments and a conditional genetic targeting system to evaluate the hypothesis that mice with targeted disruption of the GLP-1 receptor develop alternative systems to mediate visceral illness. The third specific aim will evaluate the role of the CNS GLP-1 system in mediating GI-peptide induced satiety. The fourth specific aim will use tissue selective knockouts of the GLP-1 receptor to evaluate the hypothesis that the effects of peripherally administered GLP-1 agonists on body adiposity are mediated by GLP-1r on the pancreatic beta-cell rather than by GLP-1r in the CNS. While overwhelming evidence indicates that GLP-1 can influence food intake, controversy continues to surround the circumstances under which GLP-1 exerts that influence. The execution of the current proposal will result in a more complete understanding of the GLP-1 system and so will add greatly to the overall picture about how food intake and body weight are regulated. This information could lend itself to the development of therapeutic strategies for both wasting conditions as well as obesity.
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1 |
2006 — 2010 |
Seeley, Randy J. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Contribution of Cns Sensing to Hf Diet-Induced Obesity @ University of Cincinnati
Under normal circumstances, mammals accurately match their caloric intake to their caloric expenditure and this matching critically involves circuits in the hypothalamus that control both food intake and metabolism. The activity of these hypothalamic circuits is carefully regulated by peripheral signals that reflect the amount of adipose tissue. Our data indicate that the CNS becomes relatively resistant to the actions of these "adiposity signals" in the CNS when rats are placed on these high-saturated fat diets. Thus, the overall goal of this project is to elucidate the molecular and metabolic mechanisms that cause this CNS resistance to adiposity signals. The first aim will compare rats maintained on a high saturated fat diet to those maintained on a high mono unsaturated fat diet for such CNS resistance. Further, we will determine whether observed CNS resistance is associated with an inability for adiposity signals to drive changes in the expression of specific genes in the hypothalamus. Growing data indicate that these hypothalamic circuits also directly sense available fuel using mechanisms similar to peripheral cell types. As a result we will also assess how specific metabolic pathways in the CNS are altered by exposure to high saturated and mono unsaturated diets. One pathway that is impaired in beta-cells by exposure to high fat is the pyruvate cycle. Thus, the second specific aim will determine the contribution of reduced pyruvate cycling in the hypothalamus to the weight gain and CNS resistance produced by the high saturated fat diet. Another critical fuel sensitive signaling pathway in peripheral cell types is the atypical kinase mTOR. Preliminary data indicate a role for mTOR in the hypothalamus to regulate food intake and so our final specific aim will assess the contribution of reduced mTOR activity and action to the weight gain and CMS resistance produced by the high saturated fat diet. These experiments will shed considerable light on how specific dietary variables influence critical circuits in the hypothalamus and thereby lead to important insights about the etiology and treatment for common forms of obesity that continue to increase in both adult and pediatric populations in the U.S.
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1 |
2006 — 2010 |
Seeley, Randy J. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Roles of Gm-Csf in Energy and Glucose Regulation @ University of Cincinnati
[unreadable] DESCRIPTION (provided by applicant): Obesity results when the number of calories ingested exceed the number of calories expended. The ability of the body to match caloric intake to caloric expenditure depends on a number of cytokines. Leptin is a cytokine released directly from adipocytes in proportion to the amount of body fat and acts on a variety of CNS circuits to regulate food intake, energy expenditure and peripheral glucose regulation. This proposal focuses upon another cytokine that parallels at least some of these actions of leptin: Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). Our data indicate that when GM-CSF is administered into the CNS, it produces reductions in food intake and body weight that cannot be attributed to illness or motor impairment. Further, GM-CSF receptors can be found in several key hypothalamic nuclei linked to the control of food intake including the arcuate nucleus, which also shows high expression of the leptin receptor. Finally, mice that do not make GM-CSF show increased food intake and body fat. These data point to an important role for GM-CSF in the control of energy balance and the aims of this proposal focus upon elucidating key aspects of GM-CSF's biological function. First, our data implicate central production of GM- CSF as contributing to the regulation of energy balance. Consequently, we want to do map GM-CSF receptor distribution and identify the neurochemicals made by neurons that express GM-CSF receptors. We also will identity the locations and cellular types that produce GM-CSF in the CNS. Second, both leptin and GM-CSF are cytokines with similar actions on food intake and energy balance. In this aim we will test the hypothesis that GM-CSF's actions on food intake and energy balance are produced by activating aspects of the leptin receptor intracellular signaling cascade. Third, our preliminary data indicates that despite their increased adipose stores, GM-CSF mice show evidence of lowered adipose-tissue inflammation. Consequently, we hypothesize a separate function for GM-CSF in adipose tissue to contribute to the inflammatory cascade that links obesity to insulin resistance. To test this hypothesis we will measure macrophage accumulation and expression of various cytokines in adipose tissue in GM-CSF deficient mice. The aims presented here are an important step in unveiling the specific roles that GM-CSF plays in the normal regulation of body weight and its potential connection to the pathology of diabetes. [unreadable] [unreadable] [unreadable]
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1 |
2007 — 2009 |
Seeley, Randy J. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cns Glp-1 Signaling in Energy and Glucose Homeostasis @ University of Cincinnati
[unreadable] DESCRIPTION (provided by applicant): Rates of both obesity and diabetes continue to escalate and with them come rising monetary and human costs. Growing evidence links gut secreted factors as crucial for regulating both food intake and the levels of glucose in the blood. Glucagon-like-peptide-I (GLP-I) is a gut peptide with a broad role in the regulation of nutrient ingestion and disposition. GLP-I is produced in the intestine as well as in a restricted set of neurons in the hindbrain, and a single GLP-I receptor (GLP-I R) is expressed in pancreatic islets as well as neurons controlling autonomic and neuroendocrine function in the hypothalamus, amygdala and caudal brainstem. Previously it was thought that intestinal GLP-I and central GLP-I operated as independent systems, the former regulating glucose metabolism and the latter behavioral responses, particularly food intake. Recent evidence has challenged this view and it is increasingly apparent that there is overlapping activity between the peripheral and CNS GLP-I systems. In particular, it now appears that signaling through CNS GLP-I receptors regulates blood glucose, although it is not yet clear whether the signal is from GLP-I secreted in the brain, the gut or both. Moreover, peripherally administered GLP-I R agonists, like exendin-4 (Ex-4), cause weight loss in rodents and humans in addition to improving glucose tolerance, but it is unclear how this effect is mediated. The specific populations of CNS GLP-I receptors responsible for regulating blood glucose and the anorectic actions of Ex-4 remain unclear. Thus, the overarching goal of this proposal is to determine how the peripheral and central GLP-I systems interact to control food intake and glucose metabolism. Our first aim will be to determine the key sites of endogenous GLP-I and exogenous Ex-4 to regulate food intake and body weight using both pharmacological and tissue specific genetic knockdowns. Our second aim will be to determine the key sites of endogenous GLP-I and exogenous Ex-4 to regulate peripheral glucose levels. Again we will use a combination of site-specific delivery of pharmacological antagonists and tissue-specific genetic knockdowns of the GLP-I receptor. Determining the mechanisms of CNS GLP-I signaling is important for understanding carbohydrate and energy balance. Furthermore, the advent of pharmaceuticals that utilize GLP-I R signaling to treat diabetes makes understanding the physiology of GLP-I directly applicable to clinical care. [unreadable] [unreadable] [unreadable]
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1 |
2010 |
Elmquist, Joel K Grove, Kevin L Kaplan, Lee Michael Seeley, Randy J. |
RC4Activity Code Description: To support multi-year funded research with high impact ideas that may lay the foundation for new fields of investigation; accelerate breakthroughs; stimulate early and applied research on cutting-edge technologies; foster new approaches to improve the interactions among multi- and interdisciplinary research teams; or, advance the research enterprise in a way that could stimulate future growth and investments and advance public health and health care delivery. This activity code could support either a specific research question or propose the creation of a unique infrastructure/resource designed to accelerate scientific progress in the future. It is the multi-year funded companion activity code to the existing RC2; thus ICs need OER prior approval to use the RC4. |
Neuroendocrine Response to Gastric Bypass in Nonhuman Primates @ Massachusetts General Hospital
DESCRIPTION (provided by applicant): Obesity is a worldwide health epidemic and a major contributor to the increased prevalence and severity of more than 60 metabolic, inflammatory, degenerative, cognitive, and neoplastic disorders. Broadly effective preventive and therapeutic strategies have been elusive, and rates of obesity continue to increase worldwide. Among the current therapies for obesity, bariatric or gastrointestinal weight loss surgery (GIWLS) generally, and Roux-en-Y gastric bypass (RYGB) in particular, has proven to be the most effective and durable by far. Recent studies have revealed, unexpectedly, that RYGB works primarily by altering the physiological control of energy balance and body fat storage. It affects a wide variety of physiological systems, including the regulation of ingestive behavior, energy expenditure and glucose homeostasis. In contrast to restrictive diets, surgery-induced weight loss is associated with decreased hunger and hedonic drive to eat, increased satiety, and in rodent models at least, increased diet-induced thermogenesis. Moreover, the beneficial effects of this operation on diabetes and other metabolic disorders appear to include mechanisms independent of weight loss or diminished food intake. These characteristics suggest that defining the mechanisms of action of RYGB will provide a valuable roadmap for the development of new and more effective therapies and may uncover novel biomarkers of response to treatment or preventative strategies. The widespread effects of RYGB suggest that GIWLS is a powerful new tool for exploring the physiological regulation of metabolic function more broadly. Although rodent models provide an attractive means of studying the therapeutic mechanisms of RYGB, the physiological regulation of energy balance, ingestive behavior and glucose homeostasis in rodents diverges from humans in ways that may limit the applicability of rodent models to human disease. Some of these limitations can be overcome by studying humans directly;however, many experiments require interventions or assessments that are too invasive for human experimentation. For such studies, examination of nonhuman primates (NHPs) provides an attractive alternative. The combination of biological relevance and experimental flexibility provided by NHPs is particularly attractive for the study of central nervous system (CNS) and pancreatic contributors to the response to RYGB, since isolation, pathological examination and manipulation of these tissues in humans is difficult. We propose to examine the physiological effects of RYGB in the Rhesus macaque, a species of NHP that, like many humans, is susceptible to the weight gain and diabetes-promoting effects of a high fat diet. The aims of the project are (1) to establish a model of RYGB in obese Rhesus macaques and to characterize its effects on food intake, ingestive behavior, food preference and energy expenditure, phenotypes that appear highly responsive to RYGB in humans and rodents;(2) to characterize the effects of RYGB on glucose homeostasis and determine the mechanisms of these effects and the degree to which they are dependent on changes in food intake or body weight;(3) to characterize the effect of RYGB on the hypothalamic circuitry regulating ingestive behavior and energy balance;and (4) to examine the broad metabolic response to RYGB through gene expression and metabolic profiling of peripheral and portal venous blood, selected brain nuclei, pancreatic islets, liver and muscle. The proposed studies will increase our understanding of the mechanisms by which the GI tract, pancreas and CNS regulate metabolic function. They will also help to identify the mechanisms underlying the therapeutic benefits of RYGB itself, thereby contributing to the identification of new, more effective therapies for obesity and its myriad complications. PUBLIC HEALTH RELEVANCE: This project aims to exploit the unique characteristics and advantages of the nonhuman primate (NHP) model to explore the mechanisms by which Roux-en-Y gastric bypass (RYGB) alters (1) central control of energy balance and glucose homeostasis, (2) pancreatic endocrine physiology and (3) portal and systemic metabolite flux. It focuses on specific areas of physiological response, including nutrient sensing within the hypothalamus and dynamic regulation of pancreatic islet cell growth and function that are less well conserved between rodents and humans and for which well-characterized rodent models of RYGB are inadequate. The proposed studies require long-term invasive monitoring and tissue collection that is not possible in human subjects, but which can be achieved in the NHP model. The results of these studies will provide important new information about the mechanisms by which RYGB induces durable weight loss and remission of type 2 diabetes in primates, thus facilitating the development of novel approaches that mimic these effects less invasively in human patients.
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0.901 |
2012 — 2015 |
Seeley, Randy J. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dissecting Mechanisms of Glp-1 Based Therapies For Type Ii Diabetes @ University of Cincinnati
DESCRIPTION (provided by applicant): The dual epidemics of obesity and type II diabetes represent an enormous challenge to our health care system. The staggering human and monetary costs of these disorders are the direct result of having inadequate treatment options that both lower glucose levels and reduce body weight. Over the last decade, novel pharmacological strategies have become available that target the GLP-1 system. Glucagon-like-peptide- 1 (GLP-1), a regulatory peptide with a broad role in the regulation of nutrient ingestion and disposition, is produced in the intestine as well as in a small cluster of neurons in the hindbrain. Plasma GLP-1 originates from the gut, but is rapidly inactivated by the ubiquitous protease DPP-4. GLP-1's very short half-life challenges the dogma that under normal circumstances endogenous GLP-1 released by the gut acts on distant receptors in the pancreas or brain. Emerging GLP-1-based therapies use two distinct strategies: 1) Long- acting GLP-1 receptor (GLP-1R) agonists that are resistant to the actions of DPP-4; and 2) Inhibitors of DPP-4 that reduce GLP-1 inactivation, effectively prolonging the activity of endogenous GLP-1. Both classes of medication are hypothesized to stimulate GLP-1R signaling, and consequently to control hyperglycemia via a common mechanism of action. However, this cannot be the case since there are clinically important yet still unexplained differences in their spectrum of effects. Most notably, while both classes of compounds improve glucose tolerance, GLP-1R agonists additionally cause weight loss while DPP-4 inhibitors do not. Given the efficacy of GLP-1R-based therapies and the growing numbers of patients being treated with them, understanding endogenous GLP-1 and how it relates to the pharmacological action(s) of GLP-1-based therapies has immediate clinical relevance. The overarching goal of the proposed research is to identify the underlying mechanisms that mediate the effects of these novel treatments for diabetic patients, and to explain their important differences. The research will use state-of-the-art mouse genetic technologies to inactivate the only identified GLP-1 receptor selectively in pancreas, visceral sensory nerves and/or the central nervous system. Genetically modified mice will be treated with both GLP-1R agonists and DPP-4 inhibitors to determine which populations of GLP-1R are necessary for specific actions of these drugs on multiple aspects of glucose metabolism and body weight regulation. We will thus be able to identify the key receptor populations that mediate the important and varied effects of these GLP-1-based therapies. Our ability to deploy second generations of these medicines and to maximize their clinical benefit depends on identifying the key underlying mechanisms. The result of the this proposal will be to simultaneously drive new insights on the role of the endogenous GLP-1 system AND to refine and optimize current and future GLP-1-based therapies to better treat patients with type 2 diabetes.
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1 |
2016 — 2018 |
Seeley, Randy J. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Mechanism For Bariatric Surgery On Obesity and Diabetes
Abstract The dual epidemics of obesity and type 2 diabetes are among the most important challenges to improving health in the United States. The staggering human and monetary costs of these disorders are the direct result of not having treatments that can be delivered to the large number of patients in need. Interestingly, it is not because we don?t have effective treatment options. Bariatric surgical procedures provide sustained weight loss of more than 30%; much greater than can be achieved with lifestyle or current pharmacological treatments. Moreover, some of these procedures provide for substantial reductions in severity or outright remission of type 2 diabetes. However, given the high cost, risk and invasiveness of surgery, it simply is not an appropriate solution for the millions of individuals suffering with obesity and/or type 2 diabetes. While the clinical effectiveness of these procedures has become more widely appreciated, we still understand precious little about the underlying mechanisms that produce these benefits. At first blush, it would seem obvious as to how these procedures produce their effects; i.e., they are restrictive (making a smaller stomach), malabsorptive (reducing the number of calories absorbed from ingested food), or both. However, many lines of evidence have undermined these simple explanations and point to a much richer set of possibilities. We have focused our attention on a procedure termed Vertical Sleeve Gastrectomy (VSG), a procedure in which 80% of the greater curvature of the stomach is removed, reducing the remaining stomach to a tube or ?sleeve?. We have generated several lines of evidence that the ability of VSG to reduce weight and improve glucose regulation depends on changes on the levels and actions of bile acids via the nuclear bile-acid receptor, FXR. One specific goal of this proposal is understand how VSG alters levels of bile acids by infusing labelled bile acids and determining their fate in rodents with or without VSG. A second goal is to test several hypotheses directed at uncovering the key populations of FXR and the FXR-target genes that mediate the diverse effects of VSG. To do so, we will use Cre-LoxP approaches to selectively knock down expression of FXR in liver or intestine and test the effectiveness of VSG to improve a large number of metabolic variables. Identifying the molecular mechanisms by which surgery exerts these effects is an important research goal that has direct clinical implications. By identifying the key molecular underpinnings of bariatric procedures, we can harness the benefits of surgery while lowering cost and invasiveness. This research can improve surgical treatment of obesity and diabetes while we also identify new treatment strategies that would make surgical treatment obsolete.
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0.961 |
2016 — 2020 |
Dimick, Justin Brigham Seeley, Randy J. |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Obesity Surgery Scientist Training Program
? DESCRIPTION (provided by applicant): Surgery for obesity (i.e., bariatric surgery) is now the 2nd most common abdominal procedure performed in the United State. Preparing the next generation of scientists to tackle the most pressing scientific questions in obesity surgery is essential. This T32 grant, Obesity Surgery Scientist Training Program will integrate all aspects of bariatric surgery research at the University of Michigan - from bench to beside, and practice to policy- allowing us to address fundamental questions in a multidisciplinary way. This program will improve obesity surgery research by integrating these various scientific disciplines in order to produce significant cross- fertilization among scientists, clinicians and health servic investigators on this critical topic. Enhanced training will increase the number of investigators using sophisticated approaches to these large-scale problems associated with using surgical approaches to treat obesity and related co-morbidities. The University of Michigan is in a unique position to create a post-doctoral T32 training program in obesity surgery that includes both basic mechanistic science and clinical outcomes research. In additional to our existing strengths in the basic science of obesity and metabolism, we believe several recent recruits to the University of Michigan have helped us achieve an unprecedented critical mass of scientists focusing on the science of obesity surgery. These include three basic scientists: Randy Seeley, PhD, Darleen Sandoval, PhD, and Robert O'Rourke, MD. The University of Michigan is a national center of excellence in bariatric health services research with a robust profile of work funded by NIH, AHRQ, and PCORI. Justin B. Dimick, MD, MPH leads this initiative as the Director of the Center for Healthcare Outcomes & Policy, which is home to the Michigan Bariatric Surgery Collaborative (MBSC), a statewide clinical registry and quality improvement program. There are numerous scientific training programs that focus on obesity and metabolism. However, there are no programs specifically dedicated to preparing scientists and surgeon-scientists for a career dedicated to studying obesity surgery. Although this proposal will train both surgeon-scientists and non-surgeon scientists (i.e., PhDs and non-surgery clinician scientists), there is an acute need for more surgeon scientists in this field. It is important to hve scientifically trained surgeons who can ask important questions and conduct meaningful research. Specifically, more obesity surgery scientists are needed for the following: Provide more intellectual horsepower and research creativity; Provide the specialty-specific clinical expertise to steer research; To establish thought leaders who can ultimately effect change within bariatric surgery.
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0.961 |
2018 — 2021 |
Seeley, Randy J. |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Michigan Nutrition Obesity Research Center @ University of Michigan At Ann Arbor
? DESCRIPTION (provided by applicant): The Michigan Nutrition Obesity Research Center (MNORC) was initially funded in 2010 to support, integrate and enhance research related to obesity and nutrition among the faculty of the University of Michigan. The of the MNORC is to create an environment to encourage and enable researchers from preclinical, clinical and translational research disciplines to integrate advanced, phenotyping and computational tools to more fully define individual and population characteristics that arise in response to dietary nutrient composition or amount. This will be accomplished by providing core laboratory infrastructure, educational and training opportunities and large and small pilot grants to enhance research productivity. The MNORC has expanded the research infrastructure and Core offerings in response to the needs of the research community and has supported the expansion of nutrition and obesity research across the U-M campus. This is highlighted by the $2.6 million investment to expand pediatric obesity research and the creation of an epigenomics core and creation of in vitro and in vivo optogenetics capabilities in response to investigator needs. MNORC has 106 Research Base faculty with a total of annual direct grant support of $39,708, 277. The MNORC Cores include the Administrative Core, which will oversee and integrate the research, clinical and education functions of the Center, including an annual symposium, seminar series, training for undergraduates, dieticians, medical students, housestaff and fellows in the breadth of nutrition and obesity care and research; the Human Phenotyping Core, which will provide expertise and infrastructure for sophisticated metabolic and neurobehavioral testing of humans in inpatient and outpatient settings; the Molecular Phenotyping Core, which will continue supporting targeted and untargeted metabolomics profiling (enhanced by the $9.1 million funding of the Regional Comprehensive Metabolomics Resource Core (U24)) as well as new initiatives in epigenomics and microbiome sciences; the Animal Phenotyping Core which will provide services for the metabolic and molecular phenotyping and increase the capability for neurobehavioral phenotyping of rodent models by supporting optogenetics technology; and the Integrative Biostatistics and Informatics Core, which will provide personnel to assist investigators in design of experiments that integrate molecular and clinical phenotyping, database development, and advanced bioinformatics tools for integration, interpretation, visualization and reporting of molecular, metabolic and neurobehavioral data. The MNORC will continue to support the Weight Management Program which integrates research into a highly successful adult clinical weight loss program. Numerous investigators access the patients, biosamples and data collect through the program for their own research. In the next grant cycle, we will support research in a newly funded pilot project the Michigan Pediatric Comprehensive Weight Management Center. Through the next funding period, the MNORC will continue to communicate with the research base to identify new areas for support and adjust the service offerings consistent with the needs of the community.
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0.946 |
2019 — 2021 |
Seeley, Randy J. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Gut-Brain Axis in Metabolic Disease @ University of Michigan At Ann Arbor
Project Summary/Abstract A wide range of evidence points to the critical role that signals from the gut, acting in the CNS, play in the regulation of food intake, body weight and the disposition of metabolic fuels including glucose. Some of the most powerful evidence for the critical nature of this ?gut-brain? axis comes from direct manipulations of the GI tract that occur during various bariatric surgical procedures. These procedures are often thought of as ?restrictive? or ?malabsorptive?, however, it is clear that the potent effects of these procedures to reduce body weight and glucose levels are the product of altering the activity of the gut-brain axis. The important point is that manipulation of the gut via these surgical interventions provides the largest and most sustained weight loss in individuals with obesity compared to any other therapeutic option. Thus a better understanding of the gut-brain axis is crucial for the development of new, less invasive and more scalable solutions to treat obesity. While the importance of the gut-brain axis is clear, our understanding of how this axis works remains incomplete. This program project grant will bring together a range of experiences and technical approaches under a single coordinated project that will allow for rapid understanding of the impact of gut, neural and hormonal signals on their crucial targets within brainstem neural circuitry. To that end, the current projects will utilize advanced neuroanatomical tracing, electrophysiology, activation and silencing of circuits, next generation sequencing and apply all of these methods exclusively in molecularly defined cell-types using a broad range of mouse models we have developed. These approaches will be combined with a range of behavioral and physiological measures of food intake, energy expenditure and GI function. Finally, we will bring to bear advanced surgical approaches that allow for assessment of the impact of bariatric surgery in these mouse models. The ultimate goal of this project is to identify key aspects of how the GI tract impacts these neuronal circuits, the identification of key neuronal populations that are the target of those GI signals and how each population can influence food intake, body weight and regulate GI function. The guiding hypothesis is that the signals generated and the neural circuit engaged by toxins and those by normal presentation of nutrients to the GI tract will be distinct in several key regions of the brainstem. The detailed understanding of these parallel circuits will allow for a better understanding of existing therapies that target the brainstem and the development of entirely new therapeutic strategies that appropriately engage this circuitry in a manner that is similar to what happens after bariatric surgery.
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0.946 |
2019 — 2021 |
Seeley, Randy J. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Gut-Brain Axis in Metabolic Disease - Administrative Core @ University of Michigan At Ann Arbor
Administrative Core (Seeley) Dr. Seeley will be responsible for all aspects of the Program Project. Day-to-day administration will be handled by Dr. Seeley with the assistance of the Administrative Coordinator, and the two will oversee all activities of all of the projects and cores. Dr. Seeley will also call meetings of the Executive Committee and External Scientific Advisory Committee, and he will be responsible for all progress reports and annual submission of requests for further funding. Other key goals of the administrative core will be to provide infrastructure for data and biological sample aggregation. This will include cloud storage of all data and building of searchable databases. The administrative core will also organize biological sample storage and organization so that all samples can be made available to any of the projects as needed. Finally, the administrative core will coordinate the use of the various mouse models. For some experiments, mouse models can be shared across projects and the transfer of these mice will be handled by the administrative core to both facilitate efficient use of the mice and ensure their use is consistent with the priorities of the overall program project. The administrative core will also convene monthly meetings of the executive committee as well as annual meetings of an external scientific advisory board.
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0.946 |
2019 — 2021 |
Seeley, Randy J. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Gdf15 and Its Receptor in the Cns Regulation of Food Intake and Body Weight @ University of Michigan At Ann Arbor
Project Summary/Abstract Obesity remains one of the largest unmet medical needs facing the US healthcare system. More than one in three adults in the US are obese and these rates continue to increase with the most severe category of obesity unfortunately growing the fastest. It is hard to overstate the human and monetary costs to the individuals impacted and society as a whole. It remains that very few of these individuals receive effective therapies. The existing behavioral interventions have limited efficacy. While the approved pharmacological therapies are more successful, none of the currently approved therapies produce even 10% sustained body weight loss on a placebo-adjusted basis. Consequently, there is still an enormous need for additional pharmacological treatments for individuals with obesity. Growth differentiation factor 15 is a member of the TGF? superfamily that has been linked to the anorexia and weight loss that occurs with some cancers. This launched a number of programs to harness GDF15 analogues as obesity therapeutics and to identify the receptor that mediates these effects. Such efforts culminated in a series of 4 high-profile papers published in late 2017 that each identified GDNF family receptor ?-like (GFRAL) as a high affinity receptor for GDF15 and is absolutely required for the potent effects of GDF15 to reduce food intake and body weight. Interestingly, GFRAL is almost exclusively expressed in the CNS. Moreover, its distribution in the CNS is almost entirely limited to a brainstem area termed the area postrema which sits outside the blood-brain barrier. Given the powerful weight loss effects of GDF15 mediated by this small population of neurons, it points to a very important role of these neurons to regulate food intake and energy balance. We have built state-of-the-art mouse models that will allow us to selectively identify, track and manipulate these neurons. To that end, we will identify the projections from these neurons both within the caudal portion of the brainstem and to hypothalamic areas that have been linked to the regulation of body weight. We will also use these tools to selectively activate or silence these neurons and assess their role in normal control of energy balance and to mediate the effects of other weight loss manipulations. This work has enormous significance and novelty. GDF15 is one of the most promising new treatment strategies for obese individuals. Maybe even more importantly, the potent effects of GDF15 point to a novel CNS circuit engaged from a very small population of neurons located in the area postrema. Establishing components of this circuit and key aspects of GDF15 biology will maximize the potential utility of GDF15 as a therapeutic and identify new targets that target key components of this system.
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0.946 |