2007 — 2008 |
Xu, Allison W. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Neurogenesis as a Compensatory Mechanism to Regulate Energy Balance @ University of California San Francisco
[unreadable] DESCRIPTION (provided by applicant): Compensatory regulation of body weight in response to physiologic insult ensures proper maintenance of energy homeostasis, but these compensatory mechanisms are largely uncharacterized. We previously generated transgenic mice in which Agouti- related protein (Agrp) neurons were progressively degenerated. These mice exhibited a mild feeding and weight phenotype compared with mice in which Agrp neurons are acutely ablated. We have obtained preliminary data to show that neurogenesis is increased specifically in the hypothalamus of adult mutant mice and that some of the proliferating cells take on Agrp neuronal cell fate. In this proposal, we will evaluate whether de novo neurogenesis serves as a functional compensatory mechanism to regulate energy homeostasis. We will investigate whether orexigenic Agrp neurons are preferentially generated relative to anorexigenic cell types in the mutant hypothalamus. Further, we will examine whether the newly generated cells are capable of responding to leptin by activating signal transducer and activator of transcription 3 (Stat3). Finally, to determine whether de novo neurogenesis serves as a functional compensatory mechanism, we will block cell proliferation in the hypothalamus of the control and mutant mice and observe whether anorexia and body weight loss are induced only in the mutant mice. The proposed studies will provide direct evidence that neurogenesis may serve as a novel compensatory mechanism to regulate energy balance and ameliorate the effects of physiological insult during development and adulthood. (Lay language relevance of this research to public health): Obesity prevalence has increased dramatically in the United States, and is a major risk factor for type 2 diabetes, cardiovascular diseases, and other health problems. Research outlined in this proposal will help better understand how body weight is normally regulated, and how obesity develops. The identification of neuronal substrates critical for body weight regulation will lay the groundwork for future therapeutic interventions designed to target these specific neurons. [unreadable] [unreadable] [unreadable]
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0.936 |
2008 — 2011 |
Xu, Allison W. |
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. |
Hypothalamic Pi3k Signaling in Regulation of Energy Balance &Glucose Homeostasis @ University of California, San Francisco
DESCRIPTION (provided by applicant): Leptin and insulin regulate energy balance by conveying the abundance of peripheral energy stores to the brain. In addition, leptin and insulin also act in the hypothalamus to regulate systemic insulin sensitivity and glucose homeostasis, and this function of leptin and insulin appears to be independent of their effects on feeding and adiposity. Our long-term objective is to understand the signaling mechanisms by which leptin and insulin regulate various physiologic processes. We have previously demonstrated that leptin and insulin directly stimulate PI3K signaling in key leptin and insulin target neurons in the hypothalamus. While PI3K signaling is important for insulin's metabolic effects, recent pharmacological studies indicate that the PI3K signaling pathway plays an important role in mediating leptin's effect on glucose homeostasis. To date, genetic evidence is still lacking to establish the functional requirement of hypothalamic PI3K signaling in energy balance and glucose homeostasis in vivo. Moreover, neuronal subgroups important for this regulation have not been identified. In this proposal, we will test the hypothesis that PI3K in leptin responsive neurons is required for proper maintenance of energy balance and glucose homeostasis. We will determine whether chronic or acute PI3K knockdown in specific leptin responsive neurons leads to altered energy balance, increased systemic insulin resistance and impaired glucose homeostasis. We will also evaluate the function of PI3K and Jak-Stat3 signaling in Pomc and Agrp neurons, two key leptin and insulin target neurons in the hypothalamus. The proposed study will elucidate the functional necessity of PI3K in mediating energy balance and glucose homeostasis, and will identify the neuronal subgroups that are important for this process. It will advance our understanding of the signaling mechanisms by which leptin and insulin regulate energy balance and glucose homeostasis, and provide insight into the etiology of obesity and type 2 diabetes.
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0.936 |
2010 — 2014 |
Xu, Allison W. |
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. |
Compensatory Regulation of Energy Balance by Neurogenesis in Adult Hypothalamus @ University of California, San Francisco
DESCRIPTION (provided by applicant): Maintenance of energy balance in an ever-changing environment requires the brain to cope with a variety of genetic and physiologic insults. Compensatory regulation of energy balance is frequently observed but its underlying mechanisms remain largely unknown. We have recently shown that hypothalamic neurons important for energy balance regulation can be regenerated in adult hypothalamus in response to progressive degeneration of orexigenic AgRP/NPY neurons, and that inhibition of cell proliferation in the mutant brain affects feeding and adiposity. Our results suggest that regulation of cell proliferation in the adult hypothalamus could serve as a compensatory mechanism to maintain hypothalamic feeding functions. To date, the functional role of adult neurogenesis in energy balance regulation remains largely unexplored. Hypothalamus is generally considered non-neurogenic in the adulthood although abundant neural progenitor cells are present. However, neurodegeneration has been shown to be a potent stimulus of neurogenesis in normally non-neurgenic regions of the brain in both rodents and humans. In this proposal, we will test the hypothesis that modulation of cell proliferation in the adult hypothalamus serves as a repair mechanism to limit the extent of energy imbalance under pathophysiologic conditions. Specifically, we will examine the spatiotemporal activation of neural progenitor cells in the adult hypothalamus in response to degeneration of specific hypothalamic neurons. We will determine whether adult born hypothalamic neurons can respond appropriately to alteration of energy balance status and peripheral metabolic hormones. We will examine survival and projection outgrowth of these adult born neurons and their synaptic connectivity. In addition, we will evaluate hypothalamic neurogenic activity during chronic obesity and diabetes, conditions that are associated with decreased brain volume and neuronal cell death in rodents and humans. By using a temporally inducible and cell type specific cell ablation approach, we will determine the functional significance of adult neural progenitors in compensatory regulation of energy balance under normal, obese and diabetes conditions. Finally, We will investigate neurogenic activity of transplanted neural progenitor cells in adult hypothalamus, and explore therapeutic potential of neural progenitor cell transplantation in treatment of obesity caused by neurodegeneration of hypothalamic neurons. Together, our study will provide critical information on the role of neurogenesis in compensatory regulation of energy balance. It will provide novel insight into therapeutic potential of neural stem cells in treatment of hypothalamic neurodegeneration that are associated with a variety of chronic diseases and brain injuries. PUBLIC HEALTH RELEVANCE: In this proposal, we will test the hypothesis that modulation of cell proliferation in the adult hypothalamus serves as a repair mechanism to limit the extent of energy imbalance under pathophysiologic conditions such as chronic obesity and diabetes. Our study will determine functional connections between neurodegeneration, neurogenesis and body weight regulation. It will provide novel insight into therapeutic potential of neural stem cells in treatment of hypothalamic neurodegeneration that are associated with a variety of chronic diseases and brain injuries.
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0.936 |
2010 |
Xu, Allison W. |
S10Activity Code Description: To make available to institutions with a high concentration of NIH extramural research awards, research instruments which will be used on a shared basis. |
Ucsf Comprehensive Lab Animal Monitoring System @ University of California, San Francisco
DESCRIPTION (provided by applicant): This shared equipment grant is for a 12-chamber Comprehensive Lab Animal Monitoring System (CLAMS) that enables efficient and precise measurements of feeding, basal metabolism, motor activities, and thermoregulation in mice. The accurate measurements of these parameters are essential for elucidating the mechanisms underlying obesity and metabolic diseases. Currently, no comparable equipment is accessible to an increasing number of UCSF investigators who are conducting research on obesity and metabolic syndromes. The inability to measure key metabolic parameters in research animals by conventional methods has impeded research progress in this field. In this application, a group of UCSF investigators have described their NIH-supported research projects that would significantly benefit from the acquisition of a CLAMS system. The CLAMS system, if funded, will be integrated into the UCSF Metabolic Core, which will be managed and maintained by designated personnel at the UCSF Diabetes Center. Detailed management plan has been formulated to ensure cost-effective operation of the instrument. With prevalence of obesity, type 2 diabetes and metabolic diseases on the rise, the installation of the proposed instrument would dramatically increase the capacity of existing research efforts, and will attract an even larger number of investigators to study obesity and metabolic disorders.
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0.936 |
2012 |
Xu, Allison W. |
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. |
Hypothalamic Pi3k Signaling in Regulation of Energy Balance & Glucose Homeostasis @ University of California, San Francisco
Leptin and insulin regulate energy balance by conveying the abundance of peripheral energy stores to the brain. In addition, leptin and insulin also act in the hypothalamus to regulate systemic insulin sensitivity and glucose homeostasis, and this function of leptin and insulin appears to be independent of their effects on feeding and adiposity. Our long-term objective is to understand the signaling mechanisms by which leptin and insulin regulate various physiologic processes. We have previously demonstrated that leptin and insulin directly stimulate PI3K signaling in key leptin and insulin target neurons in the hypothalamus. While PI3K signaling is important for insulin¿s metabolic effects, recent pharmacological studies indicate that the PI3K signaling pathway plays an important role in mediating leptin¿s effect on glucose homeostasis. To date, genetic evidence is still lacking to establish the functional requirement of hypothalamic PI3K signaling in energy balance and glucose homeostasis in vivo. Moreover, neuronal subgroups important for this regulation have not been identified. In this proposal, we will test the hypothesis that PI3K in leptin responsive neurons is required for proper maintenance of energy balance and glucose homeostasis. We will determine whether chronic or acute PI3K knockdown in specific leptin responsive neurons leads to altered energy balance, increased systemic insulin resistance and impaired glucose homeostasis. We will also evaluate the function of PI3K and Jak-Stat3 signaling in Pomc and Agrp neurons, two key leptin and insulin target neurons in the hypothalamus. The proposed study will elucidate the functional necessity of PI3K in mediating energy balance and glucose homeostasis, and will identify the neuronal subgroups that are important for this process. It will advance our understanding of the signaling mechanisms by which leptin and insulin regulate energy balance and glucose homeostasis, and provide insight into the etiology of obesity and type 2 diabetes.
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0.936 |
2013 — 2016 |
Xu, Allison W. |
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. |
Central Regulation of Hepatic Energy Stores @ University of California, San Francisco
DESCRIPTION (provided by applicant): Leptin is an adipocyte-derived hormone that circulates at levels proportional to the body's fat mass, which conveys the abundance of peripheral energy stores to the brain. We have previously shown that leptin acts centrally to suppress hepatic lipid content via activation of the sympathetic nervous system; we have further shown that central leptin resistance in the PI3K signaling pathway leads to decreased hepatic sympathetic tone and increased triglyceride levels without hyperphagia and weight gain. These results indicate that central cellular leptin resistance manifests as hepatic steatosis independent of obesity. Interestingly, like obesity, starvation also induces severe hepatic steatosis. This is generally thought to be caused by the increased delivery of free fatty acids to the liver due to th mobilization of the white adipose tissue. In this proposal, we will test the hypothesis that the decline of leptin levels during starvation is required for the development of hepatic steatosis. We will evaluate whether the increase of hepatic lipid stores in starvation serves to ensure sustained energy production from the liver to meet the energy demands of extra-hepatic tissues. We further propose that Agouti-related protein (AGRP) is a downstream effector of leptin's action on hepatic lipid metabolism in starvation, and we will define the neuronal circuitry underlying AGRP's effects. Finally, we will explore whether antagonism of AGRP in wildtype animals would alleviate hepatic steatosis in diet-induced obesity. This study, if successful, will establish that starvation-induced liver steatosis is not just a passive process caused by increased free fatty acid flux to the liver, as commonly thought, but rather an integral component of the overall adaptive regulation by leptin to ensure energy availability during long period of food deprivation. This mechanism may also operate in diet-induced obesity in that impairment of leptin signaling due to leptin resistance is perceived by the brain as a state of negative energy balance, triggering similar adaptive responses as in starvation and contributing to non-alcoholic fatty liver diseases.
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0.936 |
2014 — 2018 |
Xu, Allison W. |
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. |
A Brain-Liver Circuit in Regulation of Alcoholic Liver Disease @ University of California, San Francisco
DESCRIPTION (provided by applicant): Liver disease is one of the leading causes of illness and death in the United States. Excessive alcohol consumption is a major risk factor for liver damage, and more than 2 million Americans suffer from liver disease caused by alcohol. Although hepatic steatosis is a prevalent phenotype among heavy alcohol drinkers, the mechanisms underlying its development are not well understood. It is currently thought that alcohol acts directly on the liver to alter lipid metabolism leading to development of hepatic steatosis. Our lab has recently delineated a novel brain-liver circuit in regulation of non-alcoholc fatty liver under physiologic conditions such as starvation and obesity. We show that hypothalamic neuropeptide Agouti-related protein (AGRP) acts in the brain to suppress hepatic sympathetic activity and to stimulate lipid synthesis. AGRP is required for the development of hepatic steatosis that occurs in starvation and obesity. Intriguingly, ethanol administration stimulates Agrp expression in the mouse hypothalamus, and AGRP-deficient mice are resistant to development of ethanol-induced hepatic steatosis without alteration of feeding and body weight. The goal of this proposal is to test the hypothesis that ethanol induces hepatic steatosis, at least in part, by stimulation of hypothalamic Agrp expression, resulting in alteration of hepati sympathetic activity and development of hepatic steatosis. Signaling mechanisms underlying alcohol's effects on Agrp expression and hepatic steatosis will be determined. We will further investigate the importance of modulating hepatic sympathetic activity in ethanol-induced hepatic steatosis. Finally, we will evaluate the therapeutic potentials of RNA-interference against Agrp in alleviating liver injury induced by chronic plus binge alcohol consumption. Taken together, experiments outlined in this proposal will define a new mechanism that underlies the etiology of ethanol- induced hepatic steatosis and will explore a novel strategy to treat alcoholic liver diseases.
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0.936 |
2015 — 2021 |
Xu, Allison W. |
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. |
Core B: Mouse Metabolism and Imaging @ University of California, San Francisco
Project Summary/Abstract: Biomedical Core B-Mouse Metabolism and Imaging The study of obesity, nutrition, and metabolism relies on methods to measure feeding patterns, metabolic rate, activity, body content, and fat distribution in humans (Core A: Human Metabolism) and model organisms (Core B: Mouse Metabolism and Imaging Core). The study of these parameters within model organisms enables the researcher to rigorously control both the test subjects' genetics (Core C: Genetics) and environments (Core B) to better test hypotheses about the factors that control energy homeostasis. 21 of the 44 investigators in the proposed UCSF-NORC currently conduct research studies in which these types of parameters must be monitored in rodent models; another 6 NORC investigators indicate that their research has developed to a point where their use of facilities in the Mouse Metabolism and Imaging Core is imminent. These studies are conducted primarily in two facilities operated by different departments. The UCSF-NORC will coordinate and focus those facilities towards the provision of exceptional quality research services in technologically challenging areas of high need to the NORC membership. Experts within the Core will be able to keep abreast of the rapidly evolving application of these sophisticated methods and ensure that NORC researchers are trained in their proper implementation. The presence of the facilities, and the availability of NORC support that is designed to assist the entry of NORC researchers into technologically unfamiliar areas, will ensure the success of UCSF-NORC research. The NORC Mouse Metabolism and Imaging Core will provide access to, assistance with and training in the use of sophisticated methods and instruments for those studies. The Core will provide tools and facilities for: 1. Precisely measuring feeding, basal metabolism, motor activities, and thermoregulation in mice. 2. Analyzing lean mass, fat mass, free body fluids, and total body water in intact mice. 3. Visualizing and quantitatively measuring anatomical structures relevant to obesity, nutrition and metabolism with highly advanced radiologic imaging. 4. Imaging the fat and water content, or other functional measurement involving radiologic tracers, within those anatomical structures. Core B facilities will enable non-invasive methods that permit mice to be followed over time. The ability to conduct longitudinal studies is particularly significant for tracking the changes in body composition, feeding behavior, and metabolic activity during the development of obesity and its associated complications. Overall, this Core will lower methodologic barriers to help NORC researchers achieve the efficient and proper application of a series of highly sophisticated tools. These capabilities will accelerate a variety of diverse and interrelated studies in of obesity, nutrition, food intake, and metabolism.
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0.936 |
2019 — 2021 |
Xu, Allison W |
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. |
Blood-Hypothalamus Barrier and Metabolic Impairment in Advanced Aging @ University of California, San Francisco
Project Summary/Abstract The world population is aging. Despite our advances in extending lifespan, there is tremendous individuality in age-related morbidity and mortality. It is recognized that the breakdown of the blood-brain barrier (BBB) in hippocampus marks an early event of cognitive impairment in aging. However, how aging affects BBB in the hypothalamus, and its ensuring metabolic consequences is not well understood. The goal of this study is to test whether the age-related decline of tanycyte number contributes to the weakening of the BBB in the hypothalamus and its impact on metabolic impairment and mortality. We will determine if proliferative capacity of tanycytes decreases with age, leading to age-dependent loss of tanycytes. We will explore if inadequate tanycyte proliferation leads to weakened BBB in the mediobasal hypothalamus and its consequences. We will evaluate if aging of the AgRP neurons outside the BBB marks the decline of AgRP neuronal function and metabolic derailment in advanced aging. Lifespan is influenced by both genetic and environmental factors. Given the essential roles of the AgRP neurons in metabolic control and their unique anatomical localization outside the BBB, information obtained from this study will establish the importance of the hypothalamic BBB in metabolic control and longevity in advanced aging.
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0.936 |