Kevin Grove - US grants

Obesity is now considered a worldwide health concern, being a major contributor to the increased incidences of coronary heart disease and type II diabetes. By 1998, 18% of the adults in the United states were defined as being obese, with greater than twice that number categorized as overweight. Furthermore, the number of obese adults in the United States is increasing at a rate of 0.7% per year. Even more disturbing is the dramatic increase in obesity and type II diabetes among children. The central hypothesis of this proposal is that body weight management during adulthood is directly determined by the hypothalamic feeding circuits established during a "critical period" postnatal development. Furthermore, if exposure to perturbations in energy balance occurs during this "critical period" of neural plasticity, permanent alterations in body weight management may occur and lead to abnormal body weight phenotypes during adulthood. One of the most potent modulators of appetite and energy expenditure in the hypothalamus is neuropeptide Y (NPY). There are dynamic changes in the hypothalamic NPY system during postnatal development that implicate this system as being pivotal for the proper maturation of hypothalamic feeding circuitry. This proposal will study the postnatal period to 1) Determine the functional importance of the development of ARH projections. 2) Determine if NPY plays a role in the regulation of body weight management during early postnatal development. 3) Determine if changes in the endogenous NPY system are responsible for the obese phenotype induced by chronic overfeeding during the postnatal period. The main goal of this proposal is to use a multidisciplinary approach to determine if modification of the endogenous NPY system during postnatal development leads to abnormal body weight management during adulthood. To identify the role of the endogenous NPY system in the regulation of food intake and energy expenditure during the postnatal period we will use a combination of in vivo (changes in food intake and adiposity in whole animals) and in vitro (peptide release and electrophysiology in hypothalamic explants) physiological and pharmacological experiments, coupled with neuroanatomical measures (immunocytochemistry and in situ hybridization). The changes in the hypothalamic NPY system in these models will be correlated with changes in peripheral markers of energy expenditure and body weight status, using RIA and real-time PCR. These studies will provide important insight into the consequences of manipulation of the NPY feeding circuits, during the postnatal period on metabolic rate and body weight during childhood. Understanding of the normal and abnormal development of this circuitry is critical to determining the physiological mechanisms that underlie adult obesity and identify a critical period for possible intervention.

Abstract Not Provided

Abstract not provided.

The past several decades have revealed a devasting trend- the dramatic increase in preventable diseases in children, including obesity, diabetes, cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). The general hypothesis of this proposal is that diet and metabolic health (such as obesity and diabetes) during pregnancy and the early neonatal period significantly contribute to the development of metabolic diseases in children, predisposing them to widespread health risks throughout life. We have developed a nonhuman primate (NHP) model of high fat/calorie diet-induced maternal obesity/diabetes in which to determine the immediate and long-term effects on body weight homeostasis in offspring. The specific focus of this proposal is the melanocortin neurons in the hypothalamus, which are critical for the homoeostatic feedback control of food intake and energy balance in response to peripheral adiposity signals. We predict that consumption of a high fat/calorie diet during pregnancy, resulting in maternal hyperlipidemia and insulin resistance, will cause an abnormal development of these neurons during in the fetal period, leading to a long-term reprogramming. We also predict that this phenotype will be exacerbated by exposure to the same diet during the postnatal period. With these developmental abnormalities, we expect the offspring to be predisposed to early onset obesity and ultimately diabetes These studies will use a variety of in vivo and in vitro physiolgical assays, combined with anatomical and biochemical assays to determine the effects of maternal high fat diet induced obesity/diabetes on the development of hypothalamic melanocortin system in the offspring during the late fetal and juvenile stages. Finally, we will investigate if feeding a healthy diet to obese/diabetic NHPs specifically during pregnancy can protect against the development of metabolic abnormalties in the offspring. With these studes, we hope to demonstrate that simply being overweight and eating a high fat diet causes metabolic disease in babies; a maternal phenotype that matches the majority of pregnancies in the United States. Furthermore, that eating a healthy diet specifically during pregnancy, even in obese/diabetic animals, can protect against the development of these diseases. This information will be critical for designing a viable prevention and has enormous public health implications

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cardiovascular complications account for the vast majority of the mortality and morbidity associated with diabetes (DM). These complications can be broadly categorized as macrovascular and microvascular. Microvascular complications of DM often have devastating effects on the quality of life and survival for patients with diabetes. It is now well recognized that many of microvascular complications are directly related to the degree of hyperglycemia and insulin resistance. However, our understanding of the pathogenesis and appropriate treatment of these disorders is rudimentary. Early detection of microvascular abnormalities will be useful for identifying patients with DM, insulin resistance, or obesity who are at high risk for developing major end-organ complications and who could benefit from therapeutic intervention. A method for routinely assessing microvascular flow reserve could also be useful for early identification of patients with peripheral vascular disease who are candidates for revascularization or other treatments, similar to protocols that are currently employed for the detection of coronary artery disease. Despite the great clinical need, a reliable, non-invasive method capable of assessing perfusion of peripheral tissues at the microvascular or capillary level in patients is currently not available. The overall aim of this proposal is to characterize the microvascular complications are associated with diet induced obesity/insulin resistance in the nonhuman primate (NHP) and that these abnormal responses can be assessed by contrast-enhanced ultrasound (CEU). These studies are using a combination of noninvasive techniques to characterize the level of cardiovascular disease in rhesus macaques chronically consuming a high fat diet.

Adipose tissue; Animals; CRISP; Computer Retrieval of Information on Scientific Projects Database; Diet; Differential Gene Expression; Estrogenic Agents; Estrogenic Compounds; Estrogens; Expression Profiling; Expression Signature; Fats; Fatty Tissue; Fatty acid glycerol esters; Female; Funding; Gene Expression; Gonadal Hormones; Gonadal Steroid Hormones; Grant; Institution; Insulin Resistance; Investigators; Link; Mammals, Mice; Messenger RNA; Metabolic Diseases; Metabolic Disorder; Mice; Microarray Analysis; Microarray-Based Analysis; Molecular Fingerprinting; Molecular Profiling; Murine; Mus; NIH; National Institutes of Health; National Institutes of Health (U.S.); Obesity; PCR; Polymerase Chain Reaction; Proestrus; RNA, Messenger; Regulation; Research; Research Personnel; Research Resources; Researchers; Resources; Risk Factors; Sex Characteristics; Sex Differences; Sex Hormones; Sex Steroid Hormones; Source; Therapeutic Estrogen; Thesaurismosis; Time; Tissue-Specific Differential Gene Expression; Tissue-Specific Gene Expression; United States National Institutes of Health; Visceral; Week; adipose; adiposity; cardiovascular disease risk; cardiovascular disorder risk; cardiovascular risk; cardiovascular risk factor; corpulence; corpulency; corpulentia; gender difference; gonadal steroids; insight; insulin resistant; mRNA; male; men; men's; metabolism disorder; microarray technology; molecuar profile; molecular signature; obese; obese people; obese person; obese population; sex steroid; sexual dimorphism (noncellular); subcutaneous; white adipose tissue; yellow adipose tissue

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall purpose of this project is to determine the effect of maternal high fat/calorie diet and metabolic health on the developmental programming of metabolic systems in the liver and muscle. These studies are focusing on the reprogramming of the insulin signaling, lipogenesis/lipolysis, and gluconeogenesis pathways. Our role in these studies is primarily supportive through assistance with the animal management and obtaining samples.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Evidence indicates that an abnormal maternal metabolic status, such as diabetes, exerts deleterious effects on the cardiovascular system of the fetus that may last for a lifetime. Arthrosclerosis is the process responsible for most cardiovascular disease. Recently it was reported that children born to obese mothers had a high risk of early development of fatty streaks in major vessels (an early sign of arthrosclerosis);however, it is unknown what maternal factors may be contributing to the early signs of cardiovascular disease in these children. Maternal obesity, diabetes, fat intake, hypercholesterolemia and hyperlipidemia are some factors that could play a critical pathophysiological role in the development of arthrosclerosis in children. We have developed a nonhuman primate model maternal diet induced obesity/diabetes, where monkeys are maintained on a high fat diet (HFD) for 2-4 years. These animals develop the full compliment of metabolic disease as humans and are thus an excellent model to begin to investigate the contributing factors to early onset cardiovascular disease. The purpose of this project is to begin to determine if there are signs of cardiovascular complications in fetal and neonatal offspring of HFD animals. Furthermore, these studies will provide the preliminary data to develop a hypothesis about what maternal factors may be contributing to the cardiovascular disease in the offspring.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Over the past several decades there has been a dramatic increase in childhood obesity. The general hypothesis of this proposal is that diet and metabolic health during pregnancy and the early neonatal period significantly contribute to the development of metabolic diseases in children. For these studies we developed a nonhuman primate (NHP) model of high fat/calorie diet-induced maternal obesity/diabetes that is allowing us to determine the immediate and long-term effects on body weight homeostasis in offspring. The specific focus of this proposal is the melanocortin neurons in the hypothalamus, which are critical for the homoeostatic feedback control of food intake and energy balance in response to peripheral adiposity signals. We predicted that consumption of a high fat/calorie diet during pregnancy and during nursing will cause an abnormal development of these neurons during in the fetal period, leading to a long-term reprogramming. With these developmental abnormalities, we expect the offspring to be predisposed to early onset obesity and ultimately diabetes. Finally, we will determine if feeding a healthy diet to obese/diabetic NHPs specifically during pregnancy is protective against the development of metabolic abnormalities in the offspring. With these studies, we hope to demonstrate that simply being overweight and eating a high fat diet causes metabolic disease in babies;a maternal phenotype that matches the majority of pregnancies in the United States. This information will be critical for designing a viable prevention and has enormous public health implications.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. According to the Barker's Fetal Origins of Adult Disease Hypothesis, perturbations in the gestational milieu influence the development of adult diseases. This occurs through the reprogramming of gene expression via epigenetic changes in chromatin structure. It is clear from studies done in rodents that numerous maternal manipulations can cause epigenetic modifications in the developing fetus that results in long-term modification of body weight homeostasis. Surprisingly, there has been a lack of study of whether modification of maternal dietary fat can cause similar epigenetic modifications in the fetal offspring. Furthermore, there has been no evidence of whether epigenetic modifications occur in primate species. The general hypothesis of this proposal is that diet and metabolic health during pregnancy and the early neonatal period significantly contribute to the development of metabolic diseases in children. This proposal focuses upon the effects of a maternal high fat diet upon the fetal and postnatal epigenetic characteristics of circadian genes in the liver and hypothalamus of the NHP. For these studies liver and hypothalamic are obtained samples from offspring of animals maintained either on a control diet or a high fat diet. Changes in chromatin structure, histone modifications (histone acetylation/methylation) as well as changes in expression of genes that are epigenetically modified will be characterized. A special focus of these studies is to characterize changes in circadian regulation of energy homeostasis. These studies will provide critical insight into the underlying mechanism by which maternal nutritional manipulations can cause long-term risks of metabolic diseases in offspring.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity is one of the major health challenges facing the developed world, significantly increasing the risk of coronary disease, and of diabetes. It has recently been shown that for every "point" by which a person's body mass index (BMI) exceeds 25, there is an associated increase in the risk of cardiac disease. An estimated 9.4% of US healthcare expenditure is directly related to "obesity and inactivity", while recent costs due to diabetes were estimated at $98 billion per annum. There has become intense interest by pharmaceutical companies to develop a therapeutic intervention that will inhibit food intake and cause controlled and safe weight loss. The melanocortin neurons in the brain produce a neuropeptide that potently inhibits food intake, stimulates energy expenditure and regulates peripheral glucose homeostasis. The importance of the melanocortin system is clearly evident in rodents to humans, whereby mutations or genetic deletion of melanocortin genes cause early onset morbid obesity. In fact mutations of the melanocortin system are the most common monogenic cause of obesity in humans. The overall aim of this study is to determine if treatment with a melanocortin agonist can improve body adiposity and glucose homeostasis in a rhesus macaque model of diet induced obesity. The specific goals of this study are to 1) identify an effective dose of melanocortin agonist for the inhibition of food intake, and 2) determine if long-term treatment with a melanocortin agonist can reduce food intake, body adiposity, and improve insulin sensitivity.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cardiovascular complications account for the vast majority of the mortality and morbidity associated with diabetes (DM). These complications can be broadly categorized as macrovascular and microvascular. Microvascular complications of DM often have devastating effects on the quality of life and survival for patients with diabetes. It is now well recognized that many of microvascular complications are directly related to the degree of hyperglycemia and insulin resistance. However, our understanding of the pathogenesis and appropriate treatment of these disorders is rudimentary. Accumulation and oxidation of LDL in blood vessel walls are thought to be important factors in the process of atherosclerotic plaque formation. Upon scavenging and internalizing the oxidized LDL molecules, macrophages are activated and express pro-inflammatory molecules. The inflammatory state contributes to plaque instability and has been associated with increased risk of cardiovascular events. Presence of autoantibodies to neoepitopes on aldehyde-modified LDL have been associated with modulation of the development of atherosclerosis in rabbits and humans. MLDL1278a is a full length human IgG1 antibody which binds with high affinity to the malondialdehyde-oxidized apo-B 100 protein portion of the LDL molecule. The presence of the MLDL1278A prevents activation of macrophages upon uptake of the antigen-antibody complex in vitro, and attenuates plaque progression and induces plaque regression in a mouse model of atherosclerosis, thereby reducing the effects of inflammation on plaque development and cardiovascular events. The purpose of this study was to investigate changes in serum markers of inflammation, metabolism, and pro-coagulant activity during and following treatment with anti-oxidized LDL antibody MLDL1278A.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There is increasing evidence that abnormal maternal metabolic status exerts deleterious effects on the cardiovascular system of the fetus that may last for a lifetime. Gestational diabetes, for example, may lead to an altered maternal metabolic state characterized by abnormal plasma nutrient concentrations, increased cytokine levels and pro-oxidant profile. Abnormal placental structure and function and abnormal metabolic function of the placenta then follow. Thus the state of the mother becomes a metabolic stress to the fetus. We have discovered that pregnant female monkeys acquire gestational insulin resistance if they chronically consume a diet high in saturated fats for several years. The combination of poor maternal metabolic health and diet contribute to a broad range of health risks in the offspring. The purpose of these studies is to use the NHP model to investigate the effects maternal health and diet on the development of the cardiovascular system in the offspring. These studies will characterize: 1) pathological changes in the placenta and cardiovascular systems, 2) the cardiovascular function of the offspring at several developmental stages, and 3) microvascular function in juvenile offspring. These studies will help determine the future risk of cardiovascular disease for offspring of animals consuming a high fat diet.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity is one of the major health risk facing the developed world, significantly increasing the risk of coronary disease, and of diabetes. It has recently been shown that for every "point" by which a person's body mass index (BMI) exceeds 25, there is an associated increase (5% in men and 7% in women) in the risk of cardiac disease. Beyond the terrible human costs there are significant economic costs associated with health care for such an obese population. An estimated 9.4% of US healthcare expenditure is directly related to "obesity and inactivity", while recent costs due to diabetes were estimated at $98 billion per annum. There are two main aims of this study: Phase 1 will determine the efficacy of peripheral melanocortin agonist treatment on food intake in rhesus macaques. These are exploratory studies to optimize dose given s.c. Phase 2 will determine if chronic eripheral melanocortin agonist treatment can reduce body weight and adiposity in diet-induced obese (DIO) monkeys. This study will also determine if changes in body weight are do to chronic changes in caloric intake and/or increased energy expenditure. Finally, these studies will determine if this chronic melanocortin treatment improves glucose homeostasis and cardiovascular function. These are extensive studies that will generate critical insight into the potential of melanocortin agonist as a therapy for human obesity and diabetes.

The incidence of preventable metabolic diseases in children has increased markedly over the past 2 decades. Currently, there is little information to determine the underlying causes or whether therapeutic or dietary interventions might be successful at preventing or reducing metabolic health risks in children from obese pregnancy. These studies will use a nonhuman primate (NHP) model to investigate the impact of poor maternal metabolic health and diet on the development of metabolic systems in the developing fetus, as well as its postpartum growth, development, and susceptibility to diet induced obesity and diabetes. For these studies, breeding NHPs will be chronically maintained on a diet high in fats and calories (HFD). The NHP is a critical model as it shares developmental features similar to human fetuses, including placental function, brain, and pancreas development. This proposal will focus on the placenta, pancreas, liver and muscle as these form the core metabolic systems that are critical for normal regulation of body weight and glucose homeostasis. The hypothesis is that abnormalities beginning with placental dysfunction (i.e., blood flow, cytokine production and nutrient delivery) directly impact the development of all metabolic systems in the offspring that contribute to life-long risk for metabolic disease. Furthermore, it is hypothesized that supplementation with agents that reduce oxidative stress and inflammation will prevent or attenuate the structural, metabolic, and molecular disturbances observed during pregnancy while on a HFD, and will prevent the abnormal development of metabolic systems in primate offspring. These studies will determine if a complete dietary switch from the HFD to a low fat diet just prior to pregnancy can reduce or prevent complications in fetal development. It will also be determined if dietary supplements with either fish oil or resveratrol, to prevent inflammation, oxidative stress, will provide similar protection. These studies will identify the risks and complications in the developing fetus associated with poor maternal metabolic health and diet. Futhermore, these studies will test dietary supplements/interventions that can be quickly translated to the clinic that mav help prevent or reduce metabolic diseases in children. RELEVANCE (See instructions): Poor maternal health and nutrition are associated with an increased risk of metabolic diseases in children. However, the underlying complications and mechanisms that lead to the increase in obesity and diabetes in children is poorly understood. The NHP is a critical model to identify these mechanisms because ofthe simlarities in development, as well as structure and function of metabolic systems

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity is one of the major health challenges facing the developed world, significantly increasing the risk of coronary disease, and of diabetes. It has recently been shown that for every "point" by which a person's body mass index (BMI) exceeds 25, there is an associated increase in the risk of cardiac disease. An estimated 9.4% of US healthcare expenditure is directly related to "obesity and inactivity", while recent costs due to diabetes were estimated at $98 billion per annum. A successful understanding of the causes, consequences, and possible solutions to the metabolic disease crisis will require that the full spectrum of basic, translational, and clinical research and epidemiology be brought to bear on the problem. To develop a model to study this disease our group has chosen to use the high fat diet induced obese (DIO) NHP model. The DIO-NHP is one of the few models that develops the full spectrum of the metabolic syndrome, including, obesity, insulin resistance, diabetes, cardiovascular diseases (hypertension and atherosclerosis), and immune dysfunction. Furthermore, the NHP has a similar cyto-architecture of the pancreatic islets and the developmental ontogeny of metabolic systems is similar to humans. All of these points make the NHP the most appropriate model for the human metabolic diseases. The purpose of this resource is to provide investigators access to the extensively characterized DIO macaque model, without having to incur the whole expense themselves.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Obesity is a worldwide health epidemic and a major contributor to the increased occurrence of coronary heart disease, hypertension, fatty liver disease, and type 2 diabetes. Both clinical research and studies in rodent models have provided key insights into the pathogenesis of obesity and associated disease, as well as the impact on the brain. However, both of these models have limitations that don't always allow for direct translation. The nonhuman primate (NHP) model has emerged as being critical for integrating observations from rodent and human studies. These studies will investigate changes in metabolic systems in the NHP model caused by high fat diet induced obesity (DIO). The specific purposes of this proposal are to characterize changes in gene and protein expression levels within the hypothalamus associated with obesity in the NHP. While these studies are primarily descriptive and correlative, this information will provide a critical database for the general scientific community and will allow both clinical and basic scientist to generate novel specific hypothesis about systems within the brain that become dysfunction is association with obesity. These data will also provide key insights for the future development of therapeutics for the treatment of metabolic diseases.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over the period of the past three decades, the number of overweight/obese individuals (children, adolescents and adults) has reached epidemic proportions in the United States. Several factors are recognized to play a role in the etiology of the obesity epidemic. Altered nutritional experiences during early periods of life are recognized to impact on the development of metabolic systems (metabolic programming effects) resulting in predisposition to adult-onset metabolic diseases. The purpose of this study is to investigate the effects of early postnatal nutritional manipulation on the development of the hypothalamic melanocortin system in the rat. These studies use a rat model developed by Dr. Patel whereby rat pups are either raised on a high fat (HF) diet (similar to maternal milk) or a high carbohydrate (HC) diet. Offspring raised on a HC diet are hyperphagic and obese as adults. These studies will use a variety of neuroanatomical techniques to investigate the immediate and long-term impact on the hypothalamic melanocortin system.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The MC4 receptor is considered to be one of the most potent anorexigenic systems and thus a highly sought after drug target. This system appears to be conserved across many species from fish to humans. However, this target also has great potential for cardiovascular side effects. The purpose of this study is to investigate a novel MC4 analog to 1) validate the efficacy of this compound and show that it can have potent effects body weight and glucose homeostasis in obese prediabetic monkeys;and 2) to investigate potential cardiovascular side effects and therapeutic window. The results from these previous studies have been written into a manuscript that we expect to submit soon. These new studies are designed to further clinical studies to identify formulations that have the highest efficacy with no significant cardiovascular complications (blood pressure or heart rate). Furthermore, these studies used animals from the Obese NHP Resource.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. High levels of triglycerides and VLDL (also known as dyslipidemia) are widely accepted to be a major risk factor in the development of coronary heart disease and diabetes. This study tested the ability humanized ANGPTL4 antibodies to increase triglyceride clearance through activation of the lipoprotein lipase enzyme. In this proof of principle study we determined whether these antibodies can effectively reduce triglycerides and VLDL and improve glucose homeostasis in obese nonhuman primates. These studies will be expanded in the future to investigate prolonged treatment and investigation of other endpoints (i.e., improvement in immune function) that will lead to a publishable paper. These studies used animals from the Obese NHP Resource. Progress: These studies have been completed.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The aim of the project is to examine the involvement of the melanocortin system in the regulation of lipolysis and blood pressure and to characterise possible alternative signalling pathways of MCRs in adipocytes. In house studies in a mouse 3T3 cell line differentiated to adipocytes indicates that the MC5 receptor and possibly also the MC2 receptor are involved in direct stimulation of lipolysis (manuscript in preparation), and furthermore preliminary data indicates that other signalling pathways than cAMP are involved in the melanocortin mediated lipolysis of mouse adipocytes. Examination of mouse primary adipocytes and fat tissue is the next step in order to obtain a better understanding of the MCR distribution and the biological effects of the melanocortin system in white adipose tissue. As significant species differences with regard to lipolysis have been described for the melanocortin system (Boston &Cone 1996a), it is also important to characterise the expression pattern of the five MCR's in fat tissue from other species (incl. humans) in order to identify the species that is most optimal for studying these effects in the development of MC4R agonists as obesity drugs. A possible side effect described for the MC4R is increased blood pressure, and the effect of the melanocortin system on blood pressure are being investigated in telemeterised in vivo models, especially MC3 and MC4 knockout mice. Furthermore, it should be established whether these potential species differences exist with regard to blood pressure as well as lipolysis.

PROJECT SUMMARY (See instructions): We recently discovered that a mild elevation in testosterone (T) levels in prepubertal female monkeys led to a significant increase in the frequency of pulsatile LH secretion, as well as an increase in LH response to GnRH, and concluded that chronic exposure to mild hyperandrogenemia over the course of puberty triggers changes in the neural drive to the reproductive axis that resemble those of girls with PCOS in early adulthood. Subsequently, when monkeys were 5 years of age, we fed them a Western Style Diet (WSD) and after 14 months both T-treated and control animals had a faster than normal pulse frequency in the early follicular phase, as well as decreased LH pulse amplitude. T-treated animals also showed a significant decrease in insulin sensitivity compared to control animals (2.6-fold lower), and changes in ovarian structure function, as detailed in Project II. These pilot studies demonstrate that a combination of T+WSD can lead to neuroendocrine, ovarian and metabolic abnormalities clinically associated with hyperandrogenemia and obesity. However, the specific roles that T and WSD played in the development of these abnormalities are unclear, as this pilot study did not include a T alone group, nor a normal monkey chow group. The overall goal of Project I is to use the pubertal female rhesus monkey model to further define the effects of adolescent and early adult (1) T, (2) WSD, and (3) T+ WSD treatment, compared to (4) control conditions, on function of the metabolic and reproductive neuroendocrine axes. Aim 1 will examine the effects of these four treatments on key metabolic systems and sleep patterns, measuring metabolic substrate and hormone levels, ivGTT, ITT, measurement of metabolic rate in a metabolic chamber, hyperinsulinemic/euglycemic clamps, dexascans, and activity. Sleep disorders are linked to both elevated T and obesity in a bi-directional fashion and could be partially responsible for the metabolic pathologies associated with PCOS. Aim 2 will examine the effects of treatments on reproductive neuroendocrine secretion (LH, FSH and responsiveness to GnRH), plus peptide levels and gene expression in KNDy (Kisspeptin, Neurokinin 8, Dynorphin) neurons in the basal hypothalamus. Aim 3 will test whether decreasing circulating T levels by removing T implants and/or reinstating a lower calorie, low fat diet will reverse neurendocrine and metabolic changes occurring with hyperandrogenemia and WSD.

DESCRIPTION (provided by applicant): It is firmly established that states of energy deficiency, such as fasting, anorexia nervosa, cachexia, bulimia, lactation and exercise-induced amenorrhea, as well as states of energy overabundance, such as obesity, are both associated with disruptions in fertility. These studies focus on states of negative energy balance that are associated with a suppression of reproductive function. The identity of the specific metabolic signals or afferent neural pathways that convey information about energy balance to gonadotropin-releasing hormone (GnRH) neurons, the central hypothalamic system regulating reproduction, remains elusive. Key to elucidating this link is an understanding of the regulation of kisspeptin neurons, the primary gatekeepers in controlling GnRH neurons. Our studies use two models of negative energy balance, lactation and caloric restriction, and have shown that kisspeptin signaling is greatly suppressed during these states. A key hypothesis of this proposal is that suppression of kisspeptin signaling is the primary factor in the inhibition of GnRH during states of negative energy balance. Although it is a widely held view that hypoleptinemia is the critical factor linking energy balance and suppressed GnRH, our recent studies demonstrate that restoring leptin to normal physiological levels does not reverse the inhibition of kisspeptin r GnRH in either lactation or caloric restriction. Thus, hypoleptinemia does not appear to be the primary metabolic factor responsible for the suppression of reproductive function. The proposed studies focus on new systems for integrating metabolic signals. Our hypothesis is that brainstem systems, such as glucose sensing catecholaminergic neurons, may be the site where information about metabolic signals is relayed to hypothalamic systems regulating GnRH neurons. This proposal focuses on two hypotheses: 1) Suppression of kisspeptin signaling at the site of GnRH cell bodies and at nerve fibers and terminals are primary components in the inhibition of basal GnRH secretion during states of negative energy balance, and 2) Brainstem systems serve as a site of integration of metabolic signals and provide the afferent signals that are responsible for the suppression of kisspeptin and GnRH during negative energy balance. These studies will use transgenic and wild-type rats and mice to identify mechanisms by which a decrease in kisspeptin tone coupled with increased inhibitory input to GnRH cell bodies results in a decrease in GnRH neuronal excitability, and will explore the roles of kisspeptin and neurokinin B in regulating GnRH release from nerve terminals. Studies will also establish the functional connectivity of afferent neural input that suppresses kisspeptin neurons. We propose that once the inhibitory input to kisspeptin neurons is identified, blocking the input will not onl restore kisspeptin but also reverse the inhibition on GnRH. Elucidating the specific links between energy balance and reproductive function has been a long-term goal for the past several decades. These studies will identify new pathways that regulate kisspeptin neurons that in turn control GnRH neurons and could lead to new treatments for restoring fertility or for new contraceptive agents that inhibit fertility.

This project aims to serve the national interest by providing a regional conference focused on ethical, valid, and fair use of data science in the social sciences. This interdisciplinary conference seeks to generate an in-depth discussion on the challenges of academia’s boundaries and corporate need and use for geospatial data science. This conference will bring together scholars in several areas including geographic information science, geography, education, linguistics, humanities, social sciences, and community groups. The conference will focus on how and what to teach undergraduate students in the area of data science to assure they can apply data science ethically, accurately, usefully, and fairly to challenges facing the region of South Florida and across the nation. An edited series of articles is expected to come from this conference, thus enabling attendees and non-attendees access to many of the important aspects covered in this conference. <br/><br/><br/>The main themes of the envisaged conference will focus on pedagogical strategies to teach the ethical aspects of 1) data collection, 2) data analytics and analysis, and 3) data visualization. Conference contributions will address pressing challenges in the context of constant and rapid technological advancements, such as balancing technological and technical learning with conceptual and ethical, valid, and fair knowledge production. From the applied perspective, the workshop will also review innovative pedagogies and learning activities that integrate ethical considerations of validity and fairness into the new ways of storing, manipulating, analyzing, representing, and sharing data. From a theoretical perspective, workshop participants will discuss (re)definitions of ethical issues and brainstorm on key generative terms of geospatial data validity and fairness. Conference contributions will also survey pedagogical strategies to teach how geospatial data collection, analysis and visualization might challenge biases, misinterpretations, and issues of power of government and corporations in geospatial technologies and data practices that lead to injustice. Finally, conference contributions will also explore potential alternatives to the common forms of data collection, analytics and analysis, and visualization, such as counter-data and participatory approaches to data collection, inductive visualization, and integration of reflexive and context-sensitive approaches in geospatial data science. Keynote presentations will include contributions from social scientists working on ethical geospatial data issues and from local community organizations. Some issues of focus are gentrification, evictions and displacement, sea-level rise, systemic racism, disinvestment in public services, resilience, and preservation of the culturally diverse history of minority communities in some of the oldest neighborhoods in Miami. The NSF IUSE: EHR Program supports research and development projects to improve the effectiveness of STEM education for all students.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.