2011 — 2015 |
Rodeheffer, Matthew S |
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. |
Cellular and Molecular Mechanisms of White Adipose Tissue Mass Regulation in Deve
DESCRIPTION (provided by applicant): Obesity in the United States and other industrialized nations has increased rapidly over the last thirty years and today 65% of the adult population in the U.S. is overweight with more than 30% of the population meeting the criteria for obesity. As the weight of the nation has increased, so have the incidences of many obesity- linked disorders, such as diabetes, atherosclerosis and certain types of cancer. Despite an increase in white adipose tissue (WAT) mass being the defining characteristic of obesity, we understand little of the cellular and molecular mechanisms that regulate WAT mass in vivo. WAT is composed of several subcutaneous and visceral depots that are pertinent to the study of obesity. The differential accumulation of excessive WAT in specific depots is associated with different risks of developing diabetes and other obesity-associated pathologies. However, the cellular and molecular mechanisms that control WAT mass in distinct depots are not well understood. Therefore, establishing the differences in cellular and molecular events that regulate WAT mass in separate WAT depots will lead to a better understanding of obesity and how excessive WAT leads to the development of secondary pathologies. The excessive accumulation of WAT in obesity results from an increase of both adipocyte size (hypertrophy) and number (hyperplasia). Since mature adipocytes are post-mitotic, they are generated from the proliferation and differentiation of adipoctye precursor cells. We have recently identified adipocyte progenitors and preadipocytes in vivo, allowing us to determine the cellular and molecular mechanisms that control adipocyte progenitor contribution to WAT mass in vivo. We hypothesize that by identifying the initiating signals that regulate the tissue-intrinsic control of WAT mass in specific depots we will be able to determine the mechanisms that integrate WAT with other tissues in the body to regulate metabolism and energy balance. To address this hypothesis, we will study two different models of WAT mass accumulation: 1) the excessive accumulation of WAT mass during the onset of high fat diet-induced obesity and 2) the establishment of WAT mass during development in normal mice. In each of these models we will define the timing of the activation of adipocyte precursor proliferation and differentiation into mature adipocytes, and determine the turnover rates of mature adipocytes. We will also determine the molecular mechanisms that regulate WAT mass in development and in diet-induced obesity, potentially leading to the identification of obesity-specific mechanisms of WAT mass regulation. Identifying molecular mechanisms that regulate WAT mass will lead to the development of therapeutics for the treatment of obesity and obesity-associated pathologies, such as diabetes and heart disease. PUBLIC HEALTH RELEVANCE: Obesity, which is defined as an excessive accumulation of fat mass, is currently one of the leading public health challenges. Obesity is a legitimate public health concern for two reasons: 1) several other diseases are associated with obesity, including diabetes, cardiovascular disease and cancer, and 2) the rates of obesity have increased rapidly over the last forty years with almost one third of the adult population in the U.S. being classified as obese today. The goal of this proposal is to identify signals within fat that regulate fat mass, which may lead to the development of novel therapies for the treatment of obesity and obesity-related pathologies.
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0.97 |
2012 |
Rodeheffer, Matthew S |
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. |
Cellular & Molecular Mechanisms of White Adipose Tissue Mass Regulation
DESCRIPTION (provided by applicant): Obesity in the United States and other industrialized nations has increased rapidly over the last thirty years and today 65% of the adult population in the U.S. is overweight with more than 30% of the population meeting the criteria for obesity. As the weight of the nation has increased, so have the incidences of many obesity- linked disorders, such as diabetes, atherosclerosis and certain types of cancer. Despite an increase in white adipose tissue (WAT) mass being the defining characteristic of obesity, we understand little of the cellular and molecular mechanisms that regulate WAT mass in vivo. WAT is composed of several subcutaneous and visceral depots that are pertinent to the study of obesity. The differential accumulation of excessive WAT in specific depots is associated with different risks of developing diabetes and other obesity-associated pathologies. However, the cellular and molecular mechanisms that control WAT mass in distinct depots are not well understood. Therefore, establishing the differences in cellular and molecular events that regulate WAT mass in separate WAT depots will lead to a better understanding of obesity and how excessive WAT leads to the development of secondary pathologies. The excessive accumulation of WAT in obesity results from an increase of both adipocyte size (hypertrophy) and number (hyperplasia). Since mature adipocytes are post-mitotic, they are generated from the proliferation and differentiation of adipoctye precursor cells. We have recently identified adipocyte progenitors and preadipocytes in vivo, allowing us to determine the cellular and molecular mechanisms that control adipocyte progenitor contribution to WAT mass in vivo. We hypothesize that by identifying the initiating signals that regulate the tissue-intrinsic control of WAT mass in specific depots we will be able to determine the mechanisms that integrate WAT with other tissues in the body to regulate metabolism and energy balance. To address this hypothesis, we will study two different models of WAT mass accumulation: 1) the excessive accumulation of WAT mass during the onset of high fat diet-induced obesity and 2) the establishment of WAT mass during development in normal mice. In each of these models we will define the timing of the activation of adipocyte precursor proliferation and differentiation into mature adipocytes, and determine the turnover rates of mature adipocytes. We will also determine the molecular mechanisms that regulate WAT mass in development and in diet-induced obesity, potentially leading to the identification of obesity-specific mechanisms of WAT mass regulation. Identifying molecular mechanisms that regulate WAT mass will lead to the development of therapeutics for the treatment of obesity and obesity-associated pathologies, such as diabetes and heart disease. PUBLIC HEALTH RELEVANCE: Obesity, which is defined as an excessive accumulation of fat mass, is currently one of the leading public health challenges. Obesity is a legitimate public health concern for two reasons: 1) several other diseases are associated with obesity, including diabetes, cardiovascular disease and cancer, and 2) the rates of obesity have increased rapidly over the last forty years with almost one third of the adult population in the U.S. being classified as obese today. The goal of this proposal is to identify signals within fat that regulate fat mass, which may lead to the development of novel therapies for the treatment of obesity and obesity-related pathologies.
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0.97 |
2016 — 2020 |
Rodeheffer, Matthew S |
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. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Cellular and Molecular Mechanisms of White Adipose Tissue Regulation in Development and Disease
? DESCRIPTION (provided by applicant): The rates of obesity, which is defined as an excessive increase in white adipose tissue (WAT) mass, has increased rapidly over the last several decades and today 65% of the adult population in the U.S. is overweight with more than 30% of the population meeting the criteria for obesity. As the weight of the nation has increased, so have the incidences of many obesity-linked disorders, such as diabetes, cardiovascular disease and certain types of cancer. Despite the importance of WAT in normal physiology and disease, we understand little of the cellular and molecular mechanisms that regulate WAT mass in vivo. WAT is composed of several subcutaneous and visceral depots that are pertinent to the study of obesity. The differential accumulation of excessive WAT in specific depots is associated with differential risks of developing diabetes and other obesity-associated pathologies. However, the mechanisms that control WAT mass in distinct depots is not well understood. Therefore, establishing the differences in cellular and molecular events that regulate WAT mass in separate WAT depots will lead to a better understanding of obesity and how excessive WAT leads to the development of secondary pathologies. The excessive accumulation of WAT in obesity results from an increase of both adipocyte size (hypertrophy) and number (hyperplasia). Since mature adipocytes are post-mitotic, they are generated from the proliferation and differentiation of adipocyte precursors (APs). We have recently identified APs in vivo, allowing us to directly interrogate the mechanisms that control WAT mass and function in vivo. We have recently reported that there is an obesity-specific mechanism of adipogenesis. In addition, our preliminary data shows there are discreet periods of AP activation at separate life stages and that remarkable sex-specific differences in AP activation occur in obesity. We, therefore, hypothesize that distinct regulatory mechanisms control depot-specific WAT expansion in different physiologically relevant contexts. Furthermore, by identifying the initiating signals tha regulate the tissue-intrinsic control of WAT mass in specific depots we may be able to determine the mechanisms that integrate WAT with other tissues in the body to regulate metabolism and energy balance. Here we will characterize depot-specific mechanisms of adipogenesis during key stages of embryonic and postnatal development, as well as the mechanisms driving sexually dimorphic WAT expansion and function in obesity. Identifying molecular mechanisms that regulate WAT mass will lead to the development of therapeutics for the treatment of obesity and obesity-associated pathologies, such as diabetes and cardiovascular disease.
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0.97 |
2016 — 2019 |
Rodeheffer, Matthew S |
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. |
Dietary Regulation of Adipocyte Hyperplasia in Obesity: Impact On Adipose Mass and Metabolic Disease
Project Summary The forces driving the current obesity epidemic remain a matter of debate, but obesity has largely been assumed to result from increased caloric intake. However, diets high in fat result in increased adiposity even in the absence of increased caloric intake. These findings suggest that dietary fats play an important role in increased WAT mass in obesity. While the amount of fat in the diet has increased during the obesity epidemic, the types of fats in the diet that have changed even more drastically. However, our understanding of how specific fatty acids affect the onset of obesity, fat distribution and metabolic disease is limited. Since mature adipocytes are post-mitotic, they are generated from the proliferation and differentiation of adipocyte precursors (APs). We have recently identified the adipocyte cellular lineage in vivo, and we have developed assays to directly interrogate the cellular and molecular mechanisms that control AP contribution to WAT mass in physiologically relevant contexts in vivo. We have since characterized when adipogenesis occurs in response to high fat diet (HFD) feeding and have established that HFD-induced adipogenesis occurs in specifically in visceral WAT of male mice. In addition, we found that HFD-induced adipocyte formation requires Akt2 in the adipocyte cellular lineage, but Akt2 null mice establish WAT mass and adipocyte number normally during development. These findings indicate that the molecular regulation of adipogenesis in obesity is distinct from developmental adipogenesis. To establish how HFD induces adipogenesis in obesity, we have determined the adipogenic response to HFDs composed of different fat sources. We found only diets high in monounsaturated fats induce adipocyte hyperplasia and that these adipogenic fat sources affect fat distribution in obesity. As oleic acid is the major dietary monounsaturated fatty acid, and we have shown that oleic acid can function as a signaling molecule to induce adipogenesis directly on APs, we hypothesize that dietary oleic acid acts as a signaling molecule that drives adipocyte hyperplasia in obesity in mice and humans. Preliminary data indicates that oleic acid simulated adipogenesis in primary APs is dependent on Akt2 and the fatty acid receptor GPR120. Here we will characterize the dietary components that affect adipocyte hyperplasia, determine the metabolic consequences of oleic acid induced adipogenesis and define the molecular mechanisms that control adipocyte hyperplasia in both mouse and human models. These studies will improve our understanding of how modern diets may have contributed to the obesity epidemic and metabolic disease, potentially leading to new dietary recommendations and novel therapeutic strategies for sustained weight loss and improved health outcomes.
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0.97 |
2021 |
Horvath, Tamas L [⬀] Rodeheffer, Matthew S |
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. |
The Role of Mitochondrial Dynamics in Diet-Influenced Regulation of Food Intake and Adiposity
We have identified a role for mitochondrial dynamics (fission and fusion) in central regulation of feeding, energy- and glucose metabolism. We showed that mitochondrial fission is important for proper promotion of feeding and body weight gain by hypothalamic AgRP neurons, while mitochondrial fusion is critical for hypothalamic POMC neurons to support satiety and related adjustment of systemic glucose metabolism. In our preliminary studies we also found that interference with mitochondrial dynamics selectively in adult adipocytes has a robust impact on systemic metabolism, in which knockdown of the mitochondrial fusion protein, mitofusin 2 (Mfn2), resulted in rapid weight gain and elevated feeding of mice with concomitant elevations in hypothalamic transcripts for AgRP. These observations indicate weight gain is supported both centrally and peripherally by mitochondrial fission, and, that mitochondrial dynamics in either of the hypothalamus or adipocytes reciprocally impacts mitochondrial function in these tissues to affect behavior and systemic energy and glucose metabolism. In support of this, we revealed in an in vitro system that elevated fatty acid levels, which are critical for weight gain do promote mitochondrial fission. We observed that different fatty acids species have different effects on mitochondrial dynamics, and that altering dietary fat composition alone results in elevated in food intake and body weight gain. Taken together our observations gave impetus to the central hypothesis of this grant proposal that mitochondrial fission is a key dietary-influenced mechanism both in the hypothalamus and adipocytes that regulates body weight and adiposity. We propose the following Specific Aims to test our hypothesis: Specific aim 1 will assess the role of mitochondrial dynamics in food intake and energy expenditure by assessing the effects of both altered mitochondrial fission and fusion in mature adipocytes and in central feeding circuitry neurons. In addition, aim 1 will explore the afferent signaling from adipocytes that impacts the function of feeding circuitry neurons. Specific Aim 2 will use both in vitro and in vivo approaches to establish the role of hypothalamic and adipocyte mitochondrial dynamics on dietary fat-influenced food intake.
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0.97 |