2000 — 2003 |
Bass, Joseph T |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Molecular Componenents of Insulin Receptor Biogenesis @ Evanston Northwestern Healthcare
Dr. Bass has had extensive training in metabolism related biomedical research beginning with work as an M.D., Ph.D. student at the Medical College of Pennsylvania under the direction of Drs. Julian Marsh and Edward Fisher. There the role of tissue macrophages in the secretion of apolipoprotein E and cholesterol uptake was investigated. Subsequently, the P.I. completed residency in Internal Medicine and a Fellowship in Endocrinology under the Clinical Investigator Pathway of the American Board of Internal Medicine. For the past 3 years the P.I. has worked with Drs. Donald Steiner and Graeme Bell at the University of Chicago where he investigated the biosynthesis and structure of the insulin receptor. This work provided the foundation for the present application. The insulin receptor is a large and complex glycoprotein that undergoes extensive posttranslational modification important in its translocation and expression. Yet, the molecular details underlying the biosynthetic pathway remain inadequately understood. Recently, Dr. Bass has shown that nascent insulin receptors associate with three resident endoplasmic reticulum (ER) molecular chaperones, calnexin (Cnx), calreticulin (Crt) and binding protein (BiP) and blocking these interactions reduces the cell surface expression of the receptor. The aim of this project is to dissect the molecular mechanisms by which these chaperones effect insulin receptor biogenesis. The approach is to use pulse-chase labeling, coimmunoprecipitation with antibodies to the receptor and to the three chaperones, in combination with pharmacologic and genetic methods to disrupt receptor-chaperone interactions. The experiments will involve site-directed mutagenesis, transfections, and analytic techniques such as sucrose velocity sedimentation and confocal microscopy. These studies will illuminate the quality control mechanisms that regulate delivery of functional receptors to the cell surface. The University of Chicago provides an outstanding environment for basic diabetes-related research. The Department of Medicine has long fostered the careers of young scientists. The ability of the P.I. to interact with the sponsor, Dr. Steiner, in addition to Drs. Graeme Bell, Susan Lindquist and other excellent scientists at the University of Chicago will promote his continued development as an independent researcher.
|
0.911 |
2003 — 2006 |
Bass, Joseph T |
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. |
Impact of Sleep On Feeding and the Metabolic Syndrome @ Evanston Northwestern Healthcare
DESCRIPTION (provided by applicant): Over the past two decades, an increased prevalence of sleep deprivation in the US has become a major public health challenge. Sleep deprivation been implicated in the epidemic of the metabolic syndrome, a condition characterized by insulin resistance, hyperlipidemia, cardiovascular disease and hypertension. Presently, 30% of the US population is overweight or obese and diabetes affects nearly 17% of persons over the age of 65. Recent clinical research indicates that sleep deprivation may pose a risk for the development of diabetes and the metabolic syndrome, however the underlying physiological and pathophysiological basis for the connection between sleep and metabolic homeostasis remains incompletely understood. This application proposes to exploit a novel experimental model of acute and chronic partial sleep deprivation in order to dissect the link between sleep loss and the metabolic syndrome. Already, we have found that chronic partial sleep loss in our animal model reproduces features of the metabolic syndrome including changes in hypothalamo-adrenal axis, decreased leptin and increased fatty acids. We have also made exciting discovery that suggest a role for alterations in the biological clock and clock regulated metabolic pathways that may lead to the metabolic syndrome. We now propose to apply the model we have developed together with molecular genetic tools to investigate the basic mechanisms that link sleep, circadian rhythms, food intake and energy homeostasis. Insight gained from these studies will provide new strategies to prevent metabolic complications associated with sleep deprivation and uncover novel metabolic targets for treatment of obesity and its co-morbidities.
|
0.911 |
2009 — 2013 |
Bass, Joseph T |
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. |
Impact of Sleep Loss and Circadian Disruption On Neural Regulation of Metabolism
Seeinstructions): The long-term goal of this project is to dissect the molecular basis for accelerated metabolic aging induced by circadian disruption and sleep loss in mice. Consistent with the overall goals of this program project, our focus will be to exploit mouse genetic tools to uncover the effect of circadian disruption at distinct time points in life on the progression of sleep impairment, and metabolic phenotypes. Our focus stems from work that has established that (1) circadian Clock mutant mice develop sleep loss and severe cardiometabolic disease during aging and (2) that high-fat diet itself leads to altered behavioral and molecular circadian rhythms in mice. We hypothesize that a 'vicious cycle' interconnects sleep and circadian disruption with cardiometabolic diisease. Moreover, we propose that there circadian disruption during critical windows in life effect the severity of cardiometabolic disease. We propose to exploit a genetic rescue strategy in which we have engineered clock mice harboring tetracycline-inducible wild-type alleles of the clock gene that can be selectively turned on or off within brain at distinct time points throughout life. Clock brain rescue mice have normal locomotor activity rhythms, but we do not know whether they also have normalized sleep and/or normalized metabolic profiles. Here we propose to test they hypothesis that clock gene rescue in brain at distinct ages either in early life or adulthood has different effects on sleep and the progression of cardiometabolic disease. In Aim 1, we propose to rescue clock function in brain throughout life; in Aim 2 we propose to rescue only in early life; and in Aim 3 we propose to rescue clock function in brain in adult life. We will then analyze sleep (REM/NREM/delta power) and metabolic endpoints (feeding rhythms, body composition, hormonal/biochemical markers and tissue metabolic gene networks). Results of these studies will establish the cause-and-effect relationship between disruption of circadian systems, sleep, and metabolic homeostasis and pinpoint the most vulnerable periods in life that set in motion an irreversible course of accelerated aging. RELEVANCE (See instructions): The goal of this proposal is to dissect the molecular basis for accelerated metabolic aging induced by circadian disruption and sleep loss in mice. Insight gained from these studies will advance our knowledge of the interdependence of circadian disruption, sleep impairment, and cardiometabolic disease. We will establish the age-dependence of altered behavior on metabolic aging and create new insight for both prevention and rational theranies that will avert diabetes and ohfisitv durinn aninn.
|
0.905 |
2009 — 2012 |
Bass, Joseph T. Imai, Shin-Ichiro (co-PI) [⬀] |
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 Basis of Circadian Desynchrony in Cardiometabolic Disease @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): Strong evidence has implicated the molecular circadian clock as a key integrator of behavior and physiology, and both genetic and epigenetic perturbation of circadian systems has been associated with obesity and cardiovascular disease. Conversely, we have found that high-fat diet leads to disruption of circadian behavioral and molecular rhythms. Interestingly, we have also observed that animals provided high-fat diet only during the dark period gain less weight than those fed only during the light. Collectively, these observations underscore interconnections between overnutrition, circadian disruption, and cardiometabolic pathologies. Recently, we have made the discovery that Nampt, the rate-limiting enzyme in NAD+ biosynthesis, is a clock-controlled gene that produces 24 hr oscillations in levels of NAD+. NAD+ is also an essential cofactor in hepatic lipid and carbohydrate metabolism and may function as an oscillating nutrient sensor coupling circadian and metabolic pathways. Indeed, both Nampt and NAD+ levels are low in Clock19 and Bmal1-/- mice (and increased in Cry1-/-/Cry2-/-animals). In turn, alterations in Nampt/NAD+ modulate the nutrient-responsive deacetylase SIRT1, which we and others have found to inhibit transcription of the clock repressor Per2. Thus the overarching goal of this proposal is to test the hypothesis that high-fat diet, together with alterations in feeding time induced by high-fat intake, disrupts synchrony between cycles of energy storage and utilization in fat and liver and leads to alterations in the nutrient-responsive feedback loop comprised of CLOCK/BMAL1 and NAMPT/NAD+/SIRT1. Taken together, our recent combined findings on cardiometabolic, energy balance, and circadian clock networks have put us in position to test novel hypotheses regarding the mechanisms by which circadian coupled cellular processes regulate cardiometabolic function and energy balance. The Specific Aims are as follows: Specific Aim 1: To test the hypothesis that high-fat diet disrupts circadian control of metabolic physiology due to (a) changes in feeding time and/or (b) due to changes in dietary nutrient composition. Specific Aim 2: To test the hypothesis that high-fat diet disrupts properties of the cell autonomous circadian oscillator either (a) due to changes in feeding time and/or (b) due to changes in nutrient composition of diet. Specific Aim 3: To test the hypothesis that high-fat diet disrupts the novel circadian-metabolic feedback loop involving NAD+ biogenesis and the NAD+-dependent deacetylase SIRT1. (End of Abstract)
|
0.958 |
2011 — 2014 |
Bass, Joseph T |
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. |
Integration of Feeding and Glucose Metabolism by the Circadian Gene Network @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): Emergent data from public health and clinical epidemiological studies have provided convincing evidence for a new risk factor in obesity and type 2 diabetes mellitus: introduction of extended periods of wakefulness in the workplace and at home giving rise to temporal disruption between the external environment and internal integrative physiological systems coordinating feeding, nutrient storage and energy expenditure. In very recent large-scale association studies, polymorphisms in key genes involved in circadian processes have been implicated in glucose homeostasis at the genetic level in humans. Against this backdrop, a long-line of clinical and pre-clinical research into ingestive behavior and glucose metabolism has also shown that perturbations in the rhythmic control of both feeding and glucose turnover are hallmarks of dysmetabolic states; however the mechanistic links between circadian disruption, energetics and metabolism have remained obscure. A major breakthrough in our understanding of the impact of circadian disruption on integrative physiology originated in discoveries over the past 5 years that have uncovered a central role for the biological clock in the control of both body weight and metabolism. While the central tenet of circadian research prior to the 1990s held that the brain master pacemaker was the unitary center for mammalian timekeeping, a remarkable development has been the finding that core clock genes comprise a transcription-translation feedback loop oscillating every ~24 hrs in nearly all tissues in addition to the SCN. In 2005, we reported that ENU-derived Clock 19 mutant mice exhibit susceptibility to diet-induced obesity, altered day-night feeding patterns, hyperglycemia and, surprisingly, hypoinsulinemia; however, to date, our understanding of the tissue-specific roles of clock genes in feeding behavior and integrative physiology remains incomplete. In efforts to refine our knowledge of the local function of clock genes within both brain pacemaker neurons and in extra-SCN and peripheral locations, we have assembled a unique interdisciplinary team, and now propose to combine conditional tissue-specific gene targeting with an extensive platform for behavioral, physiological and molecular analyses. Based upon our exciting preliminary results which demonstrate feasibility of conditional knockout of clock function within either brain or pancreas, the forward-reaching goal of this proposal will be to determine the relative contribution of clock disruption within brain (Aim 1) or within endocrine pancreas (Aim 2) to the obesity and hyperglycemia observed in multi-tissue circadian mutants. Results from the proposed research will advance knowledge at the intersection of genes and behavior and provide new therapeutic targets and strategies to intervene in both obesity and diabetes mellitus.
|
0.958 |
2014 — 2018 |
Bass, Joseph T |
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. |
Interplay of Dietary Lipid and Circadian Dysregulation in Metabolic Syndrome @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): The expansion across industrialized nations of both visceral obesity and metabolic syndrome has caused an escalation of co-morbidities including cardiovascular disease, stroke, blindness, renal failure and thrombosis. The clear rise in these disorders tracks with high-saturated fat diet and overnutrition, suggesting that macronutrient and lipid specifically play a major role in the onset and progression of disease. A surprising observation has been that both shiftwork and night-eating are associated with increased risk of metabolic syndrome. Exciting studies completed subsequent to our previous submission of this proposal now establish that the molecular clock, a conserved internal system that evolved to synchronize physiology in anticipation of the rotation of the Earth, regulates mitochondrial oxidative capacity and that circadian disruption phenocopies the metabolic myopathy syndrome in humans that is characterized by liver lipid accumulation, mitochondrial dysfunction, and fasting-induced seizures. Remarkably, we have also established that we can reverse the mitochondrial defects in circadian disruption using the prodrug NMN, which boosts intracellular NAD+ levels and enhances the activity of NAD+-dependent deacetylases critical in metabolic adaptation. Indeed, it is now apparent that clocks exist throughout all tissues of the body and that the normal phase alignment of the brain clock with peripheral tissue clocks undergoes misalignment with shiftwork, night-eating, and even with high-fat diet. Thus a long-term objective of our proposal is to test the hypothesis that circadian disruption contributes to metabolic disorders by altering mitochondrial oxidative capacity across the sleep/wake-fasting/feeding cycle. An innovation of our work is to integrate studies of clock and mitochondrial biology and to dissect the impact of clock time on macronutrient metabolism. Ultimately, we are now poised to create deeper insight into the contribution of timing to mitochondrial function that will be applicable to obesity, metabolic syndrome, and type 2 diabetes therapeutics.
|
0.958 |
2016 — 2020 |
Bass, Joseph T |
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. |
Integration of Feeding Time and Glucose Metabolism by the Circadian Gene Network @ Northwestern University At Chicago
? DESCRIPTION (provided by applicant): The escalation in the linked epidemics of obesity and diabetes mellitus has led to intensive investigation into environmental and genetic factors that contribute to the spread of these diseases. In addition to sedentary lifestyle and overnutrition, several environmental factors associated with industrialization are now believed to be linked to the development of obesity and metabolic dysfunction, including an increase in night-time shiftwork, jetlag, sleep restriction, and late-night eating, all of which can be traced to the spred of electric light. More recently, the overuse of illuminated screens that emit blue light in eReaders are also believed to induce a persistent jetlag state. While epidemiologic studies have provided mounting evidence for circadian disruption as a risk factor for metabolic disease, this work is limited as it is primarily correlative and the mechanistic basis linking circadian disorder to metabolic pathophysiology are not well established. Transformative discoveries have been that the core clock transcription factors CLOCK/BMAL1 are present not only in master pacemaker neurons of the hypothalamus, but also with within peripheral metabolic tissues, and that mutation of the mammalian Clock gene leads to obesity and metabolic syndrome, characterized by alterations in feeding time and intake, sleep, and energy expenditure. Further, during our previous grant cycle, we established that CLOCK/BMAL1 dysfunction specifically in pancreas leads to hypoinsulinemic diabetes mellitus independently of effects of the mutation on early growth and development. With analysis of the interplay between the ?-cell and brain clock as the centerpiece of our grant, we have now developed inducible genetic and genomic approaches to define the molecular regulatory mechanisms through which (i) the ?-cell clock controls rhythms of endogenous glucose-stimulated insulin secretion, nutrient signaling, and triggering of vesicle release through pathways involving protein kinase C and phosphoinositide, and (ii) the brain clock coordinates feeding time with activity of hypothalamic neurons regulating energy homeostasis. Our long-term objective is to test the hypothesis that circadian disruption, and the corresponding misalignment of rhythmic genomic cycles in peripheral ?-cells and liver with those of brain, contributes to metabolic disorders by impairing glucose- responsive insulin secretion and desynchronizing hepatic gluconeogenesis with the sleep/wake-fasting/feeding cycle. An innovation of our work is the integration of studies of cellular and brain clock with genomic analyses to dissect the impact of clock time on glucose metabolism. Ultimately we are now poised to uncover new insight into how the central and peripheral clocks synchronize behavioral and transcriptional rhythms to impact physiology, findings which have broad implications for the treatment and prevention of obesity, metabolic syndrome, and type 2 diabetes mellitus.
|
0.958 |
2017 — 2020 |
Bass, Joseph T Stein, Roland 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. |
Control of Islet Beta Specific Pdx-1 and Mafa Transcription
The Pancreas Duodenum Homeobox-1 protein (Pdx1) is one of the most important transcriptional regulators in the pancreas, since it plays a fundamental role in the early formation of all pancreatic cell types and in the production and function of adult islet ? cells. Moreover, inactivation of human Pdx1 contributes to diabetic islet ? cell dysfunction. Gene regulation by transcription factors (TFs) like Pdx1 necessitates the recruitment through protein-protein interactions of coregulators, which confer a second level of specificity to the transcriptional response due to their positive and/or negative actions. Because little was known about the coregulators recruited by islet-enriched TFs, a principal objective during the prior funding cycle was to isolate coregulators of Pdx1 from mouse ? cells. While many were identified, we focused on determining the significance to Pdx1 of the Swi/Snf chromatin remodeling complex. Our studies not only strongly suggest that Swi/Snf is a critical regulator in ? cell lines, but that recruitment to Pdx1 is compromised under the dysfunctional conditions associated with human Type 2 diabetes. A major objective in this proposal will be to determine the in vivo significance of Pdx1:Swi/Snf control in the developing pancreas and islet ? cells postnatally, with preliminary results supporting a prominent role. Because Swi/Snf does not have as powerful a regulatory impact as Pdx1, we will also work towards defining the underlying transcriptional mechanisms of other Pdx1 recruited coregulators on islet ? cell activity. Our earlier transgenic- and cell line-based experiments localized pancreatic cell-type-specific transcriptional regulatory areas of the Pdx1 gene to conserved 5'-flanking region sequences. We have constructed deletion mutants in the Area IV (base pair (bp) -6200/-5670) and Area II (bp -2153/-1923) control regions of the endogenous mouse Pdx1 gene to analyze the individual contributions of these enhancers to pancreatic cell type specification, differentiation, and function in vivo. Strikingly, the molecular and physiological impact of the Pdx1?Area IV mutant was almost exclusively during the postnatal weaning period. Another principal focus will be on determining if islet ? cell dysfunction in this mutant disrupts the activity of the circadian clock, as the mediating CLOCK and BMAL1 TFs reside within Pdx1 bound transcriptionally active enhancers and yield a similar in vivo TF mutant phenotype to Pdx1?Area IV. Collectively, our studies will focus on defining mechanisms used by Pdx1 in controlling the normal formation and activity of islet ? cells, and determining their possible contribution in the pathogenesis of diabetes. These findings will have a significant positive impact by providing knowledge relevant to those developing diagnostic and therapeutic approaches for disease treatment.
|
0.905 |
2017 — 2021 |
Bass, Joseph T |
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. |
Metabolic and Molecular Laboratory Core @ Northwestern University At Chicago
The main function of the Core is to provide state-of-the-art analytic methods to advance the proposed research in all three projects of the Program Project. We will provide reliable measurements and analyses of blood glucoregulatory, appetitive, and circadian hormones and other metabolite from human subjects who are affected by aging and/or sleep duration and quality in Projects 1 and 2. Assays will include leptin, ghrelin, gastric inhibitory polypeptide (GIP), C-peptide, cortisol, melatonin (from blood and saliva), 6-sulfatoxymelatonin (MTS6 in urine), glucose, insulin, lactate, pyruvate, free fatty acids (FFA), triglycerides, LDL, HDL, HbA1c, and NAD+. We will all also provide metabolic phenotyping methods to study tissue-specific and cellular metabolic flux in both the animal tissues and human blood samples and biopsies. The analytical procedures include high- performance liquid chromatography and mass spectrometry for metabolite analyses, cellular bioenergetics, real time monitoring of cellular redox state, biochemical analysis of sirtuin activity, gene expression analysis using quantitative PCR methods, as well as transcriptome analyses using next-generation sequencing for animal models in Project 3. All analytical methods have been validated and operational in our laboratory. The Metabolic and Molecular Core will provide critical support for the implementation of all Projects, explore potential use of novel analytical techniques, and will be closely integrated with the Analysis Core to ensure timely and safe archival of laboratory data.
|
0.958 |
2017 — 2021 |
Bass, Joseph T |
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. |
NW University Program in Endo Diabetes and Hormone Action @ Northwestern University At Chicago
? DESCRIPTION (provided by applicant): Rapid advances in scientific knowledge have resulted in unparalleled opportunities for new discoveries that could substantially improve human health and cure disease. A cadre of scientists who can work at the interface between fundamental science and clinical medicine is essential to accomplish this goal. It is the overarching objective of the Northwestern University Program in Endocrinology, Diabetes and Hormone Action (NUPEDHA) to enable such research in endocrinology, diabetes and metabolism. This objective will be accomplished by training basic and clinical scientists in an environment that integrates rigorous fundamental science into a disease-oriented context. An essential component of this training program is the superb, highly interactive training faculty of 17 outstanding mentors whose research focuses on translational science related to endocrinology, diabetes, obesity and metabolism. There are also 4 co-mentors who will provide expertise in state-of-the-art Omics and Big Data approaches. There is also 1 mentor in training to ensure that there is a pathway to develop junior faculty as mentors. The overall program objectives are to 1) provide training in the fundamental biology and integrative physiology of endocrinology, diabetes, obesity and metabolism in a disease-oriented environment; 2) integrate innovative Omics and Big Data approaches into trainee research projects through co-mentorships.3) mentor the next generation of investigators who can work at the interface between the laboratory and clinical medicine to ensure that scientific advances are rapidly translated to improve the care of patients with endocrine and metabolic disorders, including diabetes and obesity. The combined training of graduate students, PhDs and Clinical Fellows in Endocrinology and Metabolism emphasizes these objectives as well as the continuum between fundamental science and patient care. The training program contains a core of didactic activities with additional didactic experiences tailored to the needs of each trainee. There are options for training in basic-translational scienc or clinical research. The Individual Development Plan (IDP) was implemented for all trainees in 2010, well before it was an NIH requirement. Professional development opportunities include training in manuscript and grant writing, presentation skills, time management and pathways to academic success. The rigorous, ongoing program evaluation will continue to be overseen by the Northwestern University Searle Center for Advancing Learning & Teaching. NUPEDHA has an outstanding record of accomplishment. Over the past 10 years, NUPEDHA has supported 10 predoctoral trainees and 18 postdoctoral trainees. Seventy percent (7/10) of the predoctoral trainees have academic appointments or are continuing in training. Ninety-two percent (11/12) of the 12 postdoctoral trainees who completed training have academic appointments; 58% (7/12) of these former postdoctoral trainees have been successful at obtaining independent grant support. Six of the 28 trainees (21%) over the past 10 years have been underrepresented minorities (URM). Fifty percent of current trainees are URM.
|
0.958 |
2018 — 2021 |
Bass, Joseph T |
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 Circadian System as a Neuronal Regulator of Feeding Time and Body Weight Setpoint @ Northwestern University At Chicago
Project Summary The escalating prevalence of obesity and metabolic syndrome suggest that both underlying genetic and environmental factors contribute to this epidemic. We have made the exciting discoveries that genetic ablation of the clock leads to obesity and metabolic syndrome, and high-fat feeding to wild-type mice induces circadian disruption and increases food intake during the incorrect circadian time (i.e., their normal rest period) that is directly linked to obesity and insulin resistance. While these observations suggest a fundamental role for the ?timing? of food intake in energy balance, the underlying central nervous system clock mechanisms coordinating behavioral and metabolic rhythms remain poorly understood. A springboard for our studies has been the transformative discovery of the core molecular components of the clock, a negative transcription feedback loop that cycles in both pacemaker neurons of the suprachiasmatic nucleus (SCN) and nearly all peripheral metabolic cells. However, how the brain pacemaker cells entrain extra-SCN clocks to the light cycle, and the role of clocks within genetically distinct cells of the SCN in the regulation of energy balance, remains unknown. Given the mounting evidence that circadian and sleep cycle disruption lead to metabolic disorders through impeding signaling at the level of brain, a primary challenge is now to define the function of pacemaker neurons and clocks within energy-sensing neurons in establishing body weight setpoint. Our approach herein is to exploit powerful new genetic models in the mouse, with the ability to cause adult-onset ablation of the core clock machinery, and to do so within specific region of the hypothalamus, focusing on the master pacemaker, the SCN. We also implement stereotactically-guided DREADD technology (Designer Receptors Exclusively Activated by Designer Drugs) to pharmacologically manipulate the phase of SCN firing in distinct subpopulations, thus causing genetic jetlag, and to then probe the impact of this ?on/off? switch of the central clock on behavior and energy balance. We seek to integrate behavioral, physiological, and molecular analyses to dissect actions of the clock within SCN and appetitive neurons in feeding and glucose metabolism. Our work has direct translation to human health since we will elucidate how the clock system contributes to weight loss with hypocaloric diets and maintenance of weight loss following cessation of dieting. In summary, our proposed research will provide detailed mechanistic insight into how disruption of pacemaker neuron activity and clock transcription factor regulation of neuronal gene transcription impacts the coordination of hunger, energy balance, and health. In summary, our proposed research will provide detailed mechanistic insight into how disruption of pacemaker neuron activity and clock-regulated neuronal gene transcription in both SCN and extra-SCN regions impact the coordination of hunger, energy balance and metabolic health.
|
0.958 |
2019 — 2021 |
Bass, Joseph T |
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. |
Bioenergetic Mechanisms Underlying Circadian Dietary Intervention @ Northwestern University At Chicago
Project Summary The rise in age-related metabolic disorders and obesity has reached epidemic proportions. We have made the exciting discoveries that circadian clock mutant animals develop diet-induced obesity and metabolic syndrome, and that high fat feeding dampens circadian oscillations and increases food consumption during the `wrong' time of day (i.e., the normal rest period). In contrast, restricting access to high fat diet to the `right' (i.e., active) time of day as a circadian dietary intervention prevents the development of obesity and diabetes. Together, these findings suggest disrupted circadian control of feeding rhythms contributes to diet-induced obesity and its comorbidities, similar to the adverse consequences of night-eating in humans, and provide a springboard for our proposed studies here to elucidate the bioenergetics mechanisms underlying this circadian dietary intervention. Importantly, we recently discovered that adipose thermogenesis is required for the metabolic benefits of time-restricted feeding. Mounting evidence has also indicated that circadian and energetic pathways are coupled at the molecular level through circadian clock control of NAD+, a cofactor for nutrient-sensing sirtuin deacetylases which feedback to regulate both core clock activity and mitochondrial respiration. Remarkably, we found that NAD+ supplementation augments mitochondrial oxidative metabolism in circadian mutant mice and enhances rhythmic metabolic gene transcription during aging. Here, we will first test the hypothesis that circadian dietary intervention (i.e., dark-only feeding) improves metabolic healthspan through enhanced thermogenesis and oxidative metabolism in adipose and liver (Aim 1). To do so, we will determine the impact of time-restricted feeding (i) on the metabolic health of mice with defective (Ucp1-/-) or enhanced (Zfp423-/-) thermogenesis; (ii) on weight maintenance in animals following caloric restriction; (iii) on metabolic flux in adipose- and liver-specific clock deficient mice (Bmal1?adipose and Bmal1?liver); and (iv) on transcriptional rhythms. Results of Aim 1 will elucidate the mechanism through which the clock and time-restricted feeding regulate the metabolic fate of dietary nutrient and body weight setpoint. In Aim 2, we will test the hypothesis that NAD+ supplementation can augment time-restricted feeding as a countermeasure for metabolic decline with aging and overnutrition (Aim 2). Specifically, we will examine whether NAD+ supplementation improves circadian control of thermogenesis, metabolic flux, and transcriptional activity of the core clock in young and old animals during time-restricted feeding. Results of Aim 2 will elucidate the role of NAD+ in circadian control of the metabolic fate of dietary nutrient, thermogenesis, and healthspan. Collectively, the integration of behavioral, genomic, and physiologic analyses in the present proposal will define the role of time-of-day in nutrient flux and thermogenesis, leading to significant advance in the design of treatments to preserve ideal body weight and metabolic health with aging.
|
0.958 |
2021 |
Bass, Joseph T |
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. |
Cross-Regulation of Immunometabolism and Circadian Pathways in Obesity Pathophysiology @ Northwestern University At Chicago
Project Summary Obesity and diabetes are increased among individuals subjected to shiftwork, reduced sleep, and social jetlag. High fat diet (HFD) misaligns intrinsic circadian cycles with the light/dark cycle and alters oscillations of metabolic genes in visceral adipose tissue, a key site in the control of energy balance, glucose regulation, and inflammatory disorders. Conversely, restricting HFD to the dark period only realigns meal time with circadian rhythms and enhances insulin sensitivity, promoting healthful obesity. How circadian disruption in visceral adipose tissue contributes to obesity pathophysiology remains unknown. In exciting new data, we show strong day/night rhythms in adipocyte mitochondrial respiration with maximal uncoupling at the onset of the active period that is dependent upon a functional clock. Further, 13C-glucose entry into the tricarboxylic acid (TCA) cycle is also highest at the beginning of the active period, indicating autonomous circadian control of WAT metabolic flux across the day/night cycle. Surprisingly, in Bmal1-/- adipocytes, we observe reprogramming of adipocyte metabolism with increased 13C labeling in succinate and reduced levels of other TCA intermediates, a signature of stress and ROS accumulation. Here we seek to test the hypothesis that the circadian clock controls energy flux within visceral adipose tissue at the level of fuel entry into the TCA cycle through a process disrupted by HFD. In Aim 1, we will test the hypothesis that circadian coordination of feeding time and adipose energy utilization cycles promote healthful adipose expansion using genetic lineage tracer animals and metabolic phenotyping. We will assess adipose tissue remodeling and 13C glucose flux into the TCA cycle in addition to lipid and organic acids across the light-dark cycle in mice fed regular chow or HFD either ad lib or time-restricted to the light (misttimed feeding) or dark (optimal time feeding) period at thermoneutrality (30oC). We will also test the requirement of the WAT clock and the effect of adipose-specific BMAL1 overexpression in HFD on adipose remodeling, inflammation, fibrosis, and glucose homeostasis. Aim 1 results will establish the interplay between the WAT clock and feeding time in energy flux, metabolic health, and capacity for healthful adipose expansion, particularly with the new addition of the light-only feeding group for comparison to the dark- only and AL cohorts. In Aim 2, we will test the hypothesis that HFD abrogates circadian energetic cycles in visceral adipose tissue and induces epigenetic remodeling towards a proinflammatory cell fate. We will perform tandem chromatin and expression profiling in adipocytes to identify the time signature and molecular drivers of visceral WAT remodeling in ad lib and light- and dark-only-fed mice on HFD. Finally, we will examine whether BMAL1 overexpression during HFD preserves the healthful chromatin landscape of regular chow fed mice. Results of Aim 2 will determine how clock control of chromatin activity and transcription contributes to healthful obesity. Collectively, these studies will define the role of time-of-day in adipogenesis and nutrient flux, uncovering novel targets to combat the immunometabolic complications of obesity and circadian disruption.
|
0.958 |