Invertebrate Models of Fat Storage

Summary

Principal Investigator: Jonathan M Graff
Abstract: DESCRIPTION (provided by applicant): The intertwined epidemics of obesity and diabetes have produced a public health crisis that demands an improved understanding of fat biology and metabolism. Through genetic screens in C. elegans and D. melanogaster, we identified many genetic regulators of invertebrate fat storage/metabolism that also have a conserved role in mammals. We focused our attention on one gene, Adipose (Adp), because its striking anti-obesity and anti-diabetes function in worms, flies, and mammals highlight its importance in metabolism and potential as a therapeutic target. The goal of this proposal is to unravel the physiological and molecular mechanisms underlying these striking effects. Our hope is that these metabolic and molecular studies will enhance our understanding of mammalian metabolism and lead to novel therapeutic strategies for obesity and diabetes. Adp regulates an ancient metabolic pathway. Reducing Adp function in worms, flies, mammalian adipogenic cells, and mice stimulates fat formation (obesity) and Adp mutant flies and mice have diabetes. These effects result from actions of Adp within adipocytes, as adipocyte-restricted expression of dominant negative Adp in mice caused obesity and diabetes. Conversely, fat selective expression of wild-type Adp produces lean, glucose sensitive flies and mice. Yet, there remain several unexplored issues relating to the in vivo metabolic phenotypes. In Aim I, we will characterize the metabolic physiology of our various invertebrate and mouse models in which Adp action is modified. These studies will rigorously test our hypothesis that altered energy expenditure underlies the anti-obesity actions of Adp. Then, we will examine how Adp regulates the responses to high fat diet and other metabolically relevant stimuli (Aims I and II). In parallel (Aim III), we unravel the molecular mechanisms underlying the Adp effects. Our initial studies show that Adp binds to and functions with several Adp interacting proteins (AIPs) that regulate chromatin dynamics and gene transcription. A unifying mechanism for how Adp regulates these AIPs stems from our data that Adp appears to control the substrate specificity of a novel ubiquitin E3 ligase complex. In Aim III, we will characterize the role that this E3 ligase has in fat biology;knowledge that is key in order to develop the fundamental insights required to ultimately manipulate the Adp pathway for therapeutic ends.
Funding Period: 2003-03-01 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc Adipose is a conserved dosage-sensitive antiobesity gene
    Jae Myoung Suh
    Department of Developmental Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, NB5 118, Dallas, TX 75390 9133, USA
    Cell Metab 6:195-207. 2007
  2. pmc Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies
    Drew Stenesen
    Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Cell Metab 17:101-12. 2013
  3. pmc A mouse model of rhabdomyosarcoma originating from the adipocyte lineage
    Mark E Hatley
    Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
    Cancer Cell 22:536-46. 2012
  4. pmc Wnt signaling activation in adipose progenitors promotes insulin-independent muscle glucose uptake
    Daniel Zeve
    Department of Developmental Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390 9133, USA
    Cell Metab 15:492-504. 2012
  5. pmc Osteoclast progenitors reside in the peroxisome proliferator-activated receptor γ-expressing bone marrow cell population
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9041, USA
    Mol Cell Biol 31:4692-705. 2011
  6. pmc Biphasic and dosage-dependent regulation of osteoclastogenesis by β-catenin
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9041, USA
    Mol Cell Biol 31:4706-19. 2011
  7. pmc Thiazolidinediones regulate adipose lineage dynamics
    Wei Tang
    Department of Developmental Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390 9133, USA
    Cell Metab 14:116-22. 2011
  8. pmc Fighting fat with fat: the expanding field of adipose stem cells
    Daniel Zeve
    Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, 75390 9133, USA
    Cell Stem Cell 5:472-81. 2009
  9. pmc White fat progenitor cells reside in the adipose vasculature
    Wei Tang
    Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Science 322:583-6. 2008
  10. pmc The developmental origins of adipose tissue
    Daniel C Berry
    Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Development 140:3939-49. 2013

Research Grants

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  2. Age Dependent Role of Bisphenol A in Obesity and Insulin Resistance
    Andrew S Greenberg; Fiscal Year: 2013
  3. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
  4. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013
  5. Transcriptional role of TLE3 in brown adipose tissue development and metabolism
    Claudio J Villanueva; Fiscal Year: 2013
  6. Novel mechanisms of mitochondrial regulation by sirtuin deacetylases
    DAVID BENNER LOMBARD; Fiscal Year: 2013
  7. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  8. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
  9. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
  10. Alerations of Sleep and Circadian Timing in Aging
    Eve Van Cauter; Fiscal Year: 2013

Detail Information

Publications11

  1. pmc Adipose is a conserved dosage-sensitive antiobesity gene
    Jae Myoung Suh
    Department of Developmental Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, NB5 118, Dallas, TX 75390 9133, USA
    Cell Metab 6:195-207. 2007
    ..Thus Adp appears to be involved in an ancient pathway that regulates fat accumulation...
  2. pmc Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies
    Drew Stenesen
    Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Cell Metab 17:101-12. 2013
    ....
  3. pmc A mouse model of rhabdomyosarcoma originating from the adipocyte lineage
    Mark E Hatley
    Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
    Cancer Cell 22:536-46. 2012
    ..Our findings suggest that adipocyte progenitors can be a cell of origin for Sonic hedgehog-driven ERMS, showing that RMS can originate from nonskeletal muscle precursors...
  4. pmc Wnt signaling activation in adipose progenitors promotes insulin-independent muscle glucose uptake
    Daniel Zeve
    Department of Developmental Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390 9133, USA
    Cell Metab 15:492-504. 2012
    ..Thus, adipose progenitor Wnt activation dissociates lipodystrophy from dysfunctional metabolism and highlights a fat-muscle endocrine axis, which may represent a potential therapy to lower blood glucose and improve metabolism...
  5. pmc Osteoclast progenitors reside in the peroxisome proliferator-activated receptor γ-expressing bone marrow cell population
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9041, USA
    Mol Cell Biol 31:4692-705. 2011
    ..These findings not only identify the long-sought-after osteoclast progenitors but also establish unprecedented tools for their visualization, isolation, characterization, and genetic manipulation...
  6. pmc Biphasic and dosage-dependent regulation of osteoclastogenesis by β-catenin
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9041, USA
    Mol Cell Biol 31:4706-19. 2011
    ..Importantly, these findings suggest that Wnt activation is a more effective treatment for skeletal fragility than previously recognized that confers dual anabolic and anti-catabolic benefits...
  7. pmc Thiazolidinediones regulate adipose lineage dynamics
    Wei Tang
    Department of Developmental Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390 9133, USA
    Cell Metab 14:116-22. 2011
    ..These data unravel unknown aspects of adipose dynamics and provide a basis to manipulate the adipose lineage for therapeutic ends...
  8. pmc Fighting fat with fat: the expanding field of adipose stem cells
    Daniel Zeve
    Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, 75390 9133, USA
    Cell Stem Cell 5:472-81. 2009
    ..Thus, the field is moving in a direction that may allow us to manipulate adipose stem cells to beneficial therapeutic ends...
  9. pmc White fat progenitor cells reside in the adipose vasculature
    Wei Tang
    Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Science 322:583-6. 2008
    ..Thus, the adipose vasculature appears to function as a progenitor niche and may provide signals for adipocyte development...
  10. pmc The developmental origins of adipose tissue
    Daniel C Berry
    Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Development 140:3939-49. 2013
    ..In this Review, we highlight recent efforts to unveil adipose developmental cues, adipose stem cell biology and the regulators of adipose tissue homeostasis and dynamism. ..

Research Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  2. Age Dependent Role of Bisphenol A in Obesity and Insulin Resistance
    Andrew S Greenberg; Fiscal Year: 2013
    ..abstract_text> ..
  3. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
    ..abstract_text> ..
  4. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013
    ....
  5. Transcriptional role of TLE3 in brown adipose tissue development and metabolism
    Claudio J Villanueva; Fiscal Year: 2013
    ..The proposed studies are a logical transition from my postdoctoral studies in adipogenesis to the burgeoning field of brown adipocyte biology. ..
  6. Novel mechanisms of mitochondrial regulation by sirtuin deacetylases
    DAVID BENNER LOMBARD; Fiscal Year: 2013
    ..Hence this work falls within the overall mission of NIGMS. ..
  7. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  8. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  9. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  10. Alerations of Sleep and Circadian Timing in Aging
    Eve Van Cauter; Fiscal Year: 2013
    ..Core B (Methods and Analysis) will standard operating procedures for data collection, archival and analysis. Core C will assay peripheral levels of hormones, cytokines and other blood constituents. ..
  11. Integration of Feeding and Glucose Metabolism by the Circadian Gene Network
    JOSEPH T BASS; Fiscal Year: 2013
    ..Ultimately, our studies will lead to new therapeutic strategies and, at the public health level, insight gained from our work will enable behavioral modifications to improve metabolic health. ..
  12. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
    ..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
  13. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  14. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  15. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  16. Nuclear Receptor Coactivator Functions and Mechanisms
    Robert G Roeder; Fiscal Year: 2013
    ..By identification of new factors and mechanisms, and thus of novel therapeutic targets, these studies will have important implications for the control of obesity and muscle dystrophy. ..