Role of Txnip in adapting fuel metabolism to nutritional state

Summary

Principal Investigator: SIMON HUI
Abstract: The ability to properly respond to prolonged periods of nutritional scarcity is vital to the survival of all living organisms. Thioredoxin interacting protein (Txnip) is a key metabolic regulator of this important adaptation process. Txnip modulates cellular sulfhydryl redox through its binding to thioredoxin and thereby inhibiting its redox function. Txnip knockout (TKO) mice become hypoglycemia, hypertriglycerdemia and hyperketonemia when fasted and cannot survive long-term fasting. Using tissue-specific Txnip knockout mice, we have identified that impaired mitochondrial oxidation in the muscle is the major contributor leading to these metabolic abnormalities. To compensate for energy deficiency, glucose uptake and glycolysis are elevated. Despite having impaired mitochondrial oxidation, TKO mice showed increased insulin/Akt signaling due to decreased amount of active PTEN (reduced form) and were resistance to high fat diet-induced diabetes. The goal of our proposed studies is to understand the molecular mechanisms by which Txnip alters mitochondrial function. Aim 1 is focused on identification of molecular defects leading to impaired mitochondrial oxidation in TKO mice. Electron microscopy will be used to detect alterations in mitochondrial ultrastructure. Mitochondrial respiration will be measured by polarography and the defective component in the oxidative phosphorylation pathway will be identified. Preliminary data obtained since our last submission showed that cellular NADPH level is decreased in TKO hearts. In Aim 2, we will test the hypothesis that lower NADPH availability increases mitochondrial oxidative stress, thereby leads to impaired fuel oxidation. Cellular antioxidant and ROS defense system will be measured as well as the levels of oxidative modified proteins, DNA and lipids in the mitochondria. To show the causative link between NADPH levels and mitochondrial function, NADPH levels in TKO embryonic fibroblasts will be modulated by adenoviral expression of NAD kinase. Correlation between cellular NADPH levels and mitochondrial oxidative stress and respiration will be determined. Our preliminary data also showed that AMPK signalling pathway is blunted in TKO mice. Aim 3 is to determine the link between blunted AMPK signaling and impaired mitochondrial function in TKO mice. The AMPK regulatory pathway will be dissected so as to determine how Txnip ablation causes impaired AMPK activation. Constitutively active AMPK will be expressed in TKO fibroblasts to test if correct AMPK signalling could rescue the respiration defective phenotype. Aim 4 is to determine how Txnip modulates mitochondrial function. Using targeted expression of wild-type and various mutations of Txnip in TKO fibroblasts, we will identify the subcellular site of action of Txnip and its essential functional features necessary for modulating mitochondrial oxidation. In addition, proteomics approach will be used to identify partners interacting with Txnip. This integrative approach will provide fundamental new knowledge on how Txnip regulates mitochondrial function and its link to metabolic regulation. PUBLIC HEALTH RELEVANCE: We have identified that Txnip is essential for maintaining proper metabolic response to changes in nutritional status and demonstrated that Txnip modulates mitochondrial fuel oxidation and insulin sensitivity in cardiac and skeletal muscle. Mitochondrial dysfunction and abnormal fuel metabolism are linked to the development of obesity, diabetes and cardiovascular disease. Results of this proposed research will provide fundamental information that may lead to better prevention and/or therapeutics for diabetes and cardiovascular disease in humans.
Funding Period: 2009-08-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc Diminished AMPK signaling response to fasting in thioredoxin-interacting protein knockout mice
    Allen M Andres
    Department of Biology, BioScience Center, San Diego State University, San Diego, CA 92182, USA
    FEBS Lett 585:1223-30. 2011
  2. pmc Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome
    Christine M Oslowski
    Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Cell Metab 16:265-73. 2012
  3. pmc Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits
    Anatole Ghazalpour
    Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
    Mamm Genome 23:680-92. 2012
  4. pmc Induction of the metabolic regulator Txnip in fasting-induced and natural torpor
    Laura E Hand
    Faculty of Life Sciences, AV Hill Building, University of Manchester, Manchester M13 9PT, UK
    Endocrinology 154:2081-91. 2013
  5. pmc Targeted metabolomics connects thioredoxin-interacting protein (TXNIP) to mitochondrial fuel selection and regulation of specific oxidoreductase enzymes in skeletal muscle
    Karen L Debalsi
    From the Sarah W Stedman Nutrition and Metabolism Center
    J Biol Chem 289:8106-20. 2014

Research Grants

  1. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
  2. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
  3. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
  4. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  5. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
  6. Shock Center for Aging Research at The Jackson Laboratory
    Gary Churchill; Fiscal Year: 2013
  7. Mitochondrial Proteins in Parkinson's Disease
    J Timothy Greenamyre; Fiscal Year: 2013
  8. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
  9. Mitochondrial-targeted CoQ: Metabolic and Redox Effects and role in Diabetes
    WILLIAM IRVING SIVITZ; Fiscal Year: 2013
  10. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013

Detail Information

Publications5

  1. pmc Diminished AMPK signaling response to fasting in thioredoxin-interacting protein knockout mice
    Allen M Andres
    Department of Biology, BioScience Center, San Diego State University, San Diego, CA 92182, USA
    FEBS Lett 585:1223-30. 2011
    ..These data suggest Txnip deficiency has a higher impact on oxidative muscle than glycolytic muscles and provide new insights into the metabolic role of Txnip...
  2. pmc Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome
    Christine M Oslowski
    Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Cell Metab 16:265-73. 2012
    ..Collectively, our results suggest that TXNIP is a potential therapeutic target for diabetes and ER stress-related human diseases such as Wolfram syndrome...
  3. pmc Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits
    Anatole Ghazalpour
    Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
    Mamm Genome 23:680-92. 2012
    ..In this essay, we review our experience with the HMDP, describe various ongoing projects, and discuss how the HMDP may fit into the larger picture of common diseases and different approaches...
  4. pmc Induction of the metabolic regulator Txnip in fasting-induced and natural torpor
    Laura E Hand
    Faculty of Life Sciences, AV Hill Building, University of Manchester, Manchester M13 9PT, UK
    Endocrinology 154:2081-91. 2013
    ....
  5. pmc Targeted metabolomics connects thioredoxin-interacting protein (TXNIP) to mitochondrial fuel selection and regulation of specific oxidoreductase enzymes in skeletal muscle
    Karen L Debalsi
    From the Sarah W Stedman Nutrition and Metabolism Center
    J Biol Chem 289:8106-20. 2014
    ..Considering that TXNIP expression increases in response to starvation, diabetes, and exercise, these findings point to a novel role for TXNIP in coordinating mitochondrial fuel switching in response to nutrient availability. ..

Research Grants31

  1. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  2. 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. ..
  3. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  4. 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. ..
  5. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  6. Shock Center for Aging Research at The Jackson Laboratory
    Gary Churchill; Fiscal Year: 2013
    ..In the long term, JSC will continue to focus JAX expertise in genomics and biology on aging, leading to enhanced resources for the research community and a better understanding of the molecular mechanisms of lifespan and healthspan. ..
  7. Mitochondrial Proteins in Parkinson's Disease
    J Timothy Greenamyre; Fiscal Year: 2013
    ....
  8. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
    ..This highly-integrated Program will make significant progress toward understanding the pathobiology of the enteric system in gastric emptying disorders and translate this knowledge into new diagnostic tools and therapy. ..
  9. Mitochondrial-targeted CoQ: Metabolic and Redox Effects and role in Diabetes
    WILLIAM IRVING SIVITZ; Fiscal Year: 2013
    ..4. Determine the effects of MTQAs on mitochondrial membrane potential and respiratory coupling when administered to live mice and delineate the mechanism(s) underlying this effect. ..
  10. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
    ..The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery. ..
  11. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013
    ....
  12. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  13. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  14. Linking Mitochondrial Bioenergetics to Muscle Insulin Sensitivity
    P Darrell Neufer; Fiscal Year: 2013
    ....
  15. Superfund Metal Mixtures, Biomarkers and Neurodevelopment
    David C Bellinger; Fiscal Year: 2013
    ..Aim 4- To promote rapid dissemination of significant research findings;and Aim 5- Compliance- To ensure compliance with NIH requirements for data and resource-sharing and the human and animal institutional review board requirements ..
  16. Injury and Recovery in Developing Brain
    Flora M Vaccarino; Fiscal Year: 2013
    ..The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth. ..
  17. Hopkins Center for Health Disparities Solutions
    THOMAS ALEXIS LAVEIST; Fiscal Year: 2013
    ..abstract_text> ..
  18. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..