Stable isotope-based fate mapping to quantify adipogenesis in obesity

Summary

Principal Investigator: MATTHEW STEINHAUSER
Abstract: DESCRIPTION (provided by applicant): Recent evidence from human studies suggests that adipocytes turnover throughout adult life. While it has long been thought that adult adipocytes are generated from a stem cell population, recent lineage mapping experiments in mice provide strong evidence for an adipocyte precursor residing within adipose tissue. Many questions regarding the role of adipocyte turnover during normal homeostasis and in obesity remain incompletely elucidated, in large part because there have not been definitive methods to quantitate adipogenesis in vivo. The central hypothesis of this project is that caloric excess results in dynamic changes in precursor-dependent white adipose turnover. Deconstructing the role of adipogenesis in obesity and diabetes will not only yield important mechanistic insight into these disease processes, but may provide the rationale to directly target adipogenesis with pharmacotherapies. To address the central hypothesis, novel approaches to quantitate adipogenesis in vivo using stable isotope labeling and two mass spectrometry based platforms will be utilized. Rare stable isotopes differ in mass from more common isotopic forms of elements, but they are not radioactive, and thus are entirely safe and biologically inert. Preliminary data suggests that stable isotope-enriched thymidine is an effective tracer to detect DNA synthesis and cellular division. Using pulse-chase strategies and mass spectrometry, including multi-isotope mass spectrometry (MIMS) an exciting new microscopy methodology that can detect areas of stable isotope incorporation within tissues with sub-cellular resolution, adipogenesis can be quantified after biologically relevant interventions, in vivo. Aim 1: To test the hypothesis that high fat feeding will result in a dynamic increase in white adipose adipogenesis. Adult mice will be randomized to a normal diet or an adipogenic (high-fat) diet, and two stable isotope based approaches will be used to determine whether adipose expansion as occurs in obesity is associated with increased generation of new adipocytes. Aim 2: To test the hypothesis that prolonged high fat feeding with resultant obesity-related insulin resistance results in a relative deficiency in subcutaneous adipogenesis in favor of increased visceral adipogenesis. The rates of adipogenesis will be compared between obese and lean mice in response to a high fat diet, with the aim to answer the question of whether obesity results in depot specific defects in adipogenesis, which may contribute to coexistent insulin resistance. Aim 3: To test the hypothesis that PPAR-gamma activation will stimulate white adipose adipogenesis, in vivo. Stable isotope methods will be used to quantitate adipogenesis after pharmacologic stimulation of PPAR-gamma with a thiazolidinedione in obese and lean mice.
Funding Period: 2012-01-01 - 2016-12-31
more information: NIH RePORT

Top Publications

  1. pmc Mammalian heart renewal by pre-existing cardiomyocytes
    Samuel E Senyo
    Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Cambridge, Massachusetts 02139, USA
    Nature 493:433-6. 2013
  2. pmc Braveheart, a long noncoding RNA required for cardiovascular lineage commitment
    Carla A Klattenhoff
    Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
    Cell 152:570-83. 2013
  3. pmc Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy
    Francesco S Loffredo
    Harvard Stem Cell Institute, Brigham and Women s Hospital, Boston, MA 02115, USA
    Cell 153:828-39. 2013
  4. pmc An engineered bivalent neuregulin protects against doxorubicin-induced cardiotoxicity with reduced proneoplastic potential
    Steven M Jay
    Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, USA
    Circulation 128:152-61. 2013

Research Grants

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013

Detail Information

Publications5

  1. pmc Mammalian heart renewal by pre-existing cardiomyocytes
    Samuel E Senyo
    Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Cambridge, Massachusetts 02139, USA
    Nature 493:433-6. 2013
    ..These data reveal pre-existing cardiomyocytes as the dominant source of cardiomyocyte replacement in normal mammalian myocardial homeostasis as well as after myocardial injury...
  2. pmc Braveheart, a long noncoding RNA required for cardiovascular lineage commitment
    Carla A Klattenhoff
    Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
    Cell 152:570-83. 2013
    ..Together, our work provides evidence for a long noncoding RNA with critical roles in the establishment of the cardiovascular lineage during mammalian development...
  3. pmc Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy
    Francesco S Loffredo
    Harvard Stem Cell Institute, Brigham and Women s Hospital, Boston, MA 02115, USA
    Cell 153:828-39. 2013
    ..Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging...
  4. pmc An engineered bivalent neuregulin protects against doxorubicin-induced cardiotoxicity with reduced proneoplastic potential
    Steven M Jay
    Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, USA
    Circulation 128:152-61. 2013
    ..Here, we hypothesized that a newly formulated, covalent NN would be cardioprotective with reduced proneoplastic effects in comparison with NRG...

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. ..