Molecular Mechanisms Mediating Resistance to Leptin Signaling During Fat Gain

Summary

Principal Investigator: Virend Somers
Abstract: Obesity is associated with increased risk for the development of type 2 diabetes mellitus and cardiovascular disorders. New frontiers in therapeutic intervention against obesity lie in the recognition of novel mechanisms involved during the initial stages of weight gain in humans. There has been increasing interest in the role leptin, a peripheral circulating satiety factor, which plays a key role in balancing energy expenditure and preventing fat gain. However, leptin is found at higher levels in obese humans than in non-obese humans. The failure of elevated leptin to elicit weight loss in common forms of human obesity suggests the attenuation of leptin action (leptin resistance). To this end, we propose a novel hypothesis that resistance to leptin signaling is a result of molecular and structural changes in caveolar membrane microdomains. To test our hypothesis we propose a series of studies directed at investigating the molecular mechanisms involved in disruption of leptin signaling during weight gain, using abdominal adipose tissue obtained from healthy human subjects who gain body fat in response to an overfeeding protocol. We also propose to investigate the reversibility of these changes during fat loss. In our preliminary studies we have observed first, increases in circulating leptin levels during weight gain accompanied by decreased endothelium mediated vasodilation and increased adipocyte fat accumulation. Second, increases in caveolin-1 and endothelial nitric oxide synthase (eNOS) expression during weight gain and reversal of these changes during weight loss. Third, increases in leptin-dependent caveolin-1 expression in vitro. Fourth, the ability of caveolin-1 to inhibit leptin signaling in-vitro. These observations point to a probable role of caveolin-1 and caveolar microdomains in disruption of leptin signaling as a feedback mechanism in response to high leptin levels. In this proposal we will combine histological and molecular biologic approaches to study the morphological and compositional changes in caveolar membrane microdomains associated with weight gain and weight loss (AIM#1), and the role of caveolin-1 during weight gain and weight loss in adipocytes and adipose tissue microvasculature (AIM#2). We hypothesize that during weight gain, increased circulating leptin leads to increased caveolin-1 expression in adipose tissue, which in turn leads to increased caveolin-1 and Ob-R interaction in the caveolar microdomains. This increased interaction may result in disruption of downstream Ob-R signaling which would then lead to leptin resistance. Attenuation of leptin signaling will result in increased lipid accumulation and decreased eNOS activity. The uniqueness and translational strength of this proposal lies in studying at the molecular level dynamic weight changes in human subjects, and in our ability to differentially study them in adipocytes and adipose tissue microvessels along with in-vitro studies. The long term significance of the proposal will be in understanding the mechanisms involved in attenuation of leptin signaling during weight gain in human subjects and its reversibility during weight loss. This understanding would be pivotal in development of therapeutics related to leptin resistance and obesity. PUBLIC HEALTH RELEVANCE: The proposed studies will have clear and important implications regarding the molecular mechanisms involved in attenuation of leptin signaling during weight gain and its reversibility during weight loss. In addition the results of our proposed studies may be critical in development of therapeutics relating to leptin resistance and obesity.
Funding Period: 2008-09-30 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. pmc Leptin signaling in adipose tissue: role in lipid accumulation and weight gain
    Prachi Singh
    Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
    Circ Res 111:599-603. 2012
  2. pmc Effects of weight gain and weight loss on regional fat distribution
    Prachi Singh
    Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
    Am J Clin Nutr 96:229-33. 2012
  3. ncbi Obstructive sleep apnea and risk of stroke: time for a trial
    Andrew D Calvin
    Division of CardiovascularDiseases, Mayo Clinic, Rochester, MN 55905, USA
    Nat Clin Pract Cardiovasc Med 6:90-1. 2009
  4. pmc Obstructive sleep apnea, inflammation, and the metabolic syndrome
    Andrew D Calvin
    Mayo School of Graduate Medical Education, Mayo Clinic, Rochester, Minnesota 55905, USA
    Metab Syndr Relat Disord 7:271-8. 2009
  5. pmc Trends in 10-year predicted risk of cardiovascular disease in the United States, 1976 to 2004
    Francisco Lopez-Jimenez
    Divisions of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Circ Cardiovasc Qual Outcomes 2:443-50. 2009
  6. pmc Modest visceral fat gain causes endothelial dysfunction in healthy humans
    Abel Romero-Corral
    Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA
    J Am Coll Cardiol 56:662-6. 2010
  7. pmc Leptin upregulates caveolin-1 expression: implications for development of atherosclerosis
    Prachi Singh
    Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
    Atherosclerosis 217:499-502. 2011

Scientific Experts

  • Francisco Lopez-Jimenez
  • Prachi Singh
  • Virend K Somers
  • Michael D Jensen
  • Fatima H Sert-Kuniyoshi
  • Abel Romero-Corral
  • Andrew D Calvin
  • Snigdha Pusalavidyasagar
  • Diane E Davison
  • Timothy E Peterson
  • Jason A Glenn
  • Diane Davison
  • Marek Orban
  • Apoor Gami
  • Justo Sierra-Johnson
  • Christine Huyber
  • Susanne Votruba
  • Felipe N Albuquerque

Detail Information

Publications8

  1. pmc Leptin signaling in adipose tissue: role in lipid accumulation and weight gain
    Prachi Singh
    Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
    Circ Res 111:599-603. 2012
    ..Increases in leptin have been shown to impair leptin signaling via caveolin-1-dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known...
  2. pmc Effects of weight gain and weight loss on regional fat distribution
    Prachi Singh
    Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
    Am J Clin Nutr 96:229-33. 2012
    ..Normal-weight adults gain lower-body fat via adipocyte hyperplasia and upper-body subcutaneous (UBSQ) fat via adipocyte hypertrophy...
  3. ncbi Obstructive sleep apnea and risk of stroke: time for a trial
    Andrew D Calvin
    Division of CardiovascularDiseases, Mayo Clinic, Rochester, MN 55905, USA
    Nat Clin Pract Cardiovasc Med 6:90-1. 2009
    ..While this study contributes to our understanding of the interactions between OSA and the risk of both cardiovascular and cerebrovascular events, it also raises several important questions...
  4. pmc Obstructive sleep apnea, inflammation, and the metabolic syndrome
    Andrew D Calvin
    Mayo School of Graduate Medical Education, Mayo Clinic, Rochester, Minnesota 55905, USA
    Metab Syndr Relat Disord 7:271-8. 2009
    ..Whether some or all of these metabolic alterations mechanistically link OSA to metabolic syndrome remains to be proven, but it is an area of intense scientific interest...
  5. pmc Trends in 10-year predicted risk of cardiovascular disease in the United States, 1976 to 2004
    Francisco Lopez-Jimenez
    Divisions of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Circ Cardiovasc Qual Outcomes 2:443-50. 2009
    ..We assessed these trends by applying the Framingham Heart Study prediction model to national data...
  6. pmc Modest visceral fat gain causes endothelial dysfunction in healthy humans
    Abel Romero-Corral
    Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA
    J Am Coll Cardiol 56:662-6. 2010
    ..The aim of this study was to determine the impact of fat gain and its distribution on endothelial function in lean healthy humans...
  7. pmc Leptin upregulates caveolin-1 expression: implications for development of atherosclerosis
    Prachi Singh
    Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
    Atherosclerosis 217:499-502. 2011
    ..To determine the role of hyperleptinemia on caveolin-1 expression and leptin signaling...