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Loss of pericyte smoothened activity in mice with genetic deficiency of leptin.

Publication ,  Journal Article
Xie, G; Swiderska-Syn, M; Jewell, ML; Machado, MV; Michelotti, GA; Premont, RT; Diehl, AM
Published in: BMC Cell Biol
April 20, 2017

BACKGROUND: Obesity is associated with multiple diseases, but it is unclear how obesity promotes progressive tissue damage. Recovery from injury requires repair, an energy-expensive process that is coupled to energy availability at the cellular level. The satiety factor, leptin, is a key component of the sensor that matches cellular energy utilization to available energy supplies. Leptin deficiency signals energy depletion, whereas activating the Hedgehog pathway drives energy-consuming activities. Tissue repair is impaired in mice that are obese due to genetic leptin deficiency. Tissue repair is also blocked and obesity enhanced by inhibiting Hedgehog activity. We evaluated the hypothesis that loss of leptin silences Hedgehog signaling in pericytes, multipotent leptin-target cells that regulate a variety of responses that are often defective in obesity, including tissue repair and adipocyte differentiation. RESULTS: We found that pericytes from liver and white adipose tissue require leptin to maintain expression of the Hedgehog co-receptor, Smoothened, which controls the activities of Hedgehog-regulated Gli transcription factors that orchestrate gene expression programs that dictate pericyte fate. Smoothened suppression prevents liver pericytes from being reprogrammed into myofibroblasts, but stimulates adipose-derived pericytes to become white adipocytes. Progressive Hedgehog pathway decay promotes senescence in leptin-deficient liver pericytes, which, in turn, generate paracrine signals that cause neighboring hepatocytes to become fatty and less proliferative, enhancing vulnerability to liver damage. CONCLUSIONS: Leptin-responsive pericytes evaluate energy availability to inform tissue construction by modulating Hedgehog pathway activity and thus, are at the root of progressive obesity-related tissue pathology. Leptin deficiency inhibits Hedgehog signaling in pericytes to trigger a pericytopathy that promotes both adiposity and obesity-related tissue damage.

Duke Scholars

Published In

BMC Cell Biol

DOI

EISSN

1471-2121

Publication Date

April 20, 2017

Volume

18

Issue

1

Start / End Page

20

Location

England

Related Subject Headings

  • Smoothened Receptor
  • Receptors, Leptin
  • Paracrine Communication
  • Obesity
  • Myofibroblasts
  • Mice, Obese
  • Mice
  • Mesenchymal Stem Cells
  • Leptin
  • Hepatic Stellate Cells
 

Citation

APA
Chicago
ICMJE
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Xie, G., Swiderska-Syn, M., Jewell, M. L., Machado, M. V., Michelotti, G. A., Premont, R. T., & Diehl, A. M. (2017). Loss of pericyte smoothened activity in mice with genetic deficiency of leptin. BMC Cell Biol, 18(1), 20. https://doi.org/10.1186/s12860-017-0135-y
Xie, Guanhua, Marzena Swiderska-Syn, Mark L. Jewell, Mariana Verdelho Machado, Gregory A. Michelotti, Richard T. Premont, and Anna Mae Diehl. “Loss of pericyte smoothened activity in mice with genetic deficiency of leptin.BMC Cell Biol 18, no. 1 (April 20, 2017): 20. https://doi.org/10.1186/s12860-017-0135-y.
Xie G, Swiderska-Syn M, Jewell ML, Machado MV, Michelotti GA, Premont RT, et al. Loss of pericyte smoothened activity in mice with genetic deficiency of leptin. BMC Cell Biol. 2017 Apr 20;18(1):20.
Xie, Guanhua, et al. “Loss of pericyte smoothened activity in mice with genetic deficiency of leptin.BMC Cell Biol, vol. 18, no. 1, Apr. 2017, p. 20. Pubmed, doi:10.1186/s12860-017-0135-y.
Xie G, Swiderska-Syn M, Jewell ML, Machado MV, Michelotti GA, Premont RT, Diehl AM. Loss of pericyte smoothened activity in mice with genetic deficiency of leptin. BMC Cell Biol. 2017 Apr 20;18(1):20.
Journal cover image

Published In

BMC Cell Biol

DOI

EISSN

1471-2121

Publication Date

April 20, 2017

Volume

18

Issue

1

Start / End Page

20

Location

England

Related Subject Headings

  • Smoothened Receptor
  • Receptors, Leptin
  • Paracrine Communication
  • Obesity
  • Myofibroblasts
  • Mice, Obese
  • Mice
  • Mesenchymal Stem Cells
  • Leptin
  • Hepatic Stellate Cells