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SirT1 Regulates Adipose Tissue Inflammation

Gillum, Matthew P., Kotas, Maya E., Erion, Derek M., Kursawe, Romy, Chatterjee, Paula, Nead, Kevin T., Muise, Eric S., Hsiao, Jennifer J., Frederick, David W., Yonemitsu, Shin, Banks, Alexander S., Qiang, Li, Bhanot, Sanjay, Olefsky, Jerrold M., Sears, Dorothy D., Caprio, Sonia, Shulman, Gerald I.·2011·Diabetes
DOI 10.2337/db11-0616PMC PMC3219953
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Abstract

OBJECTIVE: Macrophage recruitment to adipose tissue is a reproducible feature of obesity. However, the events that result in chemokine production and macrophage recruitment to adipose tissue during states of energetic excess are not clear. Sirtuin 1 (SirT1) is an essential nutrient-sensing histone deacetylase, which is increased by caloric restriction and reduced by overfeeding. We discovered that SirT1 depletion causes anorexia by stimulating production of inflammatory factors in white adipose tissue and thus posit that decreases in SirT1 link overnutrition and adipose tissue inflammation. RESEARCH DESIGN AND METHODS: We used antisense oligonucleotides to reduce SirT1 to levels similar to those seen during overnutrition and studied SirT1-overexpressing transgenic mice and fat-specific SirT1 knockout animals. Finally, we analyzed subcutaneous adipose tissue biopsies from two independent cohorts of human subjects. RESULTS: We found that inducible or genetic reduction of SirT1 in vivo causes macrophage recruitment to adipose tissue, whereas overexpression of SirT1 prevents adipose tissue macrophage accumulation caused by chronic high-fat feeding. We also found that SirT1 expression in human subcutaneous fat is inversely related to adipose tissue macrophage infiltration. CONCLUSIONS: Reduction of adipose tissue SirT1 expression, which leads to histone hyperacetylation and ectopic inflammatory gene expression, is identified as a key regulatory component of macrophage influx into adipose tissue during overnutrition in rodents and humans. Our results suggest that SirT1 regulates adipose tissue inflammation by controlling the gain of proinflammatory transcription in response to inducers such as fatty acids, hypoxia, and endoplasmic reticulum stress.

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  • Reduction of SIRT1 levels correlates with the development and progression of many inflammatory diseases.

    “reduction of SIRT1 levels correlates with the development and progression of many inflammatory diseases”

    From The Hallmarks of Aging (2013) · cites this paper as Gillum et al., 2011

    The Results (Fig. 6; page unavailable) report an inverse correlation between SirT1 expression and macrophage markers in human adipose tissue. The Conclusions (page unavailable) link reduced SirT1 to adipose tissue inflammation during overnutrition. The paper does not establish a correlation with the development or progression of many inflammatory diseases; that extends beyond the condition studied. (LLM, conf=0.88)

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  • Pharmacologic activation of SIRT1 may prevent inflammatory responses in mice.

    “pharmacologic activation of SIRT1 may prevent inflammatory responses in mice”

    From The Hallmarks of Aging (2013) · cites this paper as Gillum et al., 2011

    The Results section reports that genetic SirT1 overexpression reduced high-fat-diet-induced adipose tissue inflammation in mice. It does not establish that pharmacologic activation has this effect; the paper also cautions that polyphenols used to modify SirT1 function are not direct activators. Its findings are specific to the high-fat-diet setting, while SirT1-overexpressing mice on regular chow showed elevated inflammatory markers. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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Citations

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Research works printed but not linked: 31

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Metadata

Authors
Gillum, M. P., Kotas, M. E., Erion, D. M., Kursawe, R., Chatterjee, P., Nead, K. T., Muise, E. S., Hsiao, J. J., Frederick, D. W., Yonemitsu, S., Banks, A. S., Qiang, L., Bhanot, S., Olefsky, J. M., Sears, D. D., Caprio, S., & Shulman, G. I.
Affiliations
  • Howard Hughes Medical Institute, Chevy Chase, Maryland
  • Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut
  • Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
  • Merck, Rahway, New Jersey
  • Department of Cell Biology, Harvard School of Medicine, Boston, Massachusetts
  • Columbia University, New York, New York
  • Isis Pharmaceuticals, Carlsbad, California
  • University of California San Diego, San Diego, California
Venue
Diabetes
Publisher
American Diabetes Association
Published
2011-11-13
Volume
60
Issue
12
Pages
3235-3245
ISSN
  • 0012-1797
  • 1939-327X
DOI
10.2337/db11-0616
PMC
PMC3219953
Cited by
260
References
17
Language
en
Licence
creativecommons.org/licenses/by-nc-nd/3.0/ (vor, 3575 d)

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