SirT1 regulates adipose tissue inflammation

Matthew P. Gillum, Maya E. Kotas, Derek M. Erion, Romy Kursawe, Paula Chatterjee, Kevin T. Nead, Eric S. Muise, Jennifer J. Hsiao, David W. Frederick, Shin Yonemitsu, Alexander S. Banks, Li Qiang, Sanjay Bhanot, Jerrold M. Olefsky, Dorothy D. Sears, Sonia Caprio, Gerald I. Shulman

Research output: Contribution to journalArticle

160 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3235-3245
Number of pages11
JournalDiabetes
Volume60
Issue number12
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

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Sirtuin 1
Adipose Tissue
Inflammation
Macrophages
Overnutrition
Subcutaneous Fat
Fats
Caloric Restriction
White Adipose Tissue
Endoplasmic Reticulum Stress
Histone Deacetylases
Antisense Oligonucleotides
Anorexia
Chemokines
Histones
Transgenic Mice

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Gillum, M. P., Kotas, M. E., Erion, D. M., Kursawe, R., Chatterjee, P., Nead, K. T., ... Shulman, G. I. (2011). SirT1 regulates adipose tissue inflammation. Diabetes, 60(12), 3235-3245. https://doi.org/10.2337/db11-0616

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.

In: Diabetes, Vol. 60, No. 12, 01.12.2011, p. 3235-3245.

Research output: Contribution to journalArticle

Gillum, MP, Kotas, ME, Erion, DM, Kursawe, R, Chatterjee, P, Nead, KT, Muise, ES, Hsiao, JJ, Frederick, DW, Yonemitsu, S, Banks, AS, Qiang, L, Bhanot, S, Olefsky, JM, Sears, DD, Caprio, S & Shulman, GI 2011, 'SirT1 regulates adipose tissue inflammation', Diabetes, vol. 60, no. 12, pp. 3235-3245. https://doi.org/10.2337/db11-0616
Gillum MP, Kotas ME, Erion DM, Kursawe R, Chatterjee P, Nead KT et al. SirT1 regulates adipose tissue inflammation. Diabetes. 2011 Dec 1;60(12):3235-3245. https://doi.org/10.2337/db11-0616
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. / SirT1 regulates adipose tissue inflammation. In: Diabetes. 2011 ; Vol. 60, No. 12. pp. 3235-3245.
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AU - Gillum, Matthew P.

AU - Kotas, Maya E.

AU - Erion, Derek M.

AU - Kursawe, Romy

AU - Chatterjee, Paula

AU - Nead, Kevin T.

AU - Muise, Eric S.

AU - Hsiao, Jennifer J.

AU - Frederick, David W.

AU - Yonemitsu, Shin

AU - Banks, Alexander S.

AU - Qiang, Li

AU - Bhanot, Sanjay

AU - Olefsky, Jerrold M.

AU - Sears, Dorothy D.

AU - Caprio, Sonia

AU - Shulman, Gerald I.

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N2 - 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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