SirT1 regulates adipose tissue inflammation.

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.

• Authors: 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
• Journal: Diabetes (Diabetes) Vol. 60 Issue 12 Pg. 3235-45 (Dec 2011) ISSN: 1939-327X [Electronic] United States
• PMID: 22110092 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dietary Fats
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Sirtuin 1

Topics

• Adipose Tissue (immunology, metabolism)
• Adipose Tissue, White (immunology, metabolism)
• Animals
• Body Mass Index
• Dietary Fats (adverse effects)
• Flow Cytometry
• Humans
• In Vitro Techniques
• Inflammation (chemically induced, genetics, immunology, metabolism)
• Macrophages (immunology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Sirtuin 1 (genetics, immunology, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Weight Loss (genetics, physiology)