SirT1 regulates adipose tissue inflammation.

Area of Science:

• Metabolism and Inflammation
• Adipose Tissue Biology
• Nutrient Sensing

Background:

• Macrophage recruitment to adipose tissue is a hallmark of obesity.
• The mechanisms linking overnutrition to adipose tissue inflammation and chemokine production remain unclear.
• Sirtuin 1 (SirT1), a nutrient-sensing histone deacetylase, is downregulated by overfeeding and upregulated by caloric restriction.

Purpose of the Study:

• To investigate the role of Sirtuin 1 (SirT1) in mediating the link between overnutrition and adipose tissue inflammation.
• To determine if SirT1 depletion influences chemokine production and macrophage recruitment to adipose tissue.
• To explore the potential of SirT1 as a regulatory component in adipose tissue inflammation.

Main Methods:

• Utilized antisense oligonucleotides to reduce SirT1 levels, mimicking overnutrition conditions.
• Employed SirT1-overexpressing transgenic mice and fat-specific SirT1 knockout models.
• Analyzed human subcutaneous adipose tissue biopsies from two independent cohorts.

Main Results:

• In vivo reduction of SirT1 induced macrophage recruitment to adipose tissue.
• SirT1 overexpression inhibited adipose tissue macrophage accumulation in high-fat fed mice.
• Human subcutaneous fat SirT1 expression was inversely correlated with adipose tissue macrophage infiltration.

Conclusions:

• Adipose tissue SirT1 reduction leads to histone hyperacetylation and ectopic inflammatory gene expression.
• Decreased SirT1 is a key regulator of macrophage influx into adipose tissue during overnutrition.
• SirT1 modulates adipose tissue inflammation by controlling proinflammatory transcription in response to fatty acids, hypoxia, and ER stress.