SirT1 Regulates Adipose Tissue Inflammation

Abstract

OBJECTIVEMacrophage 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 METHODSWe 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.RESULTSWe 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.CONCLUSIONSReduction 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.

A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction

“…In fact, human adipocytes from obese individuals were also characterised by increased LBP and decreased lipogenic gene expression when compared with those from non-obese individuals. Inflammation-induced AT LBP biosynthesis may promote macrophage infiltration and recruitment in AT by increasing nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NFκB) proinflammatory activity in adipocytes [36][37][38]. Supporting this idea, Lbp gene expression preceded the expression of different macrophage markers in Pparγ +/− and POKO mice.…”

Calorie restriction and sirtuins revisited

“…SIRT1 also drives the browning of white fat cells (Qiang et al 2012), which would trigger fat oxidation in situ. Consistent with these functions, inhibition of SIRT1 in WAT is associated with macrophage recruitment and inflammation (Gillum et al 2011). One target for deacetylation by SIRT1 in WAT is the nuclear receptor PPARg.…”

Central metabolic-sensing remotely controls nutrient –sensitive endocrine response in Drosophila via Sir2/Sirt1-upd2-IIS axis

“…In this regard, hepatic and adipocyte-specific disruption of Sirt1 results in hyperinsulinemia in mammals (Purushotham et al, 2009;Wang et al, 2011;Gillum et al, 2011), but the mechanisms are poorly understood. Although a role for Sir2/Sirt1 in controlling dILP2 secretion was identified (Palu and Thummel, 2016), the tissue of origin of Sir2/Sirt1-dependent dILP control is still unknown.…”