Metabolic Dysfunction Drives a Mechanistically Distinct Proinflammatory Phenotype in Adipose Tissue Macrophages

Abstract

Adipose tissue macrophage (ATM)-driven inflammation plays a key role in insulin resistance; however, factors activating ATMs are poorly understood. Using a proteomics approach, we show that markers of classical activation are absent on ATMs from obese humans, but readily detectable on airway macrophages of patients with cystic fibrosis, a disease of chronic bacterial infection. Moreover, treating macrophages with glucose, insulin, and palmitate – conditions characteristic of the metabolic syndrome – produces a ‘metabolically-activated’ phenotype distinct from classical activation. Markers of metabolic activation are expressed by pro-inflammatory ATMs in obese humans/mice and are positively correlated with adiposity. Metabolic activation is driven by independent pro- and anti-inflammatory pathways, which regulate balance between cytokine production and lipid metabolism. We identify PPARγ and p62/SQSTM1 as two key proteins that promote lipid metabolism and limit inflammation in metabolically-activated macrophages. Collectively, our data provide important mechanistic insights into pathways that drive the metabolic disease-specific phenotype of macrophages.

Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes, and subclinical atherosclerosis

“…Both in mouse and human macrophages, plasma membrane-associated ACSL1 levels increase after TLR4 and IFN-␥ stimulation ( 6,9 ) and also increase in human macrophages exposed to increased metabolic activation by insulin, elevated glucose, and palmitate ( 10 ). When these cells are exposed to metabolic or infl ammatory activation, ACSL1 is required for effective phospholipid For each of the three SNPs identifi ed in consortium studies ( Table 1 ), primary analyses in MESA focused on the phenotype analyzed in discovery of each SNP, including glucose (log-transformed) and diabetes status.…”

Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

“…These inflammatory markers have direct effects on cellular metabolism, leading to decreased AT expandability, development of fibrosis, and dysfunction [8][9][10][11] . Similar to other inflammatory processes, white AT (WAT) inflammation is intrinsically linked to oxidative stress.…”

Luteolin reduces obesity-associated insulin resistance in mice by activating AMPKα1 signalling in adipose tissue macrophages

“…RAW264.7 cells and PCMs were planted in 24-well plates and pretreated with vehicle, 20 μmol/l LU or 2 mmol/l of the AMPKα1 activator AICAR (5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside; Sigma-Aldrich, St. Louis, MO, USA) for 12 h. To examine the effects of LU on macrophage M1 polarisation, the cells were stimulated with 100 ng/ml LPS (Sigma-Aldrich) according to previously published reports [14,25]. The MMe phenotype polarisation method was performed according to the procedures described by Kratz et al [14].…”

“…The MMe phenotype polarisation method was performed according to the procedures described by Kratz et al [14]. These cells were treated with PIG (100 μmol/l palmitate, 10 nmol/l insulin and 30 mmol/l glucose).…”

“…Although this switch of M2 to M1 macrophages has been considered to be responsible for obesity-associated metabolic complications [13], ATM polarisation is more complex in obese states. Recently, Kratz et al used a mixture of palmitate, insulin and glucose (PIG) to produce a 'metabolic activation' macrophage (MMe) and reported the existence of this phenotype in EATs of obese mice [14]. This macrophage phenotype overexpresses the proinflammatory cytokines TNF-α, IL-1β and IL-6, but not M1 macrophage surface markers [14].…”