Lipopolysaccharide binding protein is an adipokine involved in the resilience of the mouse adipocyte to inflammation

Abstract

Aims/hypothesis Lipopolysaccharide (LPS) binding protein (LBP) is a novel 65 kDa adipokine, linked to adipose tissue (AT) inflammation, obesity and insulin resistance, that inhibits adipocyte differentiation. Here, we investigated the molecular mechanisms behind these detrimental effects on adipogenesis through whole-genome transcriptomics and in vitro experiments. Methods Permanent and transient knockdown (KD) and coculture experiments were performed in 3T3-L1 and 3T3-F442A cell lines during adipocyte differentiation. Microarray gene expression was performed using Genechip Affymetrix technology and validated by real-time PCR. Results LBP KD of 3T3-L1 cells led to a potentiated adipocyte differentiation with a dose-response relationship; genes involved in mitochondrial biogenesis, fatty acid metabolism and peroxisome proliferator-activated receptor γ (PPAR-γ) action were dramatically upregulated in parallel to increased insulin signalling. Cells with LBP KD became refractory to proinflammatory cytokines and other inflammatory stimuli (LPS and palmitate). This phenotype, mediated through disrupted nuclear factor κB (NFκB) signalling, was reversed by a soluble factor present in a co-culture with native cells and by exogenous LBP. Double-silencing of LBP and toll-like receptor 4 (TLR4) again rendered these cells insensitive to co-culture, LBP and inflammatory factors. Conclusions/interpretation In summary, LBP is a proinflammatory soluble adipokine that acts as a brake for adipogenesis, strengthening the negative effects of palmitate and LPS on adipocyte differentiation.

Dysbiosis Signatures of Gut Microbiota Along the Sequence from Healthy, Young Patients to Those with Overweight and Obesity

“…However, more high‐quality evidence is required to support this hypothesis. In addition, genes related to lipopolysaccharide biosynthesis proteins and bacterial invasion of epithelial cells were increased, which indicates that candidate pathogenic commensals might attach the colonic epithelial cells and facilitate the development of obesity via inflammation‐related mechanisms . Genes related to glycolysis, gluconeogenesis, and the pentose phosphate pathway were decreased in obesity, which partly explained the lower ability of the body to utilize glucose.…”

Lipopolysaccharide-binding protein is associated with arterial stiffness in patients with type 2 diabetes: a cross-sectional study

“…Recently, moderately increased LPS in circulation, or metabolic endotoxemia, in response to a high-fat diet was shown to trigger obesity and insulin resistance in mice [42, 43]. Several studies also showed that LBP is produced by adipocytes and plays an essential role in inflammation- and obesity-associated adipose tissue dysfunction [44, 45]. The relationship between LBP and obesity, insulin resistance, and the metabolic syndrome has been demonstrated in a number of studies performed in humans in both cross-sectional [8, 9, 11, 12] and prospective [10, 13] designs.…”

Lipopolysaccharide-binding protein is a negative regulator of adipose tissue browning in mice and humans

“…In addition to its immunostimulatory functions [14], LBP has been identified as an adipokine associated with obesityinduced metabolic and proinflammatory disorders [15,16]. The promotion of BAT activity and, especially, of WAT browning are active research areas that hold promise for strategies aimed at protecting against obesity and associated metabolic abnormalities (e.g.…”

“…LBP knockdown and co-culture experiments Stable silencing of Lbp was achieved by transfecting 3T3-L1 fibroblasts with small hairpin (interfering) RNA (shRNA) targeting mouse Lbp (shLBP)or control shRNA (shControl) (Sigma Mission shRNA; Sigma-Aldrich, St Louis, MO, USA) as previously reported [16], generating transfected cells described in this paper as shRNA-mediated LBP knockdown (shLBP) or control (shControl) cells, respectively. Where indicated, shLBP adipocytes were incubated with 10 ng/ml LBP (R&D Systems; Minneapolis, MN, USA) during differentiation.…”

“…LBP is also present in adipose tissues and high levels of LBP synthesis in white adipocytes are associated with WAT dysfunction in obesity [15]. LBP expression is associated with inflammatory markers and is increased with metabolic deterioration and insulin resistance in obese patients [16]. Here, we sought to establish the role of LBP in the browning of WAT.…”