LIGHT is associated with hypertriglyceridemia in obese subjects and increased cytokine secretion from cultured human adipocytes

Abstract

Background: LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells) is a member of the tumor necrosis factor (TNF) family, primarily expressed in lymphocytes, which was associated with the induction of pro-inflammatory cytokines and alterations of lipid homeostasis in animal models. We aimed to analyze whether LIGHT has a role in the human obesity-associated inflammatory status. Methods: The association between circulating LIGHT concentrations and clinical variables was studied in 190 subjects with different degrees of obesity and glucose tolerance. The expression and release of 21 different cytokines, and the expression of genes involved in lipid metabolism were also evaluated after stimulation with LIGHT in cultured human differentiated adipocytes. Results: Serum LIGHT concentrations positively associated with body mass index (BMI), fat mass, glycated hemoglobin and fasting triglycerides, and negatively with high-density lipoprotein cholesterol. Circulating LIGHT concentrations were significantly increased in morbidly obese subjects and in patients with type 2 diabetes. LIGHT induced the secretion of several cytokines and upregulated the expression and secretion of interleukin-6 (IL-6), IL-8, Growth Regulated Oncogene (GRO) and monocyte chemotactic protein-1 (MCP-1). These observations were concomitant with the activation of nuclear factor (NF)-kB signalling in human differentiated adipocytes. LIGHT also upregulated the expression and synthesis of its own receptor (herpesvirus entry mediator (HVEM)) and decreased the expression of peroxisome proliferator-activated receptor-g (PPAR-g) and fatty acid synthase. Conclusion: These data suggest that LIGHT may have a role in mediating chronic inflammation and alterations of lipid metabolism in obese subjects.

LIGHT (TNFSF14) inhibits adipose differentiation without affecting adipocyte metabolism

“…The in vitro applied LIGHT concentrations are higher than reported serum levels. 11 Yet, it is well established that in vitro higher concentrations are necessary; and at least the EC 50 value for inhibition of differentiation determined in this study is very close to serum concentrations with tenfold difference. Despite the rather modest effect on cytokine production we observed an upregulation of the canonical NF-kB pathway by LIGHT, yet again to a much lower extent than by TNFa.…”

“…Its receptor (HVEM) was shown to be expressed in adipose tissue cells. 11 Furthermore, dysregulation of LIGHT in mouse T cells resulted in increased plasma triglycerides and cholesterol levels; 14 yet, the underlying mechanisms resulting in deregulated lipid metabolism remain unclear. Therefore, it was tempting to speculate that LIGHT has a specific function in adipose tissue.…”

“…In addition to this metabolic neutrality, we could also show that the production of proinflammatory cytokines by adipocytes was only modestly affected by LIGHT compared with TNFaFat least at the concentrations used in our experiments. Bassols et al 11 showed a proinflammatory activity of LIGHT for several chemokines at the mRNA and protein level. Yet, it is important to note that in this work the clearest proinflammatory effect was observed at tenfold higher LIGHT concentrations as used in our study, despite the fact that the concentrations used in our experiments were sufficient to potently inhibit differentiation.…”

“…11 We studied the effect of LIGHT on adipocyte-specific adipokines such as adiponectin and leptin in the supernatants of cultures of fully differentiated preadipocytes (on day 14) by enzyme linked immunosorbent assay. LIGHT did not alter total adiponectin or leptin secretion after 48 h of induction (Figures 4a and b).…”

Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

“…Soluble LIGHT (sLIGHT) concentrations are increased in morbidly obese and T2DM patients and correlate with BMI, triglycerides, fat mass, and glycated hemoglobin (HbA 1c ) (68). The expression of LIGHT and HVEM on T cells, monocytes, and adipocytes is increased in DIO mice.…”