HMGB1 is secreted by 3T3-L1 adipocytes through JNK signaling and the secretion is partially inhibited by adiponectin.

Abstract

Obesity is a chronic inflammatory disease, and adipocytes contribute to obesity-associated inflammation by releasing inflammatory mediators. High mobility group box 1 (HMGB1), a highly conserved DNA-binding protein, mainly localized to cell nuclei, has been recently recognized as an innate pro-inflammatory mediator when released extracellularly. It was hypothesized that HMGB1 is an adipocytokine that acts as an innate pro-inflammatory mediator in white adipose tissue (WAT) of patients with obesity and is associated with insulin resistance. Additionally, it was hypothesized that HMGB1 secretion is regulated by adiponectin. 3T3-L1 cells were differentiated into mature adipocytes. After tumor necrosis factor-α (TNF-α) stimulation, HMGB1 in culture media was measured. Localizations of HMGB1 in 3T3-L1 adipocytes and human WAT were examined by immunostaining. HMGB1 was secreted from TNF-α-induced 3T3-L1 adipocytes through JNK signaling. HMGB1-activated MAP kinases (ERK1/2, JNK) and suppressed insulin-stimulated Akt phosphorylation in 3T3-L1 adipocytes. The cytoplasm in 3T3-L1 adipocytes and adipocytes of WAT from a patient with obesity was intensely stained with HMGB1. Adiponectin partially inhibited TNF-α-induced HMGB1 secretion from 3T3-L1 adipocytes. These findings suggest that HMGB1 is a pro-inflammatory adipocytokine involved in WAT inflammation and insulin resistance in patients with obesity, which may contribute to the progression of metabolic syndrome, and that adiponectin protects against HMGB1-induced adipose tissue inflammation.