Reduced Expression of Collagen VI Alpha 3 (COL6A3) Confers Resistance to Inflammation-Induced MCP1 Expression in Adipocytes

Objective: Collagen VI alpha 3 (COL6A3) is associated with insulin resistance and adipose tissue inflammation. In this study, the role of COL6A3 in human adipocyte function was characterized. Methods: Immortalized human preadipocyte cell lines stably expressing control or COL6A3 shRNA were used to study adipocyte function and inflammation. Results: COL6A3 knockdown increased triglyceride content, lipolysis, insulin-induced Akt phosphorylation, and mRNA expression of key adipogenic genes (peroxisome proliferator-activated receptor-c, glucose transporter, adiponectin, and fatty acid binding protein), indicating increased adipocyte function and insulin sensitivity. However, COL6A3 knockdown decreased basal adipocyte chemokine (C-C motif) ligand 2 [CCL2, monocyte chemoattractant protein (MCP1)] mRNA expression, reduced secreted protein levels, and abrogated tumor necrosis factor-alpha-and lipopolysaccharide-induced MCP1 mRNA expression. In addition, while control adipocytes co-cultured with THP1 macrophages showed a threefold increase in adipocyte MCP1 mRNA expression, in COL6A3 knockdown adipocytes MCP1 mRNA expression was unaltered by co-culturing. Lastly, in normal differentiated adipocytes, matrix metalloproteinase-11 treatment reduced expression of COL6A3 protein, MCP1 mRNA, MCP1 secretion, and abrogated tumor necrosis factor-alpha -and lipopolysaccharide-induced MCP1 mRNA expression and protein secretion. Conclusions: COL6A3 knockdown in adipocytes leads to the development of a unique state of inflammatory resistance via suppression of MCP1 induction.