Negative Regulation of Dermal Fibroblasts by Enlarged Adipocytes through Release of Free Fatty Acids

Subcutaneous adipose tissue lies just beneath the dermal layer, but the interaction between the two types of tissue remains obscure. Recently, we reported that obesity is associated with decreased dermal elasticity. To investigate the mechanism of the adipose tissue/dermal interaction, fibroblasts were cocultured with small or enlarged adipocytes, using a membrane insert to prevent direct contact. Enlarged adipocytes reduced 3T3-L1 fibroblast proliferation and gene expression of collagen (l)-alpha 1 (col (l)-alpha 1) and elastin while increasing gene expression of matrix metalloproteinase 13 (MMP13). In contrast, small adipocytes had no such effects. These results indicate that factors secreted by enlarged adipocytes influence dermal condition. As enlarged adipocytes are known to release free fatty acids (FFAs), the effects of these acids on 3T3-L1 fibroblasts were examined. Palmitic acid decreased fibroblast proliferation, reduced gene expressions of col (l)-alpha 1 and elastin, and increased MMP13. Similar effects were observed in human dermal fibroblasts. The influence of palmitic acid on fibroblasts was inhibited by eicosapentaenoic acid (EPA), an inhibitor of Toll-like receptors (TLRs). Furthermore, EPA inhibited the effects of enlarged adipocytes on fibroblasts in the coculture system. These data indicate that enlarged adipocytes negatively control the function of dermal fibroblasts through the activation of TLRs by secreted FFAs.