Sagging may be associated with the reduction of skin elasticity and mimetic muscle function and increase of fat mass, but the relationships are different in different areas of the cheek.

Adipocytes were recently shown to secrete adipocytokines, such as adiponectin and leptin, which may have an endocrine role. Subcutaneous adipose tissue lies just beneath the dermis, and dermal condition is correlated with body mass index (BMI). However, it is not clear whether adipocytokines released by adipocytes in subcutaneous adipose tissue influence the adjacent dermis. We found that human dermal fibroblasts express genes encoding receptors for adiponectin and leptin, and that those cytokines both significantly increase production of hyaluronic acid (HA), a major extracellular matrix component (ECM) of dermis, by dermal fibroblasts. This effect is accompanied with up-regulation of HA synthase 2 gene expression. Moreover, adiponectin significantly increases production of collagen, the most abundant component of ECM in dermis, by dermal fibroblasts. These results suggest that subcutaneous adipocytes influence dermal condition by up-regulating collagen and HA production by dermal fibroblasts via secretion of adiponectin and leptin.

These results indicate that increment of subcutaneous adipose mass impairs dermal elasticity, which in turn exacerbates sagging severity.

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 (I)-α1 (col (I)-α1) 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 (I)-α1 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.

Obesity is a significant risk factor for various skin disorders, including pressure ulcer and delayed wound healing. We previously showed that increment of subcutaneous adipose tissue contributes to poor skin condition by decreasing dermal elasticity. Here, we examined the mechanism involved. Histologic observation of abdominal skin from middle-aged females with a wide range of body mass index (BMI), an indicator of subcutaneous fat mass, showed that dermal elastic fibre abundance was significantly decreased with increment of BMI. Concomitantly, adipocytes were significantly enlarged. Adipocyte enlargement was significantly negatively correlated with dermal elastic fibre abundance. We hypothesized that enlarged adipocytes negatively influence dermal elastic fibres, so we investigated elastic fibre-degrading factors in in vitro-cultured enlarged adipocytes. MMP9 gene expression and secretion were significantly increased; further, these changes were blocked by extracellular signal-regulated kinase (ERK) inhibitor. Nuclear translocation (activation) of AP-1, a downstream ERK signalling molecule, was also observed in enlarged adipocytes. MMP9 abundance was significantly increased in skin of subjects with high BMI and enlarged adipocytes. These results suggest that increment of subcutaneous adipose tissue leads to adipocyte enlargement together with increased degradation of dermal elastic fibres, mediated at least in part by an ERK signalling-mediated increase of MMP9 in enlarged adipocytes.