Body mass index and dermal remodelling.

Abstract

It is now well established that not only is raised body mass index (BMI) a risk factor for pressure ulcers and impaired wound healing but that hypertrophy of subcutaneous adipocytes is associated with remodelling of dermal collagen architecture and abundance 1. However, whilst fibrillar collagens are the most abundant proteins in the dermis, other extracellular matrix (ECM) assemblies such as those that comprise the elastic fibre system, also play key roles in mediating skin mechanical properties. Components of this elastic fibre system, whilst more sparsely distributed than dermal fibrillar collagens, confer resilience (elasticity) and crucially act as sensitive histological markers of ECM remodelling in both mild 2 and severe photo-ageing 3 and in the skin of smokers 4. Additionally, restoration of the elastic fibre architecture in the papillary dermis, which may be induced by both topical retinoids and commercial anti-ageing formulations, is also associated with a clinically measureable reduction in skin wrinkles 5. Few studies, however, have attempted to characterise the effects of raised BMI and adipocyte hypertrophy on the elastic fibre system although Orpheu and colleagues have previously reported on the differential loss of collagen but not elastin after bariatric surgery-induced weight loss 6. Previously, Ezure and Amano have shown that subcutaneous adipose tissue volume is negatively correlated with elasticity in human photo-exposed facial skin 7. Now the same investigators, in their recent study published in Experimental Dermatology, present evidence for a link between raised BMI, adipocyte hypertrophy and the loss of elastic fibres in human abdominal skin 8. Elastic fibres are complex macro-molecular assemblies 9 which adopt a well-characterised architecture in young photoprotected human skin (Fig. 1). In the reticular dermis, large diameter elastic fibres, which are rich in highly cross-linked elastin, are associated with fibrillin microfibrils. In the papillary dermis however, the ratio of elastin to fibrillin is progressively reduced until bundles of fibrillin microfibrils, known as oxytalan fibres, intercalate into the DEJ. With their recent publication in this journal, Ezure and Amano present data which suggests that, in addition to the well-characterised effects of extrinsic (photo-) and intrinsic (chronological) ageing on dermal elastic fibres, increased subcutaneous fat may also be a mediator of elastic fibre degradation. In contrast with intra-cellular proteins, structural extracellular proteins and assemblies, including elastic fibres, are thought to persist in tissues for many decades 10. As a consequence, the reduced abundance of elastic fibres in the skin of high BMI individuals is likely to be due to increased degradative activity rather than to decreased deposition. In their skin biopsies, Ezure and Amano identify increased MMP9 expression as a potential mediator of elastic fibre degradation. Whilst it is clear that this enzyme can degrade both elastin and fibrillin, it is also the case that increased MMP9 activity would be expected to impact on other dermal components such as collagen IV and collagen VII which are integral to the structure of the DEJ 11. An alternative mechanism for the loss of elastic fibres may be the increased local oxidative stress which is positively correlated with increased adipocyte hypertrophy 1. We have recently demonstrated that solar-simulated radiation (operating directly or via photodynamically produced reactive oxygen species intermediates) can selectively degrade key elastic fibre components 12. Given the potential roles played by disrupted fibrillin microfibrils in mediating downstream matrix remodelling (via the release of sequestered TGF-β or the promotion of MMP expression), it may be that selective oxidation of elastic fibre-associated components (such as fibrillin-1 and fibulin-5) could, in turn, trigger further dermal remodelling 13-15. Ezure and Amano have made an important contribution by highlighting BMI as a mediator of elastic fibre architecture in human subjects. However, as should be the case with important scientific studies, their work also raises many additional questions. First, which mechanisms drive this remodelling? Potential candidates include not only perturbations in the normal homeostasis of ECM protease expression, activation and inhibition but also the selective oxidation of cysteine, tryptophan and tyrosine-rich elastic fibre components. Second, does adipocyte hypertrophy exacerbate the effects of UV exposure? Third and most intriguingly, how rapidly are elastic fibres lost as a consequence of subcutaneous adipocyte hypertrophy and, as appears to be the case for dermal collagen, is this loss irreversible 1? The author would like to acknowledge the financial support of Walgreens Boots Alliance Inc. The authors have declared no conflicting interests.