Background/Purpose: We previously demonstrated that systemic sclerosis (SSc) patients have substantial reduction in dermal white adipose tissue (dWAT) which correlates with skin fibrosis. In animal models the loss of dWAT precedes dermal fibrosis indicating that this process may be a primary event. Leptin is a major adipokine involved in glucose homeostasis and known to be profibrotic in models of cardiac and lung fibrosis. We previously reported increased serum levels of leptin in patients with SSc. Given the important role of dWAT in SSc and skin fibrosis, we sought to investigate the role of leptin in in vivo fibrosis by comparing mice deficient in leptin (ob/ob) which have a substantially expanded dWAT with mice on diet-induced obesity which is known to increase levels of leptin.

Methods: ob/ob mice which lack functional leptin and littermate controls were treated with subcutaneous bleomycin or PBS. Wildtype mice were fed chow or high fat diet (60% kcal fat) for 12 weeks at libitum, and then treated with bleomycin or PBS injections. Skin was harvested and processed for histology, qPCR and immunohistochemical analysis. To assess the relevance of this pathway in disease, leptin expression in SSc was evaluated in publicly available gene expression datasets.

Results: ob/ob mice demonstrated significant protection from bleomycin-induced dermal fibrosis and loss of dermal white adipose tissue at both histological and gene expression level as compared to littermate mice. Conversely, although wildtype mice fed a high-fat diet showed significant expanded dWAT, bleomycin led to a complete loss of dWAT and fibrosis was comparable to mice fed a chow diet. Whereas ob/ob mice demonstrated a relative lack of inflammatory cellular infiltrate in response to fibrotic stimuli, the diet-induced obesity model showed an exuberant macrophage-rich inflammatory response. Interrogating skin biopsy transcriptome data, we found increased leptin pathway activation (p< 0.0001) in patients with SSc and mice treated with bleomycin (p=0002).

Conclusion: Our results implicate leptin as a profibrogenic mediator in skin fibrosis. Moreover, while these results continue to implicate the role of dWAT in skin fibrosis, they indicate that the quality rather than the quantity of dermal adipocytes is a key determining factor. A complex interplay between fibroblasts, adipocytes and macrophages define cutaneous fibrogenic potential.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/leptin-plays-a-critical-role-in-modulating-dermal-adipose-tissue-inflammation-and-skin-fibrosis/