{
  "abstract": "Introduction Loss of dermal white adipose tissue (dWAT) is a hallmark of scleroderma. We have shown that the dWAT change precedes and contributes to skin fibrosis in scleroderma mouse models, and that adipose derived mediators can have anti-fibrotic properties; however, the direct role of adipocytes still needs to be elucidated. In this study we sought to investigate the effect of increased adipose tissue in protection from skin fibrosis.Material and Methods We utilized complementary models of obesity including diet-induced (high-fat diet) and genetic models with mutations in the leptin pathway (ob/ob and db/db). Wildtype mice fed with chow or high-fat diet (HFD, 60% kcal fat), ob/ob mice, db/db mice and their littermate controls were treated with subcutaneous bleomycin or PBS injections. To investigate the direct effect of leptin, ob/ob mice which lack functional leptin were treated with recombinant leptin. Skin and lung were harvested and processed for histology, and skin was assessed for immunohistochemical, qPCR and RNA sequencing analysis. Whole blood samples were analyzed for adipokines using multiplex mouse assays.Results The two genetic models of obesity, ob/ob and db/db mice, showed protection from skin and and lung fibrosis with preservation of dWAT while mice fed on a HFD developed marked fibrosis with complete loss of dWAT that was exacerbated relative to bleomycin-treated mice fed on a chow-diet. Compared to ob/ob and db/db mice that demonstrated a relative lack of inflammatory cellular infiltrate in response to fibrotic stimuli, mice fed on a HFD showed marked skin inflammation including increased macrophage infiltrate and pro-inflammatory genes as well as systemic inflammation characterized by increased circulating levels of IL-6, MCP-1 and TNF-alpha. In the genetic models, RNA seq analysis demonstrated significant up-regulation of metabolic pathways including AKT/mTOR and p53 and down-regulation of the adipogenesis and fatty acid metabolism. No significant pathway differences were observed in diet-induced obesity. ob/ob mice treated with leptin maintained their protection from fibrosis.Conclusions Taken together, our results demonstrate that genetic models of obesity in the leptin pathway preserved their dWAT and were strongly protected from skin and lung fibrosis, while diet-induced obesity is not protective and may even exacerbate fibrosis. While leptin is known to have profibrotic effects, leptin replacement did not reverse the ob/ob phenotype. ob/ob and db/db mice had marked reduction in inflammation in the skin despite increased systemic markers of inflammation. Transcriptomic analysis demonstrated that this effect was mediated by metabolic pathways including up-regulation of AKT/mTOR and decreased adipogenesis pathways.",
  "authors": [
    {
      "affiliations": [
        "University of Rochester Medical Center, Rochester, USA"
      ],
      "name": "Roberta Marangoni"
    },
    {
      "affiliations": [
        "University of Rochester Medical Center, Rochester, USA"
      ],
      "name": "Gaochan Wang"
    },
    {
      "affiliations": [
        "University of Rochester Medical Center, Rochester, USA"
      ],
      "name": "Stacey Duemmel"
    },
    {
      "affiliations": [
        "University of Rochester Medical Center, Rochester, USA"
      ],
      "name": "Benjamin Korman"
    }
  ],
  "title": "P.023 Divergent effects of genetic and diet-induced obesity on dermal adipose tissue and fibrosis",
  "uid": "d801acc0-f599-567c-8c0d-902874f6d177"
}