Suppression of de-novo lipogenesis via Wnt-Dpp4 activation: A critical factor in the onset and recovery of fibrotic lipodystrophy
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Presented at: Society for Investigative Dermatology 2025
Date: 2025-05-07 00:00:00
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Summary: Skin fibrosis is characterized by lipodystrophy in the dermal white adipose tissue (DWAT), followed by accumulation of extracellular matrix (ECM) and a hallmark of diseases such as systemic sclerosis and keloids. It impacts 1 in 5,400 individuals worldwide annually, yet there are no effective treatments to prevent or reverse skin fibrosis. While many profibrotic factors and processes are implicated in dermal ECM expansion, the mechanisms underlying lipodystrophy in fibrotic DWAT remain unclear. Our inducible-reversible model of Wnt activation in fibro-adipoprogenitors of the skin showed that DWAT lipodystrophy was dependent on sustained activation of Wnt signaling and its downstream mediator dipeptidyl peptidase 4 (DPP4). Here, we test the hypothesis that the Wnt/DPP4 axis induces the early downregulation of de novo-lipogenesis (DNL) axis enzymes leading to fibrotic lipodystrophy in the skin. RNA-seq profiling of mature mouse dermal adipocytes <i>in vivo</i> revealed that all the key enzymes in the de novo lipogenesis axis were downregulated by two and also five days of Wnt activation <i>in vivo</i>. We showed that the protein expression of FASN, a key DNL enzyme, was highly dependent on Wnt activation in mature dermal adipocytes <i>in vivo</i> and <i>in vitro</i>. Wnt activation in the DPP4-/- mouse background led to dramatic rescue of FASN expression in the protected dermal adipocytes. Withdrawal from Wnt activation led to the recovery of lipodystrophic adipocytes, which was attenuated by a pharmacological blockade of FASN <i>in vivo</i>. Thus, WNT/DPP4 mediated downregulation of the DNL axis contributes to the onset and recovery from fibrotic lipodystrophy, opening new avenues for therapeutic targets in skin fibrosis. Suneeti Madhavan<sup>1</sup>, Michael Rudolf<sup>4</sup>, Radhika Atit<sup>1, 2, 3</sup> 1. Biology, Case Western Reserve University, Cleveland, OH, United States. 2. Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, United States. 3. Dermatology, Case Western Reserve University, Cleveland, OH, United States. 4. Phsiology, The University of Oklahoma Health Sciences, Oklahoma City, OK, United States. Stem Cell Biology, Tissue Regeneration and Wound Healing