DPP4 Substrate Supplementation Protects From WNT‐Induced Lipid Depletion in Dermal Adipocytes

Adipocytes exhibit remarkable plasticity, dynamically gaining and losing lipid content. However, during skin fibrosis, this adaptability becomes detrimental as adipocytes undergo lipid depletion associated with disease pathology. We previously identified the WNT signalling pathway-acting through Dipeptidyl Peptidase IV (DPP4) - as a key mediator of lipid depletion associated with skin fibrosis, but the mechanism remains unclear. DPP4 is an exopeptidase that cleaves a wide array of substrates across different cell types. Here, we investigate whether modulation of lipid-regulating DPP4 substrates is sufficient to preserve lipid content in WNT-activated dermal adipocytes. Using two complementary strategies, we found that supplementation with the DPP4 substrates Neuropeptide Y (NPY) and Glucose-dependent Insulinotropic Peptide (GIP) can partially protect lipid content in dermal adipocytes. When used in combination, we found that the protection against lipid depletion was more effective than monotherapy alone. These findings demonstrate that supplementation with DPP4 substrates provides a basis for targeted treatments for lipodystrophy syndromes and skin fibrosis.