DICER-Driven Regulation of Lipid Metabolism and Macrophage-Adipocyte Crosstalk in Partial Lipodystrophy

Using adipocyte-specific DICER-deficient models to mimic lipodystrophy, we identified early metabolic and inflammatory alterations that coincide with the onset of partial lipodystrophy. DICER deficiency in adipocytes impaired lipid metabolism, leading to increased release of saturated lipids and triglycerides into the medium while reducing the biosynthesis of anti-inflammatory lipids.

These changes promoted a pro-inflammatory environment by reprogramming macrophages to release IL-1beta. Lipidomic analyses revealed reduced levels of docosahexaenoic acid (DHA) and other polyunsaturated fatty acids (PUFAs) in DICER-deficient adipocytes, accompanied by increased expression of CYP450 enzymes linked to lipid degradation and reduced DHA biosynthesis. DHA supplementation mitigated the pro-inflammatory response triggered by conditioned media from DICER-deficient adipocytes.