DICER-driven regulation of lipid metabolism and macrophage-adipocyte crosstalk in partial lipodystrophy

Partial lipodystrophy is characterized by abnormal fat distribution, impaired thermogenesis, systemic inflammation, and diminished DICER1 expression in adipose tissue. Using adipocyte-specific Dicer1-deficient murine models to mimic lipodystrophy, we identified early metabolic and inflammatory alterations associated 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 inducing macrophages to release IL-1β. In parallel, both adipocyte-autonomous DICER deficiency and the resulting inflammatory environment impaired adipocyte thermogenic capacity. Lipidomic analyses revealed reduced levels of docosahexaenoic acid (DHA) and other polyunsaturated fatty acids (PUFAs) in Dicer1-deficient adipocytes, accompanied by increased expression of genes encoding CYP450 enzymes linked to lipid degradation, and reduced DHA biosynthesis. Co-culture experiments confirmed that Dicer1-deficient adipocytes exacerbate macrophage-driven pro-inflammatory profile and thermogenic gene suppression. Notably, DHA supplementation mitigated the pro-inflammatory response triggered by conditioned media from Dicer1-deficient adipocytes. These findings reveal a critical role for adipocyte DICER in regulating lipid metabolism, macrophage-adipocyte interactions, and thermogenic function, offering new insights into molecular mechanisms driving metabolic dysfunction and chronic inflammation associated with partial lipodystrophy.