Phosphodiesterase 3B (PDE3B) regulates NLRP3 inflammasome and metabolic cross talk in adipose tissue

Authors

• F Ahmad
• YW Chung
• Y Tang
• SC Hockman
• S Liu
• Y Khan
• K Huo
• MJ Amar
• AT Remaley
• VC Manganiello

Abstract

Activation of inflammation in white adipose tissue (WAT), which includes infiltration/expansion of WAT macrophages, contributes to pathogenesis of obesity, insulin resistance, type 2 diabetes, and metabolic syndrome. The inflammasome protein complex comprises an intracellular sensor (typically a Nod-like receptor, NLR), caspase-1 (a cysteine protease) and the adaptor ASC (apoptosis-associated speck-like protein). Inflammasome activation leads to the maturation of caspase-1 and processing of IL1β contributing to many metabolic disorders and directing adipocytes to a more insulin-resistant phenotype. Ablation of PDE3B in SVJ129 mice epididymal white adipose tissue (EWAT) prevents inflammasome activation by reducing the expressions of NLRP3, caspase-1, ASC, interferon-inducible protein AIM2, TNFα, IL1β and proinflammatory genes (i.e, cyclooxygenase2). Following IP (intraperitoneal) injection of lipopolysaccharide (LPS), serum levels of IL1β and TNFα were reduced in PDE3B-/- mice compared to WT. Moreover, chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemotactic protein-1 (MCP-1) and its receptor CCR2, which play an important role in the macrophage chemotaxis, were less highly expressed in EWAT of PDE3B-/- mice. In addition, atherosclerotic plaque formation was significantly reduced in the aorta of apoE-/-/PDE3B-/- and LDL-R-/-/PDE3B-/- mice compared to apoE-/- and LDL-R-/- mice, respectively. Collectively, these data establish a role for PDE3B in modulating the inflammatory response which may contribute to the decreased inflammatory state and reduced aortic plaque formation in PDE3B-/- mice.

Scientific Focus Area: Molecular Biology and Biochemistry

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