Abstract
Activation of inflammation in white adipose tissue (WAT), includes infiltration/expansion of WAT macrophages, contributes pathogenesis of obesity, insulin resistance, and metabolic syndrome. The inflammasome comprises an intracellular sensor (NLR), caspase-1 and the adaptor ASC. Inflammasome activation leads to 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 WAT prevents inflammasome activation by reducing expression of NLRP3, caspase-1, ASC, AIM2, TNFα, IL1β and proinflammatory genes. Following IP injection of lipopolysaccharide (LPS), serum levels of IL1β and TNFα were reduced in PDE3B−/−mice compared to WT. Activation of signaling cascades, which mediate inflammasome responses, were modulated in PDE3B−/−mice WAT, including smad, NFAT, NFkB, and MAP kinases. Moreover, expression of chemokine CCL2, MCP-1 and its receptor CCR2, which play an important role in macrophage chemotaxis, were reduced in WAT 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. Obesity-induced changes in serum-cholesterol were blocked in PDE3B−/−mice. Collectively, these data establish a role for PDE3B in modulating inflammatory response, which may contribute to a reduced inflammatory state in adipose tissue.
Highlights
Crosstalk among enlarged adipocytes, macrophages, and activated endothelial cells perpetuate a vicious cycle of macrophage infiltration mediated by monocyte chemoattractant protein (MCP-1) and aggravate the inflammatory state[5,6]
Upon analysis of Affymetrix MU74A Version 2 arrays, changes in expression of a total of 573 white adipose tissue (WAT) genes were identified as significant (p≤0 .05) (Table S1)
195 had greater than a two-fold increase or decrease in PDE3B−/−WAT compared with wild type (WT) WAT (Fig. 1a)
Summary
Changes in PDE3B−/−epididymal white adipose tissue (WAT) transcriptome. Upon analysis of Affymetrix MU74A Version 2 arrays, changes in expression of a total of 573 WAT genes were identified as significant (p≤0 .05) (Table S1). Compared to apoE−/−and LDL-R−/−mice, in the aorta of apoE−/−/PDE3B−/−and LDL-R−/−/PDE3B−/−mice fed standard diet (fat content 10 kcal%) and (HFD, fat content 60 kcal%) for 10 weeks, plaque formation was significantly reduced (Fig. 7), in PDE3B−/−crossbred mice, suggesting that reduced expression of PDE3B play a role in modulating the inflammatory response and PDE3B signaling might be a possible therapeutic target to moderate atherosclerosis. In apoE-/-/PDE3B−/−as well as LDL-R-/-/PDE3B−/−mice, increased cAMP/PKA signaling with decreased expression of PDE3B resulted in reduced macrophage infiltration and atherosclerotic plaque formation, due to reduced inflammatory serum cytokines and reduced inflammation. These studies suggest that reduced expression of PDE3B play an important role in reduced atherosclerotic plaque formation and regulation of serum cholesterol in HFD-fed mice. CAMP/PKA-signaling regulated by PDE3B in adipose tissue and potential targeting of caspase-1 activation through NLRP3 inflammasome, may be a new therapeutic target for the development of anti-obesity and anti-inflammatory drugs
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