Abstract 12656: Phosphodiesterase 4 (PDE4) Inhibition Induces Weight Loss and Improves Insulin Resistance via cAMP-EPAC-AMPK Mediated Reprogramming of Macrophages
| Autor: | Chaoneng Wu, Sanjay Rajagopalan, Zhekang Ying, Andrei Maiseyeu, Jixin Zhong, Vaishali Bagalkot, Xiaoquan Rao, Jeffrey A. Deiuliis |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Circulation. 132 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circ.132.suppl_3.12656 |
| Popis: | Objective: Recent evidence suggests an important role for cAMP-dependent pathways in modulation of innate immune function. Phosphodiesterase 4 (PDE4) is widely expressed in innate immune cells such as macrophages/dendritic cells with potent anti-inflammatory effects on pharmacologic inhibition of the enzyme. We investigated the importance of PDE4 in diet-induced obesity (DIO) and hypothesized that PDE4 inhibition will improve insulin sensitivity and reduce inflammation. Methods and Results: PDE4 was upregulated in both visceral and subcutaneous (SubQ) white adipose tissue (WAT) in DIO mice (12 weeks of high-fat diet, HFD, 60% fat) compared to normal-chow diet (NCD) mice (↑4∼10-folds, p+ F4/80 + cells, r=0.56, p50 0.39 nM) versus vehicle control (n=6∼10 in each group) for 21 days concomitant with HFD, resulted in rapid and substantial weight loss (↓45.8% fat content), enhanced thermogenesis [(∼20% higher oxygen consumption and heat production, 0.7∼1.1°C higher core body temperature in a cold environment (4°C)], brown adipose reprogramming, improvement in insulin resistance (HOMA-IR ↓ from 0.69±0.04 to 0.44±0.01, pIn-vitro treatment of mouse bone marrow-derived macrophages (BMDM) promoted Altf and increased expression of tyrosine hydroxylase (↑2.5 folds) and catecholamines secretion. Additional experiments with agents that augment/reduce intracellular cAMP/EPAC/AMPK revealed an essential role for this cascade in Altf activation and catecholamine release. Conclusions: PDE4 antagonism improves obese diabetic symptoms through convergent pathways involving Altf activation and enhancing thermogenesis via cAMP dependent modulation of macrophage catecholamine release. |
| Databáze: | OpenAIRE |
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