Increased cGMP promotes healthy expansion and browning of white adipose tissue
Increased cGMP promotes healthy expansion and browning of white adipose tissue
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DOI：
10.1096/fj.12-221580
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发表时间：
2013-04-01
期刊：
影响因子：
4.8
通讯作者：
Kilic, Ana
中科院分区：
文献类型：
--
作者：
Mitschke, Michaela M.;Hoffmann, Linda S.;Kilic, Ana
全球有超过5亿人受到影响，肥胖症已经达到了大流行的程度。白色脂肪组织(WAT)内发育的“棕色样”或“棕色”脂肪细胞具有潜在的抗肥胖和胰岛素增敏作用。我们研究了cGMP(CGMP)信号在WAT中的作用，重点研究了cGMP依赖性蛋白激酶I(PKGI)在WAT中的作用。PKGI在小鼠的Wat、原代脂肪细胞和3T3-L1中表达。用cGMP处理脂肪细胞后，脂肪细胞的成脂增加，过氧化体增殖物激活受体-γ的表达增加54%。慢病毒过表达PKGI进一步增加成脂，而缺失PKGI则显著减少成脂分化。除了成脂作用外，PKGI还通过RhoA磷酸化和减少前炎症脂肪因子的表达而具有抗肥大和抗炎作用。此外，PKGI诱导原代脂肪细胞中UCP-1的丰度增加4.3倍，并形成类似棕色的生热程序。值得注意的是，用磷酸二酯酶抑制剂西地那非(12 mg/kg/d)处理C57BL/6小鼠7d后，解偶联蛋白-1的表达增加了4.6倍，并促进了体内Wat棕色脂肪细胞样表型的建立。总之，PKGI是细胞大小、脂肪因子分泌和白色脂肪库褐化的关键调节器，因此可能成为开发肥胖新疗法的有价值的目标。-Mitschke，M.，Hoffmann，L.S.，Gnad，T.，Scholz，D.，Kruithoff，K.，Mayer，P.，Haas，B.，Sassmann，A.，Alexander Pfeifer，A.，Kilic，A。增加cGMP促进白色脂肪组织的健康扩张和褐化。FASE B J.27,1621-1630(2013)。Www.fasebj.org
With more than half a billion individuals affected worldwide, obesity has reached pandemic proportions. Development of "brown-like" or "brite" adipocytes within white adipose tissue (WAT) has potential antiobesity and insulin-sensitizing effects. We investigated the role of cyclic GMP (cGMP) signaling, focusing on cGMP-dependent protein kinase I (PKGI) in WAT. PKGI is expressed in murine WAT, primary adipocytes, and 3T3-L1. Treatment of adipocytes with cGMP resulted in increased adipogenesis, with a 54% increase in expression of peroxisome proliferator-activated receptor-gamma. Lentiviral overexpression of PKGI further increased adipogenesis, whereas loss of PKGI significantly reduced adipogenic differentiation. In addition to adipogenic effects, PKGI had an antihypertrophic and anti-inflammatory effect via RhoA phosphorylation and reduction of proinflammatory adipokine expression. Moreover, PKGI induced a 4.3-fold increase in abundance of UCP-1 and the development of a brown-like thermogenic program in primary adipocytes. Notably, treatment of C57BL/6 mice with phosphodiesterase inhibitor sildenafil (12 mg/kg/d) for 7 d caused 4.6-fold increase in uncoupling protein-1 expression and promoted establishment of a brown fat cell-like phenotype ("browning") of WAT in vivo. Taken together, PKGI is a key regulator of cell size, adipokine secretion and browning of white fat depots and thus could be a valuable target in developing novel treatments for obesity.-Mitschke, M. M., Hoffmann, L. S., Gnad, T., Scholz, D., Kruithoff, K., Mayer, P., Haas, B., Sassmann, A., Alexander Pfeifer, A., Kilic, A. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J. 27, 1621-1630 (2013). www.fasebj.org