Crosstalk between KCNK3-Mediated Ion Current and Adrenergic Signaling Regulates Adipose Thermogenesis and Obesity.
Crosstalk between KCNK3-Mediated Ion Current and Adrenergic Signaling Regulates Adipose Thermogenesis and Obesity.
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DOI：
10.1016/j.cell.2017.09.015
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发表时间：
2017-11-02
期刊：
影响因子：
64.5
通讯作者：
Spiegelman BM
中科院分区：
文献类型：
--
作者：
Chen Y;Zeng X;Huang X;Serag S;Woolf CJ;Spiegelman BM
肾上腺素能刺激促进棕色和米色脂肪细胞的脂肪动员和氧化，利用的能量在一个被称为适应性产热的过程中以热的形式消散。促进生热的信号级联和能量耗散途径已被广泛描述，但对反平衡负调控机制知之甚少。在这里，我们确定一个双孔结构域钾通道Kcnk3是一种内置的变阻器，负向调节产热。Kcnk3通过Prdm16转录连接到产热程序中，Prdm16是产热的主要调节者。Kcnk3通过促进钾离子外流来拮抗去甲肾上腺素引起的膜去极化。这限制了通过电压依赖性钙通道的钙内流，并抑制了肾上腺素能信号，从而减弱了脂解和热源性呼吸。脂肪特异性Kcnk3基因敲除小鼠表现出更多的能量消耗，并对低温和肥胖具有抵抗力。这些发现揭示了一个关键的K+-钙-肾上腺素能信号轴，以抑制产热和维持组织动态平衡，并揭示了脂肪细胞功能的电生理调节机制。阻止脂肪产热需要一种钾通道来限制钙的流动。
Adrenergic stimulation promotes lipid mobilization and oxidation in brown and beige adipocytes, where the harnessed energy is dissipated as heat in a process known as adaptive thermogenesis. The signaling cascades and energy-dissipating pathways that facilitate thermogenesis have been extensively described, yet little is known about the counter-balancing negative regulatory mechanisms. Here we identify a two-pore-domain potassium channel Kcnk3 as a built-in rheostat negatively regulating thermogenesis. Kcnk3 is transcriptionally wired into the thermogenic program by Prdm16, a master regulator of thermogenesis. Kcnk3 antagonizes norepinephrine-induced membrane depolarization by promoting potassium efflux in brown adipocytes. This limits calcium influx through voltage-dependent calcium channels and dampens adrenergic signaling, thereby attenuating lipolysis and thermogenic respiration. Adipose-specific Kcnk3 knockout mice display increased energy expenditure and are resistant to hypothermia and obesity. These findings uncover a critical K+-Ca2+-adrenergic signaling axis to dampen thermogenesis and maintain tissue homeostasis and reveal an electrophysiological regulatory mechanism of adipocyte function. Putting the breaks on adipose thermogenesis takes a potassium channel to limit calcium flux.
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影响因子：
2.7
作者：
Flaherty DP;Simpson DS;Miller M;Maki BE;Zou B;Shi J;Wu M;McManus OB;Aubé J;Li M;Golden JE
通讯作者：
Golden JE
影响因子：
29
作者：
Harms MJ;Ishibashi J;Wang W;Lim HW;Goyama S;Sato T;Kurokawa M;Won KJ;Seale P
通讯作者：
Seale P
影响因子：
64.5
作者：
Fedorenko A;Lishko PV;Kirichok Y
通讯作者：
Kirichok Y
影响因子：
18.2
作者：
Kajimura S;Saito M
通讯作者：
Saito M
DOI：
10.1152/ajpendo.00446.2013
发表时间：
2014-07-15
影响因子：
5.1
作者：
Bentley, Donna C.;Pulbutr, Pawitra;Smith, Paul A.
通讯作者：
Smith, Paul A.