Insulin Regulates Adipocyte Lipolysis via an Akt-Independent Signaling Pathway
Insulin Regulates Adipocyte Lipolysis via an Akt-Independent Signaling Pathway
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DOI：
10.1128/mcb.00797-10
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发表时间：
2010-11-01
影响因子：
5.3
通讯作者：
Birnbaum, Morris J.
中科院分区：
文献类型：
--
作者：
Choi, Sarah M.;Tucker, David F.;Birnbaum, Morris J.
餐后，胰岛素通过激活其下游激酶Akt抑制脂解，从而抑制脂解的主要正效应物蛋白激酶A（PKA）。在胰岛素抵抗期间，这一过程是无效的，导致特征性血脂异常和胰岛素作用受损和肥胖的恶化。在这里，我们描述了一个非经典的Akt独立的，磷酸肌醇-3激酶（PI 3 K）依赖性途径，调节脂肪细胞脂解使用限制性亚细胞信号。该途径选择性地改变其主要脂滴相关底物perilipin的PKA磷酸化。相比之下，另一种PKA底物，对蛋白酶敏感的脂肪酶（HSL）的磷酸化仍然依赖于Akt。此外，胰岛素以Akt依赖性方式调节总PKA活性。这些发现表明，胰岛素作用的局部变化是PKA底物差异磷酸化的原因。因此，我们确定了胰岛素通过PKA的空间区室化调节来调节脂解的途径。
After a meal, insulin suppresses lipolysis through the activation of its downstream kinase, Akt, resulting in the inhibition of protein kinase A (PKA), the main positive effector of lipolysis. During insulin resistance, this process is ineffective, leading to a characteristic dyslipidemia and the worsening of impaired insulin action and obesity. Here, we describe a noncanonical Akt-independent, phosphoinositide-3 kinase (PI3K)-dependent pathway that regulates adipocyte lipolysis using restricted subcellular signaling. This pathway selectively alters the PKA phosphorylation of its major lipid droplet-associated substrate, perilipin. In contrast, the phosphorylation of another PKA substrate, hormone-sensitive lipase (HSL), remains Akt dependent. Furthermore, insulin regulates total PKA activity in an Akt-dependent manner. These findings indicate that localized changes in insulin action are responsible for the differential phosphorylation of PKA substrates. Thus, we identify a pathway by which insulin regulates lipolysis through the spatially compartmentalized modulation of PKA.