Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKε and TBK1.
Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKε and TBK1.
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DOI：
10.7554/elife.01119
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发表时间：
2013-12-24
期刊：
影响因子：
7.7
通讯作者：
Saltiel AR
中科院分区：
文献类型：
--
作者：
Mowers J;Uhm M;Reilly SM;Simon J;Leto D;Chiang SH;Chang L;Saltiel AR
肥胖产生涉及nf - κ b通路的慢性炎症状态，导致非典型i - κ b激酶IKKε和TBK1的持续升高。在这项研究中，我们报道这些激酶减弱白色脂肪组织中的β-肾上腺素能信号。用这些激酶的特异性抑制剂治疗3T3-L1脂肪细胞恢复β-肾上腺素能信号传导和被TNFα和Poly减弱的脂肪分解（I:C）。相反，在异丙肾上腺素或福斯克林的作用下，激酶的过表达降低了Ucp1的诱导、脂肪分解、cAMP水平和激素敏感脂肪酶的磷酸化。非规范IKKs通过磷酸化和激活主要脂肪细胞磷酸二酯酶PDE3B来降低儿茶酚胺的敏感性。用氨lexanox治疗肥胖小鼠，在体内抑制这些激酶，逆转了肥胖诱导的儿茶酚胺抗性，并恢复了PKA信号，以响应注射β-3肾上腺素能激动剂。这些研究表明，通过减少脂肪细胞中cAMP的产生，IKKε和TBK1可能有助于抑制肥胖期间的能量消耗。DOI: http://dx.doi.org/10.7554/eLife.01119.001肥胖是一种复杂的代谢紊乱，是由食物摄入增加和能量消耗减少引起的。肥胖还会增加患2型糖尿病、心脏病、中风、关节炎和某些癌症的风险。有相当多的证据表明，肥胖状态下脂肪组织对儿茶酚胺（如肾上腺素）变得不那么敏感，而这种敏感性的降低反过来又减少了能量消耗。然而，这一过程的细节尚不完全清楚。众所周知，肥胖会在肝脏和脂肪组织中产生一种慢性、低度炎症状态，并伴有信号蛋白的分泌，阻止脂肪细胞对胰岛素做出反应，从而导致2型糖尿病。NFκB通路的激活被认为在引起这种炎症中起着核心作用。现在Mowers等人研究了NFκB通路激活引起的炎症是否也在脂肪细胞中产生儿茶酚胺抗性中起作用。肥胖依赖性的NFκB通路激活会增加一对酶，IKKε和TBK1的水平。Mowers等人发现，这两种酶的水平升高会降低肥胖小鼠脂肪细胞中某些受体（称为β-肾上腺素能受体）对儿茶酚胺的反应能力。这两种酶的高水平也会导致第二种信使分子cAMP的低水平，cAMP通过促进脂肪燃烧来增加能量消耗。然而，用干扰这两种酶的药物治疗脂肪细胞，恢复了对儿茶酚胺的敏感性，使脂肪细胞能够燃烧能量。Mowers等人还用amlexanox（一种抑制这些酶的药物）治疗肥胖小鼠，并发现这种治疗使小鼠对一种合成儿茶酚胺敏感，这种儿茶酚胺可以触发脂肪释放能量。因此，Mowers等人认为IKKε和TBK1通过减少儿茶酚胺信号传导来应对体内炎症，从而阻止能量消耗。针对这些酶的药物可能对治疗肥胖或2型糖尿病等疾病有用。DOI: http://dx.doi.org/10.7554/eLife.01119.002
Obesity produces a chronic inflammatory state involving the NFκB pathway, resulting in persistent elevation of the noncanonical IκB kinases IKKε and TBK1. In this study, we report that these kinases attenuate β-adrenergic signaling in white adipose tissue. Treatment of 3T3-L1 adipocytes with specific inhibitors of these kinases restored β-adrenergic signaling and lipolysis attenuated by TNFα and Poly (I:C). Conversely, overexpression of the kinases reduced induction of Ucp1, lipolysis, cAMP levels, and phosphorylation of hormone sensitive lipase in response to isoproterenol or forskolin. Noncanonical IKKs reduce catecholamine sensitivity by phosphorylating and activating the major adipocyte phosphodiesterase PDE3B. In vivo inhibition of these kinases by treatment of obese mice with the drug amlexanox reversed obesity-induced catecholamine resistance, and restored PKA signaling in response to injection of a β-3 adrenergic agonist. These studies suggest that by reducing production of cAMP in adipocytes, IKKε and TBK1 may contribute to the repression of energy expenditure during obesity. DOI: http://dx.doi.org/10.7554/eLife.01119.001 Obesity is a complex metabolic disorder that is caused by increased food intake and decreased expenditure of energy. Obesity also increases the risk of developing type 2 diabetes, heart disease, stroke, arthritis, and certain cancers. There is considerable evidence to suggest that adipose tissue becomes less sensitive to catecholamines such as adrenaline in states of obesity, and that this reduced sensitivity in turn reduces energy expenditure. However, the details of this process are not fully understood. It is well established that obesity generates a state of chronic, low-grade inflammation in liver and adipose tissue, accompanied by the secretion of signaling proteins that prevent fat cells from responding to insulin, which leads to type 2 diabetes. Activation of the NFκB pathway is thought to have a central role in causing this inflammation. Now Mowers et al. have investigated whether inflammation caused by activation of the NFκB pathway also has a role in producing catecholamine resistance in fat cells. Obesity-dependent activation of the NFκB pathway increases the levels of a pair of enzymes, IKKε and TBK1. Mowers et al. found that elevated levels of these two enzymes reduced the ability of certain receptors (called β-adrenergic receptors) in the fat cells of obese mice to respond to catecholamines. High levels of the two enzymes also resulted in lower levels of a second messenger molecule called cAMP, which increases energy expenditure by elevating fat burning. However, treating the fat cells with drugs that interfere with the two enzymes restored sensitivity to catecholamine, allowing the fat cells to burn energy. Mowers et al. also treated obese mice with amlexanox, a drug that inhibits these enzymes, and found that this treatment made the mice sensitive to a synthetic catecholamine that triggered the release of energy from fat. Mowers et al. suggest, therefore, that IKKε and TBK1 respond to inflammation in the body by reducing catecholamine signaling, thus preventing energy expenditure. Drugs targeting these enzymes may be useful for treating conditions like obesity or type 2 diabetes. DOI: http://dx.doi.org/10.7554/eLife.01119.002