Hypothalamic Actions of Tumor Necrosis Factor α Provide the Thermogenic Core for the Wastage Syndrome in Cachexia
Hypothalamic Actions of Tumor Necrosis Factor α Provide the Thermogenic Core for the Wastage Syndrome in Cachexia
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DOI：
10.1210/en.2009-0865
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发表时间：
2010-02-01
期刊：
影响因子：
4.8
通讯作者：
Velloso, Licio A.
中科院分区：
文献类型：
--
作者：
Arruda, Ana Paula;Milanski, Marciane;Velloso, Licio A.
TNF α是恶病质中促炎的重要介质。它的大多数影响都表现在外周组织中，如骨骼肌和脂肪。然而，通过直接作用于下丘脑，TNF α可以激活产热作用并调节食物摄入。在这里，我们表明，下丘脑中的高浓度TNF α导致O-2消耗/CO2产生增加，体温升高，热量摄入减少，导致体重减轻。大多数产热反应是由β 3-肾上腺素能信号传导至棕色脂肪组织（BAT）产生的，导致BAT相对质量增加、BAT脂质量减少和BAT线粒体密度增加。参与BAT产热的蛋白质，如β 3-肾上腺素能受体、过氧化物酶体增殖物激活受体-γ共激活因子-1 α和解偶联蛋白-1的表达增加。在下丘脑中，TNF α使神经肽Y、促肾上腺皮质激素基因相关肽、阿黑皮素原和黑色素浓缩激素减少，并使CRH和TRH增加。在TNF α处理的大鼠的下丘脑中，AMP活化的蛋白激酶信号通路的活性也降低。在脑室内英夫利西单抗治疗后，荷瘤和脓毒症大鼠的存活率显著增加。此外，β 3-肾上腺素能信号传导的全身抑制导致脓毒症大鼠体重减轻和存活率增加。这些数据表明下丘脑TNF α作用是恶病质中消耗综合征的重要介质。（内分泌学151：683-694，2010）
TNF alpha is an important mediator of catabolism in cachexia. Most of its effects have been characterized in peripheral tissues, such as skeletal muscle and fat. However, by acting directly in the hypothalamus, TNF alpha can activate thermogenesis and modulate food intake. Here we show that high concentration TNF alpha in the hypothalamus leads to increased O-2 consumption/CO2 production, increased body temperature, and reduced caloric intake, resulting in loss of body mass. Most of the thermogenic response is produced by beta 3-adrenergic signaling to the brown adipose tissue (BAT), leading to increased BAT relative mass, reduction in BAT lipid quantity, and increased BAT mitochondria density. The expression of proteins involved in BAT thermogenesis, such as beta 3-adrenergic receptor, peroxisomal proliferator-activated receptor-gamma coactivator-1 alpha, and uncoupling protein-1, are increased. In the hypothalamus, TNF alpha produces reductions in neuropeptide Y, agouti gene-related peptide, proopiomelanocortin, and melanin-concentrating hormone, and increases CRH and TRH. The activity of the AMP-activated protein kinase signaling pathway is also decreased in the hypothalamus of TNF alpha-treated rats. Upon intracerebroventricular infliximab treatment, tumor-bearing and septic rats present a significantly increased survival. In addition, the systemic inhibition of beta 3-adrenergic signaling results in a reduced body mass loss and increased survival in septic rats. These data suggest hypothalamic TNF alpha action to be important mediator of the wastage syndrome in cachexia. (Endocrinology 151: 683-694, 2010)