Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes
Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes
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DOI：
10.1172/jci59701
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发表时间：
2012-03-01
影响因子：
15.9
通讯作者：
Collins, Sheila
中科院分区：
文献类型：
--
作者：
Bordicchia, Marica;Liu, Dianxin;Collins, Sheila
哺乳动物抵抗体内脂肪积累的能力与它们在白色脂肪库中扩大“棕色脂肪细胞”的数量和活性的能力有关。β-肾上腺素能受体（β-AR）的激活可诱导功能性“棕色样”脂肪细胞表型。由于心脏利钠肽（NPs）和β-AR激动剂在刺激人脂肪细胞脂解方面具有相似的效力，我们研究了NPs是否可以诱导人和小鼠脂肪细胞获得棕色脂肪细胞特征，包括解偶联蛋白1（UCP 1）介导的产热能量消耗能力。在人类脂肪细胞中，心房NP（ANP）和心室NP（BNP）激活了PPAR γ共激活因子-1 α（PGC-1 α）和UCP 1表达，诱导了血管生成，并增加了解偶联呼吸和总呼吸。在低浓度下，AMP和β-AR激动剂以p38 MAPK依赖性方式叠加增强棕色脂肪和线粒体标记物的表达。暴露于低温的小鼠在棕色脂肪组织（BAT）和白色脂肪组织（WAT）中具有增加的循环NP水平以及较高的NP信号传导受体表达和较低的NP清除受体（Nprc）表达。NPR-C-/-小鼠的WAT和BAT库明显较小，但产热基因（如Ucp 1）的表达较高。将BNP输注到小鼠中强烈地增加了WAT和BAT中的Ucp 1和Pgc-1 α表达，并相应地增加了呼吸和能量消耗。这些结果表明，NP促进白色脂肪细胞的“布朗宁”以增加能量消耗，将心脏定义为脂肪组织生物学的中心调节器。
The ability of mammals to resist body fat accumulation is linked to their ability to expand the number and activity of "brown adipocytes" within white fat depots. Activation of beta-adrenergic receptors (beta-ARs) can induce a functional "brown-like" adipocyte phenotype. As cardiac natriuretic peptides (NPs) and beta-AR agonists are similarly potent at stimulating lipolysis in human adipocytes, we investigated whether NPs could induce human and mouse adipocytes to acquire brown adipocyte features, including a capacity for thermogenic energy expenditure mediated by uncoupling protein 1 (UCP1). In human adipocytes, atrial NP (ANP) and ventricular NP (BNP) activated PPAR gamma coactivator-1 alpha (PGC-1 alpha) and UCP1 expression, induced mitochondriogenesis, and increased uncoupled and total respiration. At low concentrations, AMP and beta-AR agonists additively enhanced expression of brown fat and mitochondrial markers in a p38 MAPK-dependent manner. Mice exposed to cold temperatures had increased levels of circulating NPs as well as higher expression of NP signaling receptor and lower expression of the NP clearance receptor (Nprc) in brown adipose tissue (BAT) and white adipose tissue (WAT). NPR-C-/- mice had markedly smaller WAT and BAT depots but higher expression of thermogenic genes such as Ucp1. Infusion of BNP into mice robustly increased Ucp1 and Pgc-1 alpha expression in WAT and BAT, with corresponding elevation of respiration and energy expenditure. These results suggest that NPs promote "browning" of white adipocytes to increase energy expenditure, defining the heart as a central regulator of adipose tissue biology.