The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature. 2010 Dec 16;468(7326):933-9. doi: 10.1038/nature09564.
The adipose-derived hormone leptin maintains energy balance in part through central nervous system-mediated increases in sympathetic outflow that enhance fat burning. Triggering of β-adrenergic receptors in adipocytes stimulates energy expenditure by cyclic AMP (cAMP)-dependent increases in lipolysis and fatty-acid oxidation. Although the mechanism is unclear, catecholamine signalling is thought to be disrupted in obesity, leading to the development of insulin resistance. Here we show that the cAMP response element binding (CREB) coactivator Crtc3 promotes obesity by attenuating β-adrenergic receptor signalling in adipose tissue. Crtc3 was activated in response to catecholamine signals, when it reduced adenyl cyclase activity by upregulating the expression of Rgs2, a GTPase-activating protein that also inhibits adenyl cyclase activity. As a common human CRTC3 variant with increased transcriptional activity is associated with adiposity in two distinct Mexican-American cohorts, these results suggest that adipocyte CRTC3 may play a role in the development of obesity in humans.
脂肪组织分泌的激素瘦素通过中枢神经系统介导的交感神经输出增加来维持能量平衡，从而促进脂肪燃烧。脂肪细胞中β-肾上腺素能受体的激活通过环腺苷酸 (cAMP) 依赖性脂解和脂肪酸氧化增加来刺激能量消耗。尽管其机制尚不清楚，但儿茶酚胺信号被认为在肥胖中被破坏，导致胰岛素抵抗的发展。在这里，我们表明 cAMP 反应元件结合 (CREB) 共激活因子 Crtc3 通过减弱脂肪组织中β-肾上腺素能受体信号来促进肥胖。Crtc3 被儿茶酚胺信号激活，当它通过上调 Rgs2 的表达来减少腺苷酸环化酶活性时，Rgs2 是一种 GTP 酶激活蛋白，也抑制腺苷酸环化酶活性。由于具有增加转录活性的常见人类 CRTC3 变体与两个不同的墨西哥裔美国人队列中的肥胖有关，这些结果表明脂肪细胞 CRTC3 可能在人类肥胖的发展中发挥作用。
