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下丘脑蛋白激酶A调节瘦素敏感性和肥胖。

Hypothalamic PKA regulates leptin sensitivity and adiposity.

作者信息

Yang Linghai, McKnight G Stanley

机构信息

Department of Pharmacology, University of Washington School of Medicine, 1959 North East Pacific Street, Box 357280, Seattle, Washington 98195, USA.

出版信息

Nat Commun. 2015 Sep 18;6:8237. doi: 10.1038/ncomms9237.

Abstract

Mice lacking the RIIβ regulatory subunit of cyclic AMP-dependent protein kinase A (PKA) display reduced adiposity and resistance to diet-induced obesity. Here we show that RIIβ knockout (KO) mice have enhanced sensitivity to leptin's effects on both feeding and energy metabolism. After administration of a low dose of leptin, the duration of hypothalamic JAK/STAT3 signalling is increased, resulting in enhanced POMC mRNA induction. Consistent with the extended JAK/STAT3 activation, we find that the negative feedback regulator of leptin receptor signalling, Socs3, is inhibited in the hypothalamus of RIIβ KO mice. During fasting, RIIβ-PKA is activated and this correlates with an increase in CREB phosphorylation. The increase in CREB phosphorylation is absent in the fasted RIIβ KO hypothalamus. Selective inhibition of PKA activity in AgRP neurons partially recapitulates the leanness and resistance to diet-induced obesity of RIIβ KO mice. Our findings suggest that RIIβ-PKA modulates the duration of leptin receptor signalling and therefore the magnitude of the catabolic response to leptin.

摘要

缺乏环磷酸腺苷依赖性蛋白激酶A(PKA)的RIIβ调节亚基的小鼠脂肪量减少,对饮食诱导的肥胖具有抵抗力。我们在此表明,RIIβ基因敲除(KO)小鼠对瘦素在进食和能量代谢方面的作用敏感性增强。给予低剂量瘦素后,下丘脑JAK/STAT3信号传导的持续时间增加,导致POMC mRNA诱导增强。与JAK/STAT3激活延长一致,我们发现瘦素受体信号传导的负反馈调节因子Socs3在RIIβ KO小鼠的下丘脑中受到抑制。禁食期间,RIIβ-PKA被激活,这与CREB磷酸化增加相关。在禁食的RIIβ KO小鼠下丘脑中,CREB磷酸化没有增加。对AgRP神经元中PKA活性的选择性抑制部分重现了RIIβ KO小鼠的消瘦和对饮食诱导肥胖的抵抗力。我们的研究结果表明,RIIβ-PKA调节瘦素受体信号传导的持续时间,从而调节对瘦素的分解代谢反应的幅度。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e5/4595595/916401c494bc/ncomms9237-f1.jpg

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