White-to-brown metabolic conversion of human adipocytes by JAK inhibition.
White-to-brown metabolic conversion of human adipocytes by JAK inhibition.
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DOI：
10.1038/ncb3075
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发表时间：
2015-01
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
--
作者：
肥胖症和相关疾病如糖尿病和心脏病的发病率不断上升，这使得人们越来越关注新疗法的发现。一种有希望的方法是增加白色脂肪库中棕色样脂肪细胞的数量或活性，因为这已被证明可以预防饮食诱导的肥胖症并降低2型糖尿病的发病率和严重程度。因此，将脂肪储存细胞转化为代谢活性产热细胞已成为对抗肥胖的有吸引力的治疗策略。在这里，我们报告了一个筛选平台，用于识别能够促进人类脂肪细胞中白色至棕色代谢转化的小分子。我们鉴定了两种Janus激酶（JAK）活性抑制剂，在脂肪组织生物学中没有先例，可稳定地赋予白色脂肪细胞棕色样代谢活性。重要的是，这些代谢转化的脂肪细胞表现出升高的UCP 1表达和增加的线粒体活性。我们进一步发现，JAK失活的脂肪细胞中干扰素信号传导的抑制和刺猬信号传导的激活有助于在这些细胞中观察到的代谢转化。我们的研究结果强调了JAK/STAT通路在控制脂肪细胞功能中的新作用，并建立了一个平台来识别用于治疗肥胖的化合物。
The rising incidence of obesity and related disorders such as diabetes and heart disease has focused considerable attention on the discovery of novel therapeutics. One promising approach has been to increase the number or activity of brown-like adipocytes in white adipose depots, as this has been shown to prevent diet-induced obesity and reduce the incidence and severity of type 2 diabetes. Thus, the conversion of fat-storing cells into metabolically active thermogenic cells has become an appealing therapeutic strategy to combat obesity. Here, we report a screening platform for the identification of small molecules capable of promoting a white-to-brown metabolic conversion in human adipocytes. We identified two inhibitors of Janus Kinase (JAK) activity with no precedent in adipose tissue biology that stably confer brown-like metabolic activity to white adipocytes. Importantly, these metabolically converted adipocytes exhibit elevated UCP1 expression and increased mitochondrial activity. We further found that repression of interferon signalling and activation of hedgehog signalling in JAK-inactivated adipocytes contributes to the metabolic conversion observed in these cells. Our findings highlight a novel role for the JAK/STAT pathway in the control of adipocyte function and establish a platform to identify compounds for the treatment of obesity.
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DOI：
10.1152/ajpendo.00010.2005
发表时间：
2005-10-01
影响因子：
5.1
作者：
Li, PP;Zhu, ZX;Granneman, JG
通讯作者：
Granneman, JG
影响因子：
29
作者：
Derecka M;Gornicka A;Koralov SB;Szczepanek K;Morgan M;Raje V;Sisler J;Zhang Q;Otero D;Cichy J;Rajewsky K;Shimoda K;Poli V;Strobl B;Pellegrini S;Harris TE;Seale P;Russell AP;McAinch AJ;O'Brien PE;Keller SR;Croniger CM;Kordula T;Larner AC
通讯作者：
Larner AC
DOI：
10.1152/ajpendo.00009.2005
发表时间：
2005-10-01
影响因子：
5.1
作者：
Granneman, JG;Li, PP;Lu, YY
通讯作者：
Lu, YY
DOI：
10.1124/jpet.106.109058
发表时间：
2006-12-01
影响因子：
3.5
作者：
Braselmann, Sylvia;Taylor, Vanessa;Masuda, Esteban S.
通讯作者：
Masuda, Esteban S.
影响因子：
4.8
作者：
Cao, WH;Medvedev, AV;Collins, S
通讯作者：
Collins, S