Moisan Annie, Lee Youn-Kyoung, Zhang Jitao David, Hudak Carolyn S, Meyer Claas A, Prummer Michael, Zoffmann Sannah, Truong Hoa Hue, Ebeling Martin, Kiialainen Anna, Gérard Régine, Xia Fang, Schinzel Robert T, Amrein Kurt E, Cowan Chad A
Roche Pharma Research and Early Development, Roche Innovation Center Basel, 124 Grenzacherstrasse, Basel CH 4070, Switzerland.
1] Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Massachusetts 02138, USA [2] Center for Regenerative Medicine, Massachusetts General Hospital, Boston Massachusetts 02114, USA.
Nat Cell Biol. 2015 Jan;17(1):57-67. doi: 10.1038/ncb3075. Epub 2014 Dec 8.
The rising incidence of obesity and related disorders such as diabetes and heart disease has focused considerable attention on the discovery of new 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 previously unknown role for the JAK-STAT pathway in the control of adipocyte function and establish a platform to identify compounds for the treatment of obesity.
肥胖及糖尿病和心脏病等相关疾病发病率的不断上升，已使人们相当关注新型治疗方法的发现。一种有前景的方法是增加白色脂肪库中类棕色脂肪细胞的数量或活性，因为这已被证明可预防饮食诱导的肥胖，并降低2型糖尿病的发病率和严重程度。因此，将储存脂肪的细胞转化为具有代谢活性的产热细胞已成为对抗肥胖的一种有吸引力的治疗策略。在此，我们报告了一个筛选平台，用于鉴定能够促进人类脂肪细胞白色向棕色代谢转化的小分子。我们鉴定出两种在脂肪组织生物学中无前例的 Janus激酶（JAK）活性抑制剂，它们能稳定地赋予白色脂肪细胞类棕色代谢活性。重要的是，这些代谢转化的脂肪细胞表现出UCP1表达升高和线粒体活性增加。我们进一步发现，JAK失活的脂肪细胞中干扰素信号的抑制和刺猬信号通路的激活促成了这些细胞中观察到的代谢转化。我们的发现突出了JAK-STAT通路在控制脂肪细胞功能方面以前未知的作用，并建立了一个用于鉴定治疗肥胖症化合物的平台。
