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Nat Cell Biol. 2015 Jan;17(1):57-67. doi: 10.1038/ncb3075. Epub 2014 Dec 8.

White-to-brown metabolic conversion of human adipocytes by JAK inhibition.

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1
Roche Pharma Research and Early Development, Roche Innovation Center Basel, 124 Grenzacherstrasse, Basel CH 4070, Switzerland.
2
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.

Abstract

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.

PMID:
25487280
PMCID:
PMC4276482
DOI:
10.1038/ncb3075
[Indexed for MEDLINE]
Free PMC Article

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