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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adipocytes, Brown / cytology*
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Adipocytes, White / cytology*
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Animals
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Bone Morphogenetic Protein 7
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Cell Differentiation / drug effects
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Cells, Cultured
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Gene Expression Profiling
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Hedgehog Proteins / metabolism
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Humans
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Interferon-gamma / biosynthesis
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Interferon-gamma / pharmacology
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Ion Channels / biosynthesis
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Janus Kinase 1 / antagonists & inhibitors
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Janus Kinase 3 / antagonists & inhibitors*
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Male
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Mice
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Mice, Inbred C57BL
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Mitochondria / metabolism
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Mitochondrial Proteins / biosynthesis
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Obesity / prevention & control
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Oxazines / pharmacology*
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Phosphorylation / drug effects
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Piperidines / pharmacology*
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Protein Kinase Inhibitors / pharmacology
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Pyridines / pharmacology*
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Pyrimidines / pharmacology*
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Pyrroles / pharmacology*
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STAT1 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / pharmacology
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Uncoupling Protein 1
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Veratrum Alkaloids / pharmacology
Substances
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BMP7 protein, human
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Bone Morphogenetic Protein 7
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Hedgehog Proteins
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Ion Channels
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Mitochondrial Proteins
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N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
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Oxazines
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Piperidines
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Protein Kinase Inhibitors
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Pyridines
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Pyrimidines
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Pyrroles
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Tumor Necrosis Factor-alpha
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UCP1 protein, human
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Ucp1 protein, mouse
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Uncoupling Protein 1
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Veratrum Alkaloids
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Interferon-gamma
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tofacitinib
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Janus Kinase 1
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Janus Kinase 3
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cyclopamine