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

• Published in: Nature cell biology Vol. 17; no. 1; pp. 57 - 67
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2015; Nature Publishing Group
• Subjects: 13; 13/1; 13/100; 13/106; 13/44; 38/1; 38/39; 38/47; 38/88; 49/39; 49/91; 631/443/319; 631/443/319/1642/393; 82/79; 82/80; 96/95; 96/98; Adipocytes, Brown - cytology; Adipocytes, White - cytology; Adipose tissue; Animals; Biological response modifiers; Bone Morphogenetic Protein 7; Cancer Research; Cardiovascular diseases; Care and treatment; Cell Biology; Cell Differentiation - drug effects; Cells, Cultured; Developmental Biology; Diagnosis; Gene Expression Profiling; Genetic aspects; Health aspects; Hedgehog Proteins - metabolism; Humans; Interferon-gamma - biosynthesis; Interferon-gamma - pharmacology; Ion Channels - biosynthesis; Janus Kinase 1 - antagonists & inhibitors; Janus Kinase 3 - antagonists & inhibitors; Life Sciences; Male; Mammals; Mice; Mice, Inbred C57BL; Mitochondria - metabolism; Mitochondrial Proteins - biosynthesis; Obesity; Obesity - prevention & control; Oxazines - pharmacology; Phosphorylation - drug effects; Physiological aspects; Piperidines - pharmacology; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; Pyrimidines - pharmacology; Pyrroles - pharmacology; Risk factors; STAT1 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - antagonists & inhibitors; Stem Cells; Tumor Necrosis Factor-alpha - pharmacology; Uncoupling Protein 1; Veratrum Alkaloids - pharmacology
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3075

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. Moisan, Cowan and colleagues perform a small-molecule screen to identify compounds that promote white-to-brown adipocyte conversion in vitro . They report that two inhibitors of the JAK–STAT signalling pathway stimulate browning of human adipocytes.