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

ABSTRACT: 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 permanently 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57896 | GEO | 2014/10/31

SECONDARY ACCESSION(S): PRJNA248376

REPOSITORIES: GEO

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Project description:Ramirez2017 - Human global metabolism in brown and white adipocytes Recon 2.1A, an update to Recon 2.1x, is suitable for quantitatively-realistic results for flux balance analysis in human metabolism. This model is described in the article: Integrating Extracellular Flux Measurements and Genome-Scale Modeling Reveals Differences between Brown and White Adipocytes. Ramirez AK, Lynes MD, Shamsi F, Xue R, Tseng YH, Kahn CR, Kasif S, Dreyfuss JM. Cell Rep 2017 Dec; 21(11): 3040-3048 Abstract: White adipocytes are specialized for energy storage, whereas brown adipocytes are specialized for energy expenditure. Explicating this difference can help identify therapeutic targets for obesity. A common tool to assess metabolic differences between such cells is the Seahorse Extracellular Flux (XF) Analyzer, which measures oxygen consumption and media acidification in the presence of different substrates and perturbagens. Here, we integrate the Analyzer's metabolic profile from human white and brown adipocytes with a genome-scale metabolic model to predict flux differences across the metabolic map. Predictions matched experimental data for the metabolite 4-aminobutyrate, the protein ABAT, and the fluxes for glucose, glutamine, and palmitate. We also uncovered a difference in how adipocytes dispose of nitrogenous waste, with brown adipocytes secreting less ammonia and more urea than white adipocytes. Thus, the method and software we developed allow for broader metabolic phenotyping and provide a distinct approach to uncovering metabolic differences. This model is hosted on BioModels Database and identified by: MODEL1703310000. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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

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