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Sci Signal. 2018 Apr 24;11(527). pii: eaai7838. doi: 10.1126/scisignal.aai7838.

Jak-TGFβ cross-talk links transient adipose tissue inflammation to beige adipogenesis.

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DKFZ Junior Group Metabolism and Stem Cell Plasticity (A171), German Cancer Research Center, Heidelberg 69120, Germany.
Université Côte d'Azur, CNRS, Inserm, Institute of Biology Valrose, Nice 06100, France.
Department of Toxicology, School of Public Health, Peking University, Beijing 100191, China.
Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany.
Light Microscopy Facility, German Cancer Research Center, Heidelberg 69120, Germany.
Max Planck Institute for Metabolism Research Cologne, Cologne 50931, Germany.
College of Pharmacy, Yonsei University, Incheon 406-840, South Korea.
Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Division of Chronic Inflammation and Cancer (F180), German Cancer Research Center, Heidelberg 69120, Germany.
Helmholtz Center Munich, Institute for Diabetes and Cancer (IDC), Neuherberg 85764, Germany.
Joint Heidelberg-Institute for Diabetes and Cancer Translational Diabetes Program, Heidelberg University Hospital, Heidelberg 69120, Germany.
DKFZ Junior Group Metabolism and Stem Cell Plasticity (A171), German Cancer Research Center, Heidelberg 69120, Germany.


The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as β3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFβ signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFβ signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by β3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways.


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