Tyk2 and Stat3 Regulate Brown Adipose Tissue Differentiation and Obesity

Derecka, Marta; Górnicka, Agnieszka; Koralov, Sergei B.; Szczepanek, Karol; Morgan, Magdalena; Raje, Vidisha; Sisler, Jennifer D.; Zhang, Qifang; Otero, Dennis C.; Cichy, Joanna; Rajewsky, Klaus; Shimoda, Kazuya; Poli, Valeria; Strobl, Birgit; Pellegrini, Sandra; Harris, Thurl E.; Seale, Patrick; Russell, Aaron P.; McAinch, Andrew J.; O'Brien, Paul Edmond; Keller, Susanna R.; Croniger, Colleen M.; Kordula, Tomasz; Larner, Andrew C.

doi:10.1016/j.cmet.2012.11.005

Cited by 86 publications

(85 citation statements)

References 42 publications

(46 reference statements)

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“…It has been previously shown that mice on a high-fat diet present decreased TYK2 expression in brown adipose tissue and skeletal muscle, but not in white adipose tissue and liver, suggesting that modulation of TYK2 expression by diet is tissue specific (38). We did not observe, however, changes in TYK2 expression after exposure of dispersed human islets and EndoC-bH1 human b-cells to high glucose.…”

Section: Discussioncontrasting

confidence: 51%

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

et al. 2015

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Pancreatic b-cells are destroyed by an autoimmune attack in type 1 diabetes. Linkage and genome-wide association studies point to >50 loci that are associated with the disease in the human genome. Pathway analysis of candidate genes expressed in human islets identified a central role for interferon (IFN)-regulated pathways and tyrosine kinase 2 (TYK2). Polymorphisms in the TYK2 gene predicted to decrease function are associated with a decreased risk of developing type 1 diabetes. We presently evaluated whether TYK2 plays a role in human pancreatic b-cell apoptosis and production of proinflammatory mediators. TYK2-silenced human b-cells exposed to polyinosinicpolycitidilic acid (PIC) (a mimick of double-stranded RNA produced during viral infection) showed less type I IFN pathway activation and lower production of IFNa and CXCL10. These cells also had decreased expression of major histocompatibility complex (MHC) class I proteins, a hallmark of early b-cell inflammation in type 1 diabetes. Importantly, TYK2 inhibition prevented PICinduced b-cell apoptosis via the mitochondrial pathway of cell death. The present findings suggest that TYK2 regulates apoptotic and proinflammatory pathways in pancreatic b-cells via modulation of IFNa signaling, subsequent increase in MHC class I protein, and modulation of chemokines such as CXCL10 that are important for recruitment of T cells to the islets.

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Section: Discussioncontrasting

confidence: 51%

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

et al. 2015

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“…In line with the disruption of upstream signal transduction, phosphorylation of both STAT3 and STAT5 is significantly attenuated in Jak2-deficient BAT. While the exact role of STAT5 in BAT remains to be elucidated, STAT3 has recently been implicated in BAT differentiation by binding to and enhancing protein stability of PR domain-containing protein 16, a master regulator of brown and beige adipocyte differentiation [14]. Interestingly, in tissue-specific models of Jak2 disruption, STAT3 phosphorylation is reported to be upregulated [28], probably by other protein tyrosine kinases such as members of the Src family [42].…”

Section: Discussionmentioning

confidence: 99%

“…Over the past few years, emerging evidence has linked JAK-STAT signalling to brown and beige adipocyte biology [14][15][16]. Nevertheless, the specific role of JAK2 (a ubiquitously expressed JAK family member) in these processes has not been addressed.…”

Section: Introductionmentioning

confidence: 99%

JAK2 promotes brown adipose tissue function and is required for diet- and cold-induced thermogenesis in mice

et al. 2015

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Aims/hypothesis Non-shivering thermogenesis in adipose tissue can be activated by excessive energy intake or following cold exposure. The molecular mechanisms regulating this activation have not been fully elucidated. The Janus kinase (JAK) -signal transducer and activator of transcription (STAT) pathway mediates the signal transduction of numerous hormones and growth factors that regulate adipose tissue development and function, and may play a role in adaptive thermogenesis. Methods We analysed mRNA and protein levels of uncoupling protein 1 (UCP1) and JAK2 in different adipose depots in response to metabolic and thermal stress. The in vivo role of JAK2 in adaptive thermogenesis was examined using mice with adipocyte-specific Jak2 deficiency (A-Jak2 KO). Results We show in murine brown adipose tissue (BAT) that JAK2 is upregulated together with UCP1 in response to highfat diet (HFD) feeding and cold exposure. In contrast to white adipose tissue, where JAK2 was dispensable for UCP1 induction, we identified an essential role for BAT JAK2 in diet-and cold-induced thermogenesis via mediating the thermogenic response to β-adrenergic stimulation. Accordingly, A-Jak2 KO mice were unable to upregulate BAT UCP1 following a HFD or after cold exposure. Therefore, A-Jak2 KO mice were cold intolerant and susceptible to HFD-induced obesity and diabetes. Conclusions/interpretation Taken together, our results suggest that JAK2 plays a critical role in BAT function and adaptive thermogenesis. Targeting the JAK-STAT pathway may be a novel therapeutic approach for the treatment of obesity and related metabolic disorders.

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“…The severe Jak/Stat3 mouse knockout phenotypes, along with their cooperative functions and the lack of genetic tools specifically targeting adipocyte progenitors, has so far limited functional analysis in this cell type. Derecka et al (46) have shown a requirement for Tyk2 in classical brown adipocyte differentiation. However, we observed that in white fat progenitors, Jak1/2, but not Tyk2, seem to be crucial for Stat3 activation ( fig.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as 3-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 TGF 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 TGF 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 3-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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Tyk2 and Stat3 Regulate Brown Adipose Tissue Differentiation and Obesity

Cited by 86 publications

References 42 publications

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

JAK2 promotes brown adipose tissue function and is required for diet- and cold-induced thermogenesis in mice

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

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