GSK3 is a negative regulator of the thermogenic program in brown adipocytes

Markussen, Lasse K.; Winther, Sally; Wicksteed, Barton; Hansen, Jacob B.

doi:10.1038/s41598-018-21795-y

Cited by 22 publications

(20 citation statements)

References 56 publications

(75 reference statements)

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“…GSK-3 activity was necessary throughout iTreg differentiation, as no inactive-phosphorylated GSK-3 was detected after 3 days of culturing naive CD4 + T cells in Treg media. The classical cAMP/PKA activity downstream of the β2-AR exists in tumor cells as well as adipocytes, suppressing GSK-3 activity (70,71). mice received A20 cells followed by allo-HCT with BM alone or with 2 × 10 5 T cells.…”

Section: Discussionmentioning

confidence: 99%

β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD

Mohammadpour¹,

Sarow²,

MacDonald³

et al. 2020

JCI Insight

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warmer, thermoneutral temperature (TT). Housing mice at TT substantially reduces norepinephrine and β-AR signaling on immune cells (22). Treatment of allo-HCT mice housed at ST with the pan-beta blocker propranolol increased aGvHD severity, indicating that β-AR signaling is protective against aGvHD (22). Furthermore, we demonstrated that blockade of recipient β2-ARs enhanced the GvT effect by modulating antigen presenting cells (23). It was critical to continue to define the role of T cell β2-AR signaling, especially CD4 + T cell differentiation. In addition, the detailed mechanisms of β2-AR signaling and its downstream effects on immunomodulation after allo-HCT remained incompletely understood.Adrenergic receptors (ARs) are G protein-coupled receptors, classified into 2 general classes: α-ARs and β-ARs. The α1-AR is primarily expressed on endothelial cells, and the α2-AR is more ubiquitously expressed. β1-ARs and β3-ARs are primarily expressed in cardiac and adipose tissues, respectively, while β2-ARs are extensively distributed especially in the respiratory tract (24, 25) and on immune cells (26,27). Emerging studies reinforce an inhibitory role of β2-AR signaling on T cell function, especially CD8 + T cells, in preclinical and clinical tumor models (27,28). The β2-AR is activated by catecholamines (norepinephrine and epinephrine), released by the sympathetic nervous system (27, 29) and splenic tyrosine hydroxylase-expressing cells (30). This β2-AR-mediated regulation affects T cell antitumor functions (28), DC antigen presentation (23), B cell expression of costimulatory molecules (31, 32), and myeloid-derived suppressor cell (MDSC) immunosuppression ( 26).Thus, we focused on the role of β2-AR signaling on immune cell development and pathways during aGvHD. We asked whether β2-AR expression by allogeneic donor T cells modulates aGvHD pathology and how this modulation occurs. Using major histocompatibility complex (MHC) and minor histocompatibility antigen (miHA) mismatched HCT murine models, and a humanized NOD-scid IL-2Rγ -/-(NSG) model of aGvHD, we demonstrate that β2-AR expression by allogeneic T cells regulates the differentiation of CD4 + T cells from Th1/Th17 to a Th2/Treg phenotype, ameliorating aGvHD without compromising GvT. These data lead us to propose that selective β2-AR agonists may serve as potential therapeutic agents to attenuate aGvHD while preserving the GvT effect.

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Section: Discussionmentioning

confidence: 99%

β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD

Mohammadpour¹,

Sarow²,

MacDonald³

et al. 2020

JCI Insight

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“…Recent reports have indicated that small-molecule inhibitors of GSK3 have favorable metabolic effects in rodents, which exhibit some of the same metabolic effects as FGF21 administration, including improved glucose tolerance and prevention of diet-induced obesity [87][88][89][90]. One potential mechanism by which these agents could induce thermogenenic activation is by inhibitory phosphorylation of GSK3 in a PKA-dependent manner, which in turn result in enhanced activity of p38 MAPK signaling module [91]. In our study, we found treatment of differentiated brown adipocytes with indirubin (10 μM) indeed showed a modest inhibition of GSK3β by enhanced the phosphorylation of Ser-9 (p-GSK3β) (Ser9) in vitro (Supplymentary Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Indirubin, a small molecular deriving from connectivity map (CMAP) screening, ameliorates obesity-induced metabolic dysfunction by enhancing brown adipose thermogenesis and white adipose browning

et al. 2020

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Background: Obesity occurs when the body's energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and (or) browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity.Methods: In this study, we took a multi-pronged approach to screen UCP1 activators, including in silico predictions, in vitro assays, as well as in vivo experiments. Results: Base on Connectivity MAP (CMAP) screening, we obtained multiple drugs that possess a remarkably correlating gene expression pattern to that of enhancing activity in BAT and (or) sWAT signature. Particularly, we focused on a previously unreported drug-indirubin, a compound obtained from the Indigo plant, which is now mainly used for the treatment of chronic myelogenous leukemia (CML). In the current study, our results shown that indirubin could enhance the BAT activity, as evidenced by up-regulated Ucp1 expression and enhanced mitochondrial respiratory function in vitro cellular model. Furthermore, indirubin treatment restrained high-fat diet (HFD)-induced body weight gain, improved glucose homeostasis and ameliorated hepatic steatosis which were associated with the increase of energy expenditure in the mice model. Moreover, we revealed that indirubin treatment increased BAT activity by promoting thermogenesis and mitochondrial biogenesis in BAT and induced browning of subcutaneous inguinal white adipose tissue (sWAT) of mice under HFD. Besides, our results indicated that indirubin induced UCP1 expression in brown adipocytes, at least in part, via activation of PKA and p38MAPK signaling pathways.(Continued on next page) Conclusions:Our results clearly show that as an effective BAT (as well as beige cells) activator, indirubin may have a protective effect on the prevention and treatment of obesity and its complications.

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“…This gene negatively regulates the Wnt pathway during lineage commitment towards adipogenesis in mouse embryonic stem cells. The gene product inhibits retinoic acid receptor β and negatively inhibits brown adipocyte programming [84,85]. Interestingly, cyclin D1 (Ccnd1), a cell cycle regulator that downregulates during the early phases of adipogenesis in mesenchymal stem cells [86], is downregulated specifically in treated cells in the current study.…”

Section: Discussionmentioning

confidence: 56%

Mouse Embryonic Fibroblast Adipogenic Potential: A Comprehensive Transcriptome Analysis

et al. 2020

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Our understanding of adipose tissue has progressed from an inert tissue for energy storage to be one of the largest endocrine organs regulating metabolic homoeostasis through its ability to synthesize and release various adipokines that regulate a myriad of pathways. The field of adipose tissue biology is growing due to this association with various chronic metabolic diseases. An important process in the regulation of adipose tissue biology is adipogenesis, which is the formation of new adipocytes. Investigating adipogenesis in vitro is currently a focus for identifying factors that might be utilized in clinically. A powerful tool for such work is high-throughput sequencing which can rapidly identify changes at gene expression level. Various cell models exist for studying adipogenesis and has been used in high-throughput studies, yet little is known about transcriptome profile that underlies adipogenesis in mouse embryonic fibroblasts. This study utilizes RNA-sequencing and computational analysis with DESeq2, gene ontology, protein-protein networks, and robust rank analysis to understand adipogenesis in mouse embryonic fibroblasts indepth. Our analyses confirmed the requirement of mitotic clonal expansion prior to adipogenesis in this cell model and highlight the role of Cebpa and Cebpb in regulating adipogenesis through interactions of large numbers of genes.

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GSK3 is a negative regulator of the thermogenic program in brown adipocytes

Cited by 22 publications

References 56 publications

β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD

β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD

Indirubin, a small molecular deriving from connectivity map (CMAP) screening, ameliorates obesity-induced metabolic dysfunction by enhancing brown adipose thermogenesis and white adipose browning

Mouse Embryonic Fibroblast Adipogenic Potential: A Comprehensive Transcriptome Analysis

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