Role of Transcription Factor NFAT in Glucose and Insulin Homeostasis

Yang, Teddy; Suk, Hee Yun; Yang, Xiao; Olabisi, Opeyemi; Yu, Raymond; Durand, J; Jelicks, Linda A.; Kim, Ja Young; Scherer, Philipp E.; Wang, Yuhua; Feng, Yongzeng; Rossetti, Luciano; Graef, Isabella A.; Crabtree, Gerald R.; Chow, Chi Wing

doi:10.1128/mcb.00580-06

Cited by 75 publications

(79 citation statements)

References 66 publications

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“…Indeed, the global deletion of NFATc2 in mice has been shown to increase the expression of chondrocytic-specific genes and chondrogenesis, suggesting that NFATc2 is a negative regulator of chondrocyte growth and differentiation (37). Global NFATc2/c4 double knock-out mice exhibit defects in fat accumulation and reduced adiposity, suggesting that NFAT signaling is positive regulator of adipogenesis (38). Finally, it has been shown that the number of primary myofibers and muscle size are decreased in the global NFATc3-deficient mice (39).…”

Section: Discussionmentioning

confidence: 99%

Conditional Disruption of Calcineurin B1 in Osteoblasts Increases Bone Formation and Reduces Bone Resorption

Yeo

Beck

Thompson

et al. 2007

Journal of Biological Chemistry

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We recently reported that the pharmacological inhibition of calcineurin (Cn) by low concentrations of cyclosporin A increases osteoblast differentiation in vitro and bone mass in vivo. To determine whether Cn exerts direct actions in osteoblasts, we generated mice lacking Cnb1 (Cn regulatory subunit) in osteoblasts (⌬Cnb1 OB ) using Cre-mediated recombination methods. Transgenic mice expressing Cre recombinase, driven by the human osteocalcin promoter, were crossed with homozygous mice that express loxP-flanked Cnb1 (Cnb1 f/f ). Microcomputed tomography analysis of tibiae at 3 months showed that ⌬Cnb1 OB mice had dramatic increases in bone mass compared with controls. Histomorphometric analyses showed significant increases in mineral apposition rate (67%), bone volume (32%), trabecular thickness (29%), and osteoblast numbers (68%) as well as a 40% decrease in osteoclast numbers as compared with the values from control mice. To delete Cnb1 in vitro, primary calvarial osteoblasts, harvested from Cnb1 f/f mice, were infected with adenovirus expressing the Cre recombinase. Cre-expressing osteoblasts had a complete inhibition of Cnb1 protein levels but differentiated and mineralized more rapidly than control, green fluorescent protein-expressing cells. Deletion of Cnb1 increased expression of osteoprotegerin and decreased expression of RANKL. Co-culturing Cnb1-deficient osteoblasts with wild type osteoclasts demonstrated that osteoblasts lacking Cnb1 failed to support osteoclast differentiation in vitro. Taken together, our findings demonstrate that the inhibition of Cnb1 in osteoblasts increases bone mass by directly increasing osteoblast differentiation and indirectly decreasing osteoclastogenesis.Bone is a highly dynamic structure that is constantly renewing through a process called remodeling (1). This process is critical for maintaining healthy bones and is mainly controlled by the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. The presence of these two opposing cell types with contrasting activities in close proximity requires tight regulation to maintain healthy and strong bones. Bone resorption is attained by the action of osteoclasts, which are specialized macrophages whose differentiation is primarily regulated by receptor activator of NF B ligand (RANKL) 2 and osteoprotegerin (OPG) (2). Osteoblasts originate from multipotent mesenchymal progenitors that replicate as undifferentiated cells but have the potential to differentiate into different lineages of mesenchymal tissues including bone, cartilage, fat, muscle, and marrow stroma (3, 4). Osteoblasts control bone formation not only by synthesizing bone matrix proteins and regulating mineralization but also by orchestrating the process of bone resorption through the modulation of RANKL and OPG expression (2, 4).We have recently shown that the pharmacologic inhibition of calcineurin (Cn) by low concentrations of cyclosporin A (CsA) increases osteoblast differentiation and bone formation (5). We also demonstrated that this response was...

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Section: Discussionmentioning

confidence: 99%

Conditional Disruption of Calcineurin B1 in Osteoblasts Increases Bone Formation and Reduces Bone Resorption

Yeo

Beck

Thompson

et al. 2007

Journal of Biological Chemistry

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“…There are four calcium responsive NFAT isoforms and all are expressed in 3T3-L1 adipocytes, with NFATc1 and -c3 constitutively expressed and NFATc2 and -c4 induced during adipocyte differentiation (55). Despite similar expression of the FLAG-tagged NFAT proteins, only NFATc2 and -c4 showed significant levels of interaction with lipin 1 (Fig.…”

Section: Lipin 1 Interacts With Nfatc4mentioning

confidence: 99%

“…NFATc2 and NFATc4 have also been implicated in both adipocyte differentiation and expression of adipokines. Mice deficient for both NFATc2 and NFATc4 have decreased production of resistin in adipose tissue and are resistant to diet-induced obesity (55). The role of lipin 1 in triacylglycerol synthesis, when combined with its ability to modulate the activity of a transcription factor that regulates expression of cytokines and adipokines, positions lipin 1 as a potential regulator of the negative consequences of increased triacylglycerol deposition in adipocytes.…”

mentioning

confidence: 99%

Lipin 1 Represses NFATc4 Transcriptional Activity in Adipocytes To Inhibit Secretion of Inflammatory Factors

Kim

Kumar

Wang

et al. 2010

Molecular and Cellular Biology

100

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Lipin 1 is a bifunctional protein that regulates gene transcription and, as a Mg2؉ -dependent phosphatidic acid phosphatase (PAP), is a key enzyme in the biosynthesis of phospholipids and triacylglycerol. We describe here the functional interaction between lipin 1 and the nuclear factor of activated T cells c4 (NFATc4). Lipin 1 represses NFATc4 transcriptional activity through protein-protein interaction, and lipin 1 is present at the promoters of NFATc4 transcriptional targets in vivo. Catalytically active and inactive lipin 1 can suppress NFATc4 transcriptional activity, and this suppression may involve recruitment of histone deacetylases to target promoters. In fat pads from mice deficient for lipin 1 (fld mice) and in 3T3-L1 adipocytes depleted of lipin 1 there is increased expression of several NFAT target genes including tumor necrosis factor alpha, resistin, FABP4, and PPAR␥. Finally, both lipin 1 protein and total PAP activity are decreased with increasing adiposity in the visceral, but not subcutaneous, fat pads of ob/ob mice. These observations place lipin 1 as a potentially important link between triacylglycerol synthesis and adipose tissue inflammation.

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“…Moreover, these mice do not accumulate fat. These findings could arise from changes in adipokine signaling, because NFAT also seems responsible for the production of resistin, a protein that confers insulin resistance (43 ). During the last few years, several genes predisposing to posttransplantation diabetes mellitus have been discovered (44 ).…”

Section: Brainmentioning

confidence: 99%

Molecular Diagnostics of Calcineurin-Related Pathologies

Musson

Cobbaert²,

Smit³

2012

Clinical Chemistry

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BACKGROUND The Ca2+-dependent protein phosphatase enzyme calcineurin (Cn) (protein phosphatase 3) is best known for its role as director of the adaptive immune response. One of its principal substrates is the nuclear factor of activated T cells (NFAT), which translocates to the nucleus after dephosphorylation to mediate gene transcription. Drugs targeting Cn (the Cn inhibitors tacrolimus and cyclosporin A) have revolutionized posttransplantation therapy in allograft recipients by considerably reducing rejection rates. CONTENT Owing primarily to intensive study of the side effects of the Cn inhibitors, the unique importance of Cn and Cn/NFAT signaling in the normal physiological processes of many other cell and tissue types is becoming more evident. During the last decade, it has become clear that an extensive and diverse array of clinical conditions can be traced back, at least in part, to a disturbed Cn-signaling axis. Hence, both diagnostics and therapeutic monitoring could benefit from a technique that conveniently reads out Cn/NFAT operative status. SUMMARY This review outlines the current knowledge on the pathologic conditions that have calcineurin as a common denominator and reports on the progress that has been made toward successfully applying Cn and Cn/NFAT activity markers in molecular diagnostics.

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Role of Transcription Factor NFAT in Glucose and Insulin Homeostasis

Cited by 75 publications

References 66 publications

Conditional Disruption of Calcineurin B1 in Osteoblasts Increases Bone Formation and Reduces Bone Resorption

Conditional Disruption of Calcineurin B1 in Osteoblasts Increases Bone Formation and Reduces Bone Resorption

Lipin 1 Represses NFATc4 Transcriptional Activity in Adipocytes To Inhibit Secretion of Inflammatory Factors

Molecular Diagnostics of Calcineurin-Related Pathologies

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