Brown Remodeling of White Adipose Tissue by SirT1-Dependent Deacetylation of Pparγ

Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Cell (Impact Factor: 32.24). 08/2012; 150(3):620-32. DOI: 10.1016/j.cell.2012.06.027
Source: PubMed


Brown adipose tissue (BAT) can disperse stored energy as heat. Promoting BAT-like features in white adipose (WAT) is an attractive, if elusive, therapeutic approach to staunch the current obesity epidemic. Here we report that gain of function of the NAD-dependent deacetylase SirT1 or loss of function of its endogenous inhibitor Deleted in breast cancer-1 (Dbc1) promote "browning" of WAT by deacetylating peroxisome proliferator-activated receptor (Ppar)-γ on Lys268 and Lys293. SirT1-dependent deacetylation of Lys268 and Lys293 is required to recruit the BAT program coactivator Prdm16 to Pparγ, leading to selective induction of BAT genes and repression of visceral WAT genes associated with insulin resistance. An acetylation-defective Pparγ mutant induces a brown phenotype in white adipocytes, whereas an acetylated mimetic fails to induce "brown" genes but retains the ability to activate "white" genes. We propose that SirT1-dependent Pparγ deacetylation is a form of selective Pparγ modulation of potential therapeutic import.

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Available from: Yiying Zhang, Feb 28, 2014
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    ABSTRACT: Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.
    Cell metabolism 10/2015; 22(4):546-559. DOI:10.1016/j.cmet.2015.09.007 · 17.57 Impact Factor
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    • "As compared to ROSI, the unique mode of PPARγ activation with TEL results from its differential binding to the ligand pocket, which leads to a recruitment of an altered set of cofactors including coactivators such as SRC1, GRIP, PGC1α and PGC1β, and corepressors SMRT and NCoR [28], [51]. The specificity of cofactors assembly is driven by postranscriptional modification of PPARγ protein including phosphorylation of Ser112 and Ser273 [52], [53]. We have shown that both TEL and ROSI have the same effect on dephosphorylation of Ser273, which determines insulin-sensitizing activity, but differ in their effect on dephosphorylation of Ser112, which is essential for acquisition of transcriptional adipocytic activity toward lipid accumulation [12], [13]. "
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    ABSTRACT: Peroxisome proliferator activated receptor gamma (PPARγ) controls both glucose metabolism and an allocation of marrow mesenchymal stem cells (MSCs) toward osteoblast and adipocyte lineages. Its activity is determined by interaction with a ligand which directs posttranscriptional modifications of PPARγ protein including dephosphorylation of Ser112 and Ser273, which results in acquiring of pro-adipocytic and insulin-sensitizing activities, respectively. PPARγ full agonist TZD rosiglitazone (ROSI) decreases phosphorylation of both Ser112 and Ser273 and its prolonged use causes bone loss in part due to diversion of MSCs differentiation from osteoblastic toward adipocytic lineage. Telmisartan (TEL), an anti-hypertensive drug from the class of angiotensin receptor blockers, also acts as a partial PPARγ agonist with insulin-sensitizing and a weak pro-adipocytic activity. TEL decreased S273pPPARγ and did not affect S112pPPARγ levels in a model of marrow MSC differentiation, U-33/γ2 cells. In contrast to ROSI, TEL did not affect osteoblast phenotype and actively blocked ROSI-induced anti-osteoblastic activity and dephosphorylation of S112pPPARγ. The effect of TEL on bone was tested side-by-side with ROSI. In contrast to ROSI, TEL administration did not affect bone mass and bone biomechanical properties measured by micro-indentation method and did not induce fat accumulation in bone, and it partially protected from ROSI-induced bone loss. In addition, TEL induced "browning" of epididymal white adipose tissue marked by increased expression of UCP1, FoxC2, Wnt10b and IGFBP2 and increased overall energy expenditure. These studies point to the complexity of mechanisms by which PPARγ acquires anti-osteoblastic and pro-adipocytic activities and suggest an importance of Ser112 phosphorylation status as being a part of the mechanism regulating this process. These studies showed that TEL acts as a full PPARγ agonist for insulin-sensitizing activity and as a partial agonist/partial antagonist for pro-adipocytic and anti-osteoblastic activities. They also suggest a relationship between PPARγ fat "browning" activity and a lack of anti-osteoblastic activity.
    PLoS ONE 05/2014; 9(5):e96323. DOI:10.1371/journal.pone.0096323 · 3.23 Impact Factor
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    • "This is mediated by SIRT1-dependent deacetylation of PPARγ which facilitates the recruitment of PRDM16, a transcriptional coregulator that drives the BAT adipogenic program [73]. Consequently, mice overexpressing SIRT1 have a more potent induction of a BAT-like phenotype of subcutaneous WAT upon cold exposure [60]. Overall, while we are just beginning to understand the influence of SIRT1 on adipose tissue homeostasis, it seems clear that SIRT1 exacerbates the induction of lipid mobilization and WAT-browning effect induced by cold exposure (Figure 3). "
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    ABSTRACT: SIRT1 has attracted a lot of interest since it was discovered as a mammalian homolog of Sir2, a protein that influences longevity in yeast. Intensive early research suggested a key role of SIRT1 in mammalian development, metabolic flexibility and oxidative metabolism. However, it is the growing body of transgenic models that are allowing us to clearly define the true range of SIRT1 actions. In this review we aim to summarize the most recent lessons that transgenic animal models have taught us about the role of SIRT1 in mammalian metabolic homeostasis and lifespan.
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