S6K1 Plays a Critical Role in Early Adipocyte Differentiation

Carnevalli, Larissa S.; Masuda, Kouhei; Frigerio, Francesca; Bacquer, Olivier Le; Um, Sung Hee; Gandin, Valentina; Topisirović, Ivan; Sonenberg, Nahum; Thomas, George; Kozma, Sara C.

doi:10.1016/j.devcel.2010.02.018

Cited by 176 publications

(151 citation statements)

References 69 publications

(95 reference statements)

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“…Usually, mTOR activation leads to the phosphorylation of S6K1 and 4E-BP1 in order to mediate an increase in protein synthesis and cap-dependent translation, respectively (Khaleghpour et al, 1999). Deletion of S6K1 diminishes adipogenic lineage commitment and early adipogenesis (Carnevalli et al, 2010), whereas knockout of 4E-BP1 results in a reduction in the amount of adipose tissue due to the transition of white adipocytes into brown-like adipocytes, and increased energy consumption (Tsukiyama-Kohara et al, 2001). Moreover, 4E-BP1, 4E-BP2 double KO mice suffer from severe high-fat-diet-induced obesity and insulin resistance, which could be explained partially by increased C/EBP and PPARγ transcription (Le Bacquer et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Our results suggest that Stk40 controlled translation of C/EBPβ without an isoform preference, as levels of all three C/EBPβ isoforms altered when Stk40 was deleted. To elucidate how Stk40 modulated the C/EBP translation, we examined the activity of mTOR, a 'sensor' of the synthesis of proteins, and a protein which is essential for cell proliferation, differentiation and survival (Heitman et al, 1991;Brown et al, 1995;Khaleghpour et al, 1999;Carnevalli et al, 2010). 4E-BP1 and S6K1 are downstream targets of mTOR.…”

Section: Discussionmentioning

confidence: 99%

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Stk40 represses adipogenesis through translational control of CCAAT/enhancer-binding proteins

Wang

et al. 2015

Journal of Cell Science

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A better understanding of molecular regulation in adipogenesis might help the development of efficient strategies to cope with obesity-related diseases. Here, we report that CCAAT/enhancer-binding protein (C/EBP) β and C/EBPδ, two crucial pro-adipogenic transcription factors, are controlled at a translational level by serine/threonine kinase 40 (Stk40). Genetic knockout (KO) or knockdown (KD) of Stk40 leads to increased protein levels of C/EBP proteins and adipocyte differentiation in mouse embryonic fibroblasts (MEFs), fetal liver stromal cells, and mesenchymal stem cells (MSCs). In contrast, overexpression of Stk40 abolishes the enhanced C/EBP protein translation and adipogenesis observed in Stk40-KO and -KD cells. Functionally, knockdown of C/EBPβ eliminates the enhanced adipogenic differentiation in Stk40-KO and -KD cells substantially. Mechanistically, deletion of Stk40 enhances phosphorylation of eIF4E-binding protein 1, leading to increased eIF4E-dependent translation of C/EBPβ and C/EBPδ. Knockdown of eIF4E in MSCs decreases translation of C/EBP proteins. Moreover, Stk40-KO fetal livers display an increased adipogenic program and aberrant lipid and steroid metabolism. Collectively, our study uncovers a new repressor of C/EBP protein translation as well as adipogenesis and provides new insights into the molecular mechanism underpinning the adipogenic program.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Stk40 represses adipogenesis through translational control of CCAAT/enhancer-binding proteins

Wang

et al. 2015

Journal of Cell Science

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“…pRetrosuper cells, these findings demonstrate that deletion of p70S6K1 alone does not affect 3T3-L1 differentiation, as reported previously (27). Next, we examined whether Sam68sh 3T3-L1 cells were partially rescued with siRNAs targeting p70/p31S6K1, and indeed this was the case (Fig.…”

Section: Figmentioning

confidence: 49%

“…S6K1 Ϫ/Ϫ mice have decreased adipose tissue mass, increased energy expenditure, and are resistant to dietary-induced obesity (40). S6K1 participates in the upregulation of transcription factors during the commitment phase of adipogenesis (27). Adipocytes normally express p70/p85S6K1 but not p31S6K1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The reverse primer sequence for Deptor was 5=-AGA TAT GTA ACC TGG TTC TTC CAC-3=, and for Deptor-002 it was 5=-ACC CAC CTT CCC TCC CAT TAG GTC-3=. For real-time reverse transcription-PCR (RT-PCR), mouse Rps6kb1 was amplified with 5=-CGT GGA GTC TGC GGC G-3= (located in exon 1) and 5=-CAT ATG GTC CAA CTC CCC CA-3= (located in exon 2), mouse Rps6kb1-002 was amplified with 5=-TAT GCC TTT CAG ACC GGA GG-3= (located in exon 5) and 5=-ACC TCC CTA AGA CTG CAC CT-3= (located in exon 6b), 18S rRNA was amplified with 5=-GTA ACC CGT TGA ACC CCA TT-3= and 5=-CCA TCC AAT CGG TAG TAG CG-3=, C/EBP␣ was amplified with 5=-CGC AAG AGC CGA GAT AAA GC-3= and 5=-GCG GTC ATT GTC ACT GGT CA-3=, GLUT4 was amplified with 5=-TCG TGG CCA TAT TTG GCT TTG TGG-3= and 5=-TAA GGA CCC ATA GCA TCC GCA ACA-3=, peroxisome proliferator-activated receptor ␥ (PPAR␥) was amplified with 5=-GAA CGT GAA GCC CAT CGA GGA C-3= and 5=-CTG GAG CAC CTT GGC GAA CA-3=, as previously described (27), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was amplified with 5=-AGC CAC ATC GCT CAG ACA C-3= and 5=-GCC CAA TAC GAC CAA ATC C-3=. Sam68 was amplified with 5=-GTG GAG ACC CCA AAT ATG CCC A-3= and 5=-AAA CTG CTC CTG ACA GAT ATC A-3=.…”

Section: Methodsmentioning

confidence: 99%

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Sam68 Regulates S6K1 Alternative Splicing during Adipogenesis

Song

Richard

2015

Molecular and Cellular Biology

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The requirement for alternative splicing during adipogenesis is poorly understood. The Sam68 RNA binding protein is a known regulator of alternative splicing, and mice deficient for Sam68 exhibit adipogenesis defects due to defective mTOR signaling. Sam68 null preadipocytes were monitored for alternative splicing imbalances in components of the mTOR signaling pathway. Herein, we report that Sam68 regulates isoform expression of the ribosomal S6 kinase gene (Rps6kb1). Sam68-deficient adipocytes express Rps6kb1-002 and its encoded p31S6K1 protein, in contrast to wild-type adipocytes that do not express this isoform. Sam68 binds an RNA sequence encoded by Rps6kb1 intron 6 and prevents serine/arginine-rich splicing factor 1 (SRSF1)-mediated alternative splicing of Rps6kb1-002, as assessed by cross-linking and immunoprecipitation (CLIP) and minigene assays. Depletion of p31S6K1 with small interfering RNAs (siRNAs) partially restored adipogenesis of Sam68-deficient preadipocytes. The ectopic expression of p31S6K1 in wild-type 3T3-L1 cells resulted in adipogenesis differentiation defects, showing that p31S6K1 is an inhibitor of adipogenesis. Our findings indicate that Sam68 is required to prevent the expression of p31S6K1 in adipocytes for adipogenesis to occur.

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Adipose Organ Development and Remodeling

Cinti

2018

Comprehensive Physiology

148

121

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During the last decades, research on adipose tissues has spread in parallel with the extension of obesity. Several observations converged on the idea that adipose tissues are organized in a large organ with endocrine and plastic properties. Two parenchymal components: white (WATs) and brown adipose tissues (BATs) are contained in subcutaneous and visceral compartments. Although both have endocrine properties, their function differs: WAT store lipids to allow intervals between meals, BAT burns lipids for thermogenesis. In spite of these opposite functions, they share the ability for reciprocal reversible transdifferentiation to tackle special physiologic needs. Thus, chronic need for thermogenesis induces browning and chronic positive energy balance induce whitening. Lineage tracing and data from explant studies strongly suggest other remodeling properties of this organ. During pregnancy and lactation breast WAT transdifferentiates into milk-secreting glands, composed by cells with abundant cytoplasmic lipids (pink adipocytes) and in the postlactation period pink adipocytes transdifferentiate back into WAT and BAT. The plastic properties of mature adipocytes are supported also by a liposecretion process in vitro where adult cell in culture transdifferentiate to differentiated fibroblast-like elements able to give rise to different phenotypes (rainbow adipocytes). In addition, the inflammasome system is activated in stressed adipocytes from obese adipose tissue. These adipocytes die and debris are reabsorbed by macrophages inducing a chronic low-grade inflammation, potentially contributing to insulin resistance and T2 diabetes. Thus, the plastic properties of this organ could open new therapeutic perspectives in the obesity-related metabolic disease and in breast pathologies. © 2018 American Physiological Society. Compr Physiol 8:1357-1431, 2018.

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S6K1 Plays a Critical Role in Early Adipocyte Differentiation

Cited by 176 publications

References 69 publications

Stk40 represses adipogenesis through translational control of CCAAT/enhancer-binding proteins

Stk40 represses adipogenesis through translational control of CCAAT/enhancer-binding proteins

Sam68 Regulates S6K1 Alternative Splicing during Adipogenesis

Adipose Organ Development and Remodeling

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