Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure

Dali‐Youcef, Nassim; Mataki, Chikage; Coste, Agnès; Messaddeq, Nadia; Giroud, Sylvain; Blanc, Stéphane; Koehl, C.; Champy, Marie‐France; Chambon, Pierre; Fajas, Lluís; Metzger, Daniel; Schoonjans, Kristina; Auwerx, Johan

doi:10.1073/pnas.0611568104

Cited by 106 publications

(121 citation statements)

References 38 publications

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“…Paradoxically pRB is, in contrast to the other tumor suppressors, a major modulator of oxidative metabolism. RB-specific deletion in adipose tissue results in increased mitochondrial activity and reversal from anabolic white adipose tissue to catabolic oxidative brown adipose tissue (Dali-Youcef et al, 2007). In this particular situation RB would facilitate a cancer-type metabolism.…”

Section: Counteracting Tumor Suppressor Pathwaymentioning

confidence: 99%

Metabolism and proliferation share common regulatory pathways in cancer cells

2010

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Cancer development involves major alterations in cells' metabolism. Enhanced glycolysis and de novo fatty acids synthesis are indeed characteristic features of cancer. Cell proliferation and metabolism are tightly linked cellular processes. Others and we have previously shown a close relationship between metabolic responses and proliferative stimuli. In addition to trigger proliferative and survival signaling pathways, most oncoproteins also trigger metabolic changes to transform the cell. We present herein the view that participation of cell-cycle regulators and oncogenic proteins to cancer development extend beyond the control of cell proliferation, and discuss how these new functions may be implicated in metabolic alterations concomitant to the pathogenesis of human cancers.

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Section: Counteracting Tumor Suppressor Pathwaymentioning

confidence: 99%

Metabolism and proliferation share common regulatory pathways in cancer cells

2010

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“…The CDK-Rb-E2F1 pathway, which is inhibited by p16 Ink4a , has already been shown to control adipogenesis by modulating the expression of the nuclear receptor PPARg (15,29), a master regulator of adipogenesis, as well as by controlling oxidative metabolism in adipose tissue (30). The CDK-Rb-E2F1 pathway is also a negative regulator of energy expenditure through repression of mitochondrial oxidative metabolism in muscle (16).…”

Section: Ink4amentioning

confidence: 99%

Cdkn2a/p16Ink4a Regulates Fasting-Induced Hepatic Gluconeogenesis Through the PKA-CREB-PGC1α Pathway

et al. 2014

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Type 2 diabetes (T2D) is hallmarked by insulin resistance, impaired insulin secretion, and increased hepatic glucose production. The worldwide increasing prevalence of T2D calls for efforts to understand its pathogenesis in order to improve disease prevention and management. Recent genome-wide association studies have revealed strong associations between the CDKN2A/B locus and T2D risk. The CDKN2A/B locus contains genes encoding cell cycle inhibitors, including p16 Ink4a, which have not yet been implicated in the control of hepatic glucose homeostasis. Here, we show that p16Ink4a deficiency enhances fasting-induced hepatic glucose production in vivo by increasing the expression of key gluconeogenic genes. p16Ink4a downregulation leads to an activation of PKA-CREB-PGC1a signaling through increased phosphorylation of PKA regulatory subunits. Taken together, these results provide evidence that p16Ink4a controls fasting glucose homeostasis and could as such be involved in T2D development.Type 2 diabetes (T2D) is a complex metabolic disorder involving a combination of insulin resistance, impaired insulin secretion, and increased hepatic glucose production (1,2). The pathogenesis of T2D is multifactorial, involving both genetic and environmental susceptibility factors (3). During these last few years, the search for genetic determinants of T2D greatly progressed, identifying new loci contributing to T2D. A better understanding of the function of the gene products of these loci is required to identify new strategies for the prevention and treatment of T2D (3,4). Hence, recent human genomewide association studies (GWAS) have identified a polymorphism on chromosome 9p21 (rs10811661), located 125 kb upstream of the CDKN2B and CDKN2A genes, that is strongly and reproducibly linked to T2D (5-7), establishing genes on the CDKN2A/B locus among the strongest candidates for conferring susceptibility to T2D across different ethnicities (4).The gene products are the cyclin-dependent kinase (CDK) inhibitors p16Ink4a and p14 ARF for the CDKN2A locus and p15Ink4b for the CDKN2B locus, which are tumor suppressors acting as cell cycle inhibitors (8,9). The p15Ink4b and p16 Ink4a proteins bind to either CDK4 or CDK6, thus inhibiting the action of cyclin D and preventing retinoblastoma protein phosphorylation and subsequent release of the E2F1 transcription factor. As a consequence, the transcription of genes required for cell cycle progression to the S phase is restrained.However, how the CDKN2A/B gene products modulate glucose metabolism is less clear. In murine models, increased expression of p15Ink4b in pancreatic islets is associated with islet hypoplasia and impaired glucose-induced insulin secretion (10). Moreover, p16Ink4a plays a crucial role in senescence and aging. p16Ink4a expression increases with age in pancreatic b-cells and promotes an agedependent decline in islet regenerative potential (11). Additionally, other cell cycle regulators, like CDK4, E2F1, and cyclin D, also play roles in glucose homeostasis through

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“…31 De novo DNA methylation occurs during embryogenesis, but can also occur in adult cells to alter the developmental program of the cell. 32 It is hypothesized that DNA methylation is set up in a tissuespecific manner, thereby silencing the genes opposing the proper development and leaving essential genes unmethylated and thereby helping to direct terminal differentiation.…”

Section: Discussionmentioning

confidence: 99%

Comparative expression analysis of isolated human adipocytes and the human adipose cell lines LiSa-2 and PAZ6

et al. 2008

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Objective: To obtain insight in the extent to which the human cell lines LiSa-2 and PAZ6 resemble isolated primary human adipocytes. Design: A combination of cDNA subtraction (representative difference analysis; RDA) and cDNA microarray analysis was used to select adipose specific genes to compare isolated (pre-)adipocytes with (un)differentiated LiSa-2 and PAZ6 cells. Measurements: RDA was performed on adipose tissue against lung tissue. A total of 1400 isolated genes were sequenced and cDNA microarray technology was used for further adipose related gene selection. 30 genes that were found to be enriched in adipose tissue were used to compare isolated human adipocytes and LiSa-2 and PAZ6 cells in the differentiated and undifferentiated states. Results: RDA and microarray analysis resulted in the identification of adipose enriched genes, but not in adipose specific genes. Of the 30 most differentially expressed genes, as expected, most were related to lipid metabolism. The second category consisted of methyltransferases, DNMT1, DNMT3a, RNMT and SHMT2, of which the expression was differentiation dependent and higher in differentiated adipocytes. Using the 30 adipose expressed genes, it was found that isolated adipocytes on one hand, and PAZ6 and LiSa-2 adipocytes on the other, differ primarily in lipid metabolism. Furthermore, LiSa-2 cells seem to be more similar to isolated adipocytes than PAZ6 cells. Conclusion:The LiSa-2 cell line is a good model for differentiated adipocytes, although one should keep in mind that the lipid metabolism in these cells deviates from the in vivo situation Furthermore, our results imply that methylation may have an important function in terminal adipocyte differentiation. In this study, we aimed to gain insight in the extent to which the human cell lines LiSa-2 and PAZ6 resemble human adipocytes in the in vivo situation, using adipose tissue properties. Therefore, we studied the expression levels of 30 adipose specific genes in isolated cells and in the undifferentiated and differentiated cell lines. Isolation of adipose tissue specific genes was attempted by using a combination of subtractive hybridization and microarray analysis.Subtractive hybridization, also named representation difference analysis (RDA), 16 is a method to enrich a target mRNA population, in this case mRNA from human subcutaneous adipose tissue, with low abundant and specific sequences, by removing those sequences that are also present in a second population, in this case lung mRNA. The resulting cDNA library was sequenced. The success of the subtraction procedure was assessed by spotting of the cDNA inserts on a microarray and by hybridizing this cDNA microarray with mRNA from different tissues, including adipose tissue and lung. By hybridization with RNA from adipose tissue and colon and lung tissue, 30 adipose enriched genes were selected. These were used for comparative analysis of isolated (pre-)adipocytes and (un)differentiated cell lines using cDNA microarray technology. During differentiation the medium...

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Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure

Cited by 106 publications

References 38 publications

Metabolism and proliferation share common regulatory pathways in cancer cells

Metabolism and proliferation share common regulatory pathways in cancer cells

Cdkn2a/p16Ink4a Regulates Fasting-Induced Hepatic Gluconeogenesis Through the PKA-CREB-PGC1α Pathway

Comparative expression analysis of isolated human adipocytes and the human adipose cell lines LiSa-2 and PAZ6

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