Emerging Roles for the INK4a/ARF (CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes

Kahoul, Yasmina; Oger, Frédérik; Montaigne, Jessica; Froguel, Philippe; Breton, Christophe; Annicotte, Jean-Sébastien

doi:10.3390/biom10091350

Cited by 20 publications

(21 citation statements)

References 113 publications

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“…Knockdown of p16INK4A enhanced adipogenesis in vitro, and adipose tissue formation especially in the pericardial fat was enhanced in p16INK4A knockout mice [ 208 ]. The role of p16INK4A in adipogenesis seems to be related via several molecular mechanisms to PPAR gamma (reviewed in [ 214 ]). Senolytic drug treatment or the use of INK-ATACC mice has been shown to alleviate metabolic and adipose tissue dysfunction, improve glucose tolerance, enhance insulin sensitivity, lower circulating inflammatory mediators, and promote adipogenesis in obese mice [ 239 ].…”

Section: P16ink4a P14arf/p19arf and P21 In Homeostasismentioning

confidence: 99%

“…Bone marrow-derived macrophages from p16INK4A knockout mice show polarization towards an anti-inflammatory M2 phenotype and silencing of p16INK4A in macrophages from obese patients equally shifts the phenotype towards M2 macrophages [ 227 , 228 ]. These effects seem to be independent of proliferation and senescence [ 214 ], although earlier data indicated a critical role of the p16INK4A locus in proliferation and programming of progenitor cell populations [ 243 ]. Besides the effects of p16INK4A on macrophage polarization in adipose tissue, also increased white-to-brown adipocyte conversion associated with enhanced energy expenditure and insulin sensitivity has been reported in p16INK4A knockout mice [ 215 ].…”

Section: P16ink4a P14arf/p19arf and P21 In Homeostasismentioning

confidence: 99%

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The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

Wagner

2022

Cells

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It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad of factors commonly called the senescence-associated secretory phenotype. Despite the replicative cell cycle arrest, these cells are metabolically active and functional. The release of SASP factors is mostly thought to cause tissue dysfunction and to induce senescence in surrounding cells. As major markers for aging and senescence, p16INK4, p14ARF/p19ARF, and p21 are established. Importantly, senescence is also implicated in development, cancer, and tissue homeostasis. While many markers of senescence have been identified, none are able to unambiguously identify all senescent cells. However, increased levels of the cyclin-dependent kinase inhibitors p16INK4A and p21 are often used to identify cells with senescence-associated phenotypes. We review here the knowledge of senescence, p16INK4A, p14ARF/p19ARF, and p21 in embryonic and postnatal development and potential functions in pathophysiology and homeostasis. The establishment of senolytic therapies with the ultimate goal to improve healthy aging requires care and detailed knowledge about the involvement of senescence and senescence-associated proteins in developmental processes and homeostatic mechanism. The review contributes to these topics, summarizes open questions, and provides some directions for future research.

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Section: P16ink4a P14arf/p19arf and P21 In Homeostasismentioning

confidence: 99%

Section: P16ink4a P14arf/p19arf and P21 In Homeostasismentioning

confidence: 99%

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

Wagner

2022

Cells

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“…p16 INK4a seems to inhibit adipogenesis while knock-down of p16 INK4a in 3T3-L1 mouse preadipocytes increased adipogenesis [111]. Additionally, it has been speculated that increased p16 INK4a levels during ageing and obesity might contribute to the recruitment of macrophages in adipose tissue as well as the prevention of macrophage M2 polarisation with an increased risk of developing type two diabetes [113]. Thus, p16 INK4a seems to be a key factor that is implicated in adipose tissue during ageing as well as obesity.…”

Section: P16 Ink4a and Adipocyte Senescencementioning

confidence: 99%

Senescence and DNA Damage in Adipocytes and Fat Tissues and Its Potential Amelioration through Nutritional Interventions

Ishaq¹,

Saretzki²

2022

RPN

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Accumulating evidence demonstrates that senescence and the associated inflammatory phenotype (SASP) also occur in post-mitotic cells such as mature adipocytes. Visceral adipose tissue in humans is susceptible to inflammation due to nutritional imbalance and ageing. However, while adipose tissue has been well researched in the context of obesity, senescence of differentiated adipocytes has not been investigated thoroughly. Our group recently demonstrated that ageing and normal ad libitum (AL) nutrition in mice resulted in increased adipocyte size, DNA damage, p16INK4a expression and inflammation in visceral adipose tissue while some of these senescence markers could be alleviated by dietary restriction (DR). Moreover, another dietary restriction study described a “metabolic memory” as protection against AL-induced senescence after shifting mice from DR back to AL nutrition. Other recent DR studies on mice of different ages analysed the transcriptional profile of adipose tissue and described a metabolic memory for AL at high age. Finally, our group modelled nutritional imbalance in vitro through treatment of primary human subcutaneous and omental adipocytes with the saturated fatty acid (FA) palmitic acid (PA). This resulted in a significant increase in DNA damage as well as p16INK4a levels correlating with enhanced intracellular lipid accumulation. In contrast, DNA damage could be prevented with the unsaturated FA oleic acid (OA). With olive oil being an important part of the Mediterranean diet another study found also other oils such as argan oil to have similar effects of preventing DNA damage in vivo and in vitro. This review is focused on senescence, DNA damage and inflammation in WAT and adipocytes including nutritional interventions in vivo and in vitro. It also gives some basic background on these topics. However, it is not a systematic review but aims to highlight recent developments and nutritional interventions in the areas of senescence and DNA damage related to adipocyte tissues and cells.

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“…This mechanism is repressed through the activation of CDK inhibitors, namely p16 INK4A , that bind to CDK and avoid cyclinD/CDK4 complex formation, and subsequently repress pRb phosphorylation and E2F1 transcriptional activity (25). Although these mechanisms mainly control the progression of the cell cycle (26), recent studies have reported important roles for the E2F1-pRb-CDK4 pathway beyond the sole regulation of cell proliferation (27,28). Indeed, several reports have demonstrated the role of the E2F1 pathway in the control of metabolic functions in non-proliferative cells, including adipocytes (29,30), hepatocytes (31)(32)(33), muscle and brown adipose tissue (34,35) and pancreatic b cells (17)(18)(19)36).…”

Section: Introductionmentioning

confidence: 99%

A crosstalk between E2F1 and GLP-1 signaling pathways modulates insulin secretion

Bourouh

Courty

Pasquetti

et al. 2021

Preprint

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Compromised β-cell function contributes to type 2 diabetes (T2D) development. The glucagon like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential toward T2D treatment, notably by improving β-cell functions. Recent data have shown that the transcription factor E2f1, besides its role as a cell cycle regulator, is involved in glucose homeostasis by modulating β-cell mass, function and identity. Here, we demonstrate a crosstalk between the E2F1, phosphorylation of retinoblastoma protein (pRb) and Glp-1 signaling pathways. We found that β-cell specific E2f1 deficient mice (E2f1β-/-) presented with impaired glucose homeostasis and decreased glucose stimulated-insulin secretion mediated by exendin 4 (i.e., GLP1R agonist), which were associated with decreased expression of Glp1r encoding Glp-1 receptor (GLP1R) in E2f1β-/- pancreatic islets. Decreasing E2F1 transcriptional activity with an E2F inhibitor in islets from nondiabetic humans decreased GLP1R levels and blunted the incretin effect of exendin 4 on insulin secretion. Conversely, overexpressing E2f1 in pancreatic β cells increased Glp1r expression associated with enhanced insulin secretion mediated by GLP1R agonist. Interestingly, kinome analysis of mouse islets demonstrated that an acute treatment with exendin 4 increased pRb phosphorylation and subsequent E2f1 transcriptional activity. This study suggests a molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways that modulates insulin secretion and glucose homeostasis.

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Emerging Roles for the INK4a/ARF (CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes

Cited by 20 publications

References 113 publications

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

Senescence and DNA Damage in Adipocytes and Fat Tissues and Its Potential Amelioration through Nutritional Interventions

A crosstalk between E2F1 and GLP-1 signaling pathways modulates insulin secretion

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