Obesity

P53 activation in adipocytes of obese mice study – The p53/Adipose-Tissue/Cancer Nexus

Along with all these, genetic factors also play a significant role in Obesity. Cold Spring Harbor Perspect.

These data suggest that an HFD and aging can cause increased Zbtb7c expression and thereby decreased Sirt1 expression, which can affect diverse cellular processes e. Molchadsky A. Curr Osteoporos Rep. Recently, the bone marrow has been identified as a unique adipose depot. An increased risk of cancer development and a poorer cancer prognosis is associated with increased obesity—

  • Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function.

  • The majority of studies have examined adipocyte lipolysis in relation to cytosolic neutral lipolysis Schweiger et al.

  • Identification of proteins secreted from leptin stimulated MCF-7 breast cancer oobese a dual proteomic approach. Indeed, our findings might indicate that body weight and fat mass of mice lacking p53 might respond differentially to WT when they are challenged to certain conditions such as high fat diet, but further studies will be necessary to address this issue.

  • In addition, several studies have suggested that p53 is involved in normal hepatic glucose homeostasis and lipid metabolism in liver tissue Prokesch et al.

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In patients and mice with CHI, an activating mutation of glucokinase GCK and dysfunctional ATP-sensitive potassium channels K ATP channel result in beta-cell membrane depolarization, hypersecretion of insulin and overactive glycolysis. American Journal of Physiology. Inhibition of endothelial p53 improves metabolic abnormalities related to dietary obesity. National Center for Biotechnology InformationU.

Table 5 Genotype frequencies of p53 gene polymorphism in female obese and non-obese study participants. Maeda, N. However, the genetic background of sarcopenia and sarcopenia related obesity in undefined yet. We performed additional experiments, adding 11 new data panels in Figure 7, providing a better overall metabolic profile.

The thick red color indicates the higher D'. Obesity is one of the major problem plaguing all over the world today. PloS one. Czyzyk, T.

The second reason is the unique characteristic of ohese, which has specific roles dependent on tissue or development stage. Once you have adipocytes that decision, we will be able to accept the manuscript for publication. Aging 2 — Although these results suggest that p53 is a negative regulator of the adipogenic program, data about p53 signaling in 3T3-L1 cells need to be interpreted with caution, since the transformed mouse 3T3 cell double minute 2 Mdm2 gene, whose encoded protein is the major negative regulator of p53, is highly amplified in this cell line [ 48 ].

Background

The results of the latter two studies support a role of p53 as negative regulator of adipocytds adipogenic differentiation from progenitor cells. Risk factors for both forms of diabetes include family history, genetics and age. Aging Cell. Previously performed studies have reported contrasting results regarding the role of p53 in brown adipogenesis.

M false. Insulin maintains glucose homeostasis by inhibiting glucose production gluconeogenesis in the liver and stimulating glucose uptake in peripheral tissues, such as adipose tissue and skeletal muscle [ 6263 ]. Among these, some SNPs can significantly affect biological functions. P53 KO.

There is a lack of information about p53 in nonparenchymal, adipose-resident cells. Aberrant signaling through these pathways activates expression of genes that contribute to cancer cell survival, proliferation, and migration 97 — Nevertheless, our data support metformin acts through a pdependent mechanism to affect adipocyte glucose consumption and lactate production Figure 6E-F. Chang H.

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Dis Markers. Ablation of p53 in POMC p53 activation in adipocytes of obese mice study does not alter energy balance. Fat mass c ; non-fat mass d ; locomotor activity LA e ; oebse quotient RQ f ; energy expenditure g — h ; representative infrared thermal images and temperature of the BAT area i ; representative BAT histology pictures hematoxylin-eosin j ; BAT protein levels of UCP1 k ; representative WAT histology pictures hematoxylin-eosin l ; representative liver histology pictures hematoxylin-eosin, upper and oil-red O staining, lower m ; glucose tolerance test n ; and insulin tolerance test o of control and AgRPp53 KO mice fed a HFD.

Ron, D. Neuron 37— Mice lacking p53 in AgRP neurons showed a non-significant trend toward decreased fasted-induced hyperphagia Supplementary Fig. Cell 9125—34 Kenyon, C.

Loughery J, D. These interactions also promote synaptic endocytosis, suggesting that autoinhibition both clamps and primes the synaptic endocytic machinery, thereby constraining actin assembly to drive productive membrane remodeling in response to physiological cues. Google Scholar Crossref. Per CDC reports, the incidence of non-obesity related cancers showed a decline from towhile the rates of obesity-related cancers increased 1. However, effects in the study of Inoue et al.

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Cell Metabolism 18 — Related Articles. Full size image. Cell Metabolism 19 —

  • Kung C.

  • A link between TP53 polymorphisms and metabolism.

  • American Society of Clinical Oncology position statement on obesity and cancer.

  • Autophagy acts as a pivotal innate immune response against infection. In a healthy state, adipocytes will select either glucose or fatty acids as the main energy source in feeding and fasting conditions, continuously and cyclically switching between the two substrates.

  • Article Google Scholar 9.

  • Search Search articles by subject, keyword or author. The association between TP53 rs polymorphism and the risk of sarcopenic obesity in Iranian older adults: a case-control study.

Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Putting the stress on senescence. N -values and p -values are reported as exact numbers above the bar graphs. Overall, these data support a non-canonical p53 function in the regulation of adipocyte energy homeostasis and indicate that the dysregulation of this pathway may be involved in developing metabolic dysfunction in obesity. Genotyping was carried out on obese and normal samples. Giannakou, M. Jansena, f and Muhummadh Khan a, b.

Both the basal and maximum respiration sdipocytes were lower in the pKO adipocytes than in the WT controls Figure 3Asuggesting that mitochondrial function was suppressed. In this study we evaluated the association of TP53 rs polymorphism with the susceptibility to sarcopenic obesity in Iranian old-age subjects. Heart Circ. International Journal of Obesity Furukawa, S. Advanced search.

Furthermore, insulin resistance occurred in middle-aged mice, implying that chronic reduction of p53 activity is responsible for the development of acivation resistance under normal calorie intake. A study in patients with cardiovascular diseases. Transcription factor and transcriptional target. The largest component of white adipose tissue is the large, spherical adipocyte with a unilocular lipid droplet occupying most of the cell volume. Nature —

Materials and Methods

Nature — Furthermore, the increase in fat mass, when energy intake exceeds energy expenditure, is mainly due to hypertrophy rather than hyperplasia [ 34 ]. J Neuroendocrin.

Wang Z. Role of P53 and White Adipocyte Differentiation and Lipid Metabolism p53 is a regulator of cell survival and proliferation in response to o53 stress signals against abnormal cell growth and tumorigenesis. Concomitantly, lipolysis was induced and release of FAs led to chronic p53 upregulation, detectable in visceral WAT as long as six weeks after TAC [ 68 ]. However, our collective understanding of the direct role of p53 in adipocyte differentiation and function remains insufficient. A crucial role for adipose tissue p53 in the regulation of insulin resistance.

In the interests of transparency, eLife publishes the most substantive revision requests and the accompanying author responses. Additionally, glycolysis produces the intermediate metabolite pyruvate. These markers were up-regulated by long-term HFD but unaffected by 24 hr fasting and short-term 3 days HFD feeding Figure 1D—Ewhich suggests the non-canonical function of p53 may be activated under these short-term metabolically challenging conditions. Sabir et al. Oncotarget 6—

Introduction

Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Its significant role in tumor suppression is axipocytes on its activity as a transcription factor regulating expression of genes in cell cycle regulation, apoptosis, DNA repair, differentiation, and senescence pathways Figure 1. Over the past four decades, the roles of p53 have been extensively studied because the mutation or inhibition of p53 initiates tumorigenesis [ 114818283 ]. Figure 3.

Table 3 Genotype frequencies of p53 gene polymorphism in obese and addipocytes study participants. Next, we assessed the effect of AgRP neuron-specific ablation of p53 on the intrinsic electrophysiological properties of these neurons during DIO. LD plot was constructed to evaluate the additive effect of p53 polymorphisms on its association with developing obesity, Fig. Hypothalamic AMPK: a canonical regulator of whole-body energy balance. A two-part list of links to download the article, or parts of the article, in various formats. Role of the hypothalamic-pituitary-thyroid axis in metabolic regulation by JNK1. Figure 6.

View raw image The regulation of insulin resistance by p Recently, our group used a mouse model for the codon 72 polymorphism of p53 activation in adipocytes of obese mice study in order to investigate the role of this Activatuon in obesity and diabetes. Different regulatory mechanisms for the activation of each pathway obdse been identified, including upstream signaling, post-translational modifications, and downstream activated target genes Vousden and Prives, a ; Kruiswijk et al. Gaining knowledge of the exact regulatory in- and output of signaling that pertains to wild-type p53 and its many known mutant forms in specific cells, organs, and during physiological and pathological situations, comprises both a major challenge and hope for the implementation of personalized medicine in the clinic. Diabetes phenotypes regulated by p53 In general, there are three major causes of diabetes: 1 functional deficiencies in pancreatic insulin production, 2 aberration of glucose homeostasis and 3 development of insulin resistance. The p53 family in differentiation and tumorigenesis. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

1. Introduction

It seems double knockdown significantly abolished lipolysis, but it was not as low as basal control. Article Google Scholar. Kaushik, S.

Download references. The wild-type amino acid is comparatively small in size than the mutant. Cell Metab. Primary antibodies were detected in Western blots using secondary antibodies conjugated to horseradish peroxidase Sigma diluted and chemiluminescent substrate PerkinElmer Life Sciencesfollowed by detection by Fujifilm LAS Image Analyzer.

  • The Src-family kinase Lyn in immunoreceptor signaling. Also, using a murine model of diet-induced obesity DIO weight gain was reduced in pnull mice, and the mechanism was through an increase in UCP1 expression, both in brown and white adipose tissue

  • Increased oxidative stress in obesity and its impact on metabolic syndrome.

  • This work has been supported by grants from Ministerio de Economia y Competitividad C. Cancer Immunol.

  • AgRP-specific ablation of p53 resulted in increased hypothalamic c-Jun N-terminal kinase JNK activity before the mice developed obesity, and central inhibition of JNK reversed the obese phenotype of these mice. The study is conducted in accordance to the approval obtained from the local ethics committee on biomedical research.

  • Vergoni et al.

Nat Med. National Center obesd Biotechnology InformationU. The pulled-down proteins were then analyzed by western blotting using the antibodies indicated. In mice lacking p53 ghrelin failed to cause any change in body weight Figure 1 B. Immortal brown adipocytes from pknockout mice: Differentiation and expression of uncoupling proteins. Molecular Cell 18 —

Figure 1. Chi-square test was done for genotypes and alleles frequency. In attempting to understand the underlying actibation of this non-canonical p53 pathway in metabolic regulation, we did not observe any significant changes to the key transporters or enzymes in glucose or lipid metabolic pathways, nor to any previously identified p53 downstream targets that were reportedly linked to the metabolic pathway in cancer cells data not shown. Linkage disequilibrium analysis revealed that there is a difference in strength among SNPs association in cases and controls. Correspondence to Issei Komuro. Obesity 17— Sarcopenic obesity: research advances in pathogenesis and diagnostic criteria.

1. Introduction

Naaz A. Trends Cell Biol. Critical Reviews in Eukaryotic Gene Expression 21 71 —

The chronic inflammation associated with dysfunctional adipose tissue is thought to contribute to oebse favorable microenvironment for tumor growth and progression Figures 23. Plastic and Reconstructive Surgery — Find articles by Jin Mi Chun. Subcutaneous and visceral adipose tissue: structural and functional differences. Nature Cell Biology 3 —

The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to adipocyyes you prepare a revised submission. The pcDNA3. Recent studies have demonstrated that p53 levels in WATs are increased in diet-induced or genetic obesity mouse models [ 3031 ]. This confounds the aim to establish the role of single tissues in insulin resistance. Franck D. Addict Biol. Spitsina et al.

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Animals were treated and killed before any sign of morbidity due to tumor development occurred. HIC1 is a transcriptional repressor that interacted with p53 and suppressed age-dependent cancer development in mice. Oreste Gualillo. International Journal of Molecular Medicine 23 —

Lentivirus were packing used 3 rd generation packing system. Induction of medulloblastomas in pnull mutant mice by somatic inactivation of Rb in the external granular layer adolescent obesity prevention policy of the cerebellum. Please leave this field empty. Genetic polymorphisms associated with obesity in the Arab world: a systematic review. Stereotaxic microinjection of adenoviral expression vectors Ad libitum fed rats were anesthetized by an i. Metrics details. These results are consistent with previous reports indicating that reversal of central ER stress with chemical chaperones is able to decrease food intake and adiposity 343638 ,

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Published : 20 May Only when fed a HFD, p53 knockout mice showed decreased weight and fat mass gain and BAT Ucp1 expression as reported in most studies [ 54, ] a phenomenon apparently only existing in male, but not in female, p53 knockout mice [ ]. Table 1 p53 pathway SNPs and diabetes. User Account Sign in to save searches and organize your favorite content. MDM2 and prognosis. Figure 7—source data 1 An Excel sheet with numerical quantification data.

Targeting p53 to treat diabetes potentially offers extra benefits as an inclusive approach to alleviate both diabetes and downstream symptoms. NF-kappaB, an active player in human cancers. Localization of p53 at the mitochondrial membrane and interaction with anti-apoptotic Bcl proteins stimulates apoptosis. Subcutaneous adipose tissue in humans shows a low cellular turnover rate of only about eight percent per year [ 33 ].

Evidence showed the association p53 activation in adipocytes of obese mice study rs with glioma and meningioma and also lung cancer [ 1819 ]. Independent t-test or Mann-Whitney U test was used stuey compare the anthropometric and biochemical variables differences between the sarcopenic, sarcopenic obesity and healthy participants. Rare and novel mutations in genes which are vital in several key pathways have been reported to alter the energy expenditure which regulates body weight. To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Introduction

Hotamisligil, G. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nasrin Shokrpour for editorial assistance.

  • These data also suggested that p53RE1 was critical in the transcriptional repression by Zbtb7c, and mutation of the site abolished repression by Zbtb7c. Mice lacking ghrelin receptors resist the development of diet-induced obesity.

  • Nature— Peer Review File.

  • This transition is crucial for metabolic homeostasis and is achieved through multiple regulatory mechanisms for controlling the energy fuel flux.

  • Nature —7.

  • Eur J Pharmacol.

  • Cold Spring Harbor Laboratory Press; Genetic reagent Mus.

Increased cardiovascular risk factors in breast cancer survivors identified by routine measurements of body composition, resting heart rate and arterial blood pressure. Liu Y. Arteriosclerosis, Thrombosis, and Vascular Biology 32 — Prostaglandins Leukot. Adipocytes are derived from multipotent mesenchymal stem cells MSCswhich are first committed to the adipogenic lineage and then transformed into preadipocytes.

On p53RE regions, Zbtb7c binding was increased in activatlon dose-dependent manner, but p53 binding remained constant. Skip Nav Destination Article Navigation. In adipocytes to inhibitory effects on anabolic glycolysis, p53 drives catabolic mitochondrial respiration via induction of key genes such as mitochondrial glutaminase Gls2Synthesis of cytochrome c oxidase 2 Sco2 and Complex 1 proteins that are involved in fueling the tricarboxylic acid TCA cycle and driving electron transport 50 Donehower LA. Curr Biol. Nature — T allele is a risk factor for diabetes in Caucasians.

P53 activation in adipocytes of obese mice study Study obes of high-fat diet feeding studies. The available in vitro and in vivo evidence suggests that p53 is capable of having a significant impact on all three of these pathways. Yahagi N. As mentioned previously, the T allele of TCF7L2 rs confers the strongest risk for type 2 diabetes known in Caucasians Florez This is in agreement with p53 being activated by oleic acid [ ] or palmitic acid [ 6887 ] in cultured cells and suggests that p53 may be a central player in whole body energy homeostasis upon lipid overload, at least in part, through its action in BAT.

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The ARC was targeted bilaterally using a gauge needle connected to a 1-ml syringe Neuro-Syringe, Hamilton and adenoviral vectors were delivered at a rate of 0. View author publications. Official websites use.

  • ROS-mediated p53 induction of Lpin1 regulates fatty acid oxidation in response to nutritional stress.

  • According to our best knowledge, there is no study on association betweenTP53 rs and lipid levels. Nevertheless, these data clearly demonstrate LAL-mediated lipolysis plays a key role in lipolysis.

  • Obesity induces a phenotypic switch in adipose tissue macrophage polarization. In addition to its roles in diabetes risk and severity, p53 has also been shown to play an active role in these conditions by regulating apoptosis, cell cycle arrest, senescence and inflammation Jazayeri et al.

  • Omentin-1, a new adipokine, promotes apoptosis through regulating Sirt1-dependent p53 deacetylation in hepatocellular carcinoma cells. Most recently, Wang et al.

Figure 3—source data 1 An Excel sheet with numerical quantification data. Metabolic sensing by p keeping the balance between life and death. Obesity is enormously increasing in Saudi Arabia, and it ranks 3rd in the world in obesity. Hypothalamic CaMKKbeta mediates glucagon anorectic effect and its diet-induced resistance. In insulin resistance, p53 is found to be upregulated, while p53 downregulation is associated with insulin sensitivity. Sign up for Nature Briefing.

Choi, W. As the adipose tissue becomes inflamed, production of inflammatory cytokines increases and production of adiponectin decreases, resulting in the inability to store surplus free fatty acids FFAs leading to further adipose tissue dysfunction Cell— Our studies show metformin treatment in adipocytes can activate p53 phosphorylation to some degree, but lead to the inhibition of fasting effect Figure 6E. A spectrum of different animal models with different genetic backgrounds along with variation in used diets and treatment durations are a reasonable explanation for such discrepancies. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Supporting this possibility, Chip analysis results showed that p53 binds to PRDM16 promoter regions in primary brown adipocytes [ 32 ].

Sarcopenia in Asia: consensus report of the Asian working Group for Sarcopenia. Subjects Neuroendocrine diseases Obesity. Your article has been reviewed by two peer reviewers, one of whom is a member of our Board of Reviewing Editors, and the evaluation has been overseen by David James as the Senior Editor.

Furukawa, S. Glucose and fatty acids are two main energy sources for mitochondrial respiration, but pKO stuy have a high glycolysis capacity, which led us to ask if fatty acid oxidation was regulated by p53 in adipocytes. Diabetes 60— Figure 3. The functional efficiency of the viral vectors was demonstrated by decreased protein levels of phopho-p53 active form of p53 in the ARC Fig.

Aging Clin Exp Res. Impact of G-quadruplex structures and intronic polymorphisms rs and rs on basal and ionizing radiation-induced expression of alternative p53 transcripts. Blasco, M. The minipump was inserted in subcutaneous adipocytew on the dorsal surface. According to our best knowledge, there is no study on association betweenTP53 rs and lipid levels. Recent genome-wide association studies reported that tumor suppressor gene p53 variants play a critical role in the predisposition of type 2 diabetes and obesity. It needs to mention we demonstrate AMPK is the upstream signal pathway for metabolic p53 activation, however it is unclear how p53 affects AMPK pathway in a feedback manner.

Total Akt expression was similar in the WT and knockout mice. Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. In patients and mice with CHI, an activating mutation of glucokinase GCK and dysfunctional ATP-sensitive potassium channels K ATP channel result in beta-cell membrane depolarization, hypersecretion of insulin and overactive glycolysis. Transcript ion-dependent and -independent p53 function. However, as chronic adipose tissue p53 elevation is a phenomenon that seems impossible to measure, this will likely remain a plausible, but hard-to-prove, hypothesis.

Download citation. It was proposed that rs may influence splicing or transcription factor binding or may be a target site for regulatory miRNAs [ 30 ]. The genotype frequencies of Non-obese and obese samples are shown in Table 3. The association between TP53 rs polymorphism and the risk of sarcopenic obesity in Iranian older adults: a case-control study. Alhebshi AM 1 .

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Schneeberger, M. Abstract The elevation of circulating LPS has been associated with obesity and aging. Horn, R. Lopez, M. Under these conditions, xctivation did not find any change in body weight or other metabolic parameters measured like food intake, body composition, BAT thermogenesis, or adipocyte size Supplementary Fig. This polymorphism was established to modify the expression of protein p53 [ 31 ], however, the exact mechanism is unclear.

  • Please leave this field empty. Liu S.

  • Serum lactate concentration was slightly higher in piAKO mice, but did not reach statistical significance, and blood pH remained unchanged Figure 7J—K.

  • Cancer Res.

  • Kawagishi H. Signaling to p ribosomal proteins find their way.

Ranjan A. The role of p53 in BAT function was interrogated by only few laboratories with partly overlapping and contradictory outcomes as discussed below. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. Protection against high-fat-diet-induced obesity in MDM2 CF mice due to reduced p53 activity and enhanced energy expenditure. Cell Sci. Body composition was measured in injected mice using nuclear magnetic resonance Whole Body Composition Analyzer; EchoMRI, Houston, Texasboth before ghrelin treatment and following the treatment period but before killing. Consistent with these results, a higher glycolytic capacity and glycolytic reserve were observed in the pKO 3T3-L1 adipocytes, as indicated by their extracellular acidification rates, which were measured using Seahorse XF technology Figure 2C—D.

Notably, adpiocytes phenotype mimics the metabolic syndrome seen in ataxia telangiectasia patients, who possess mutations in the p53 Ser15 kinase, ATM. Murine studies have demonstrated that excess adiposity increases the proportion of proinflammatory M1 to anti-inflammatory M2 macrophages in white adipose tissue Conceptualization, Y. These results partially agree with previous reports indicating that p53 plays an important role in adipose tissue 18 Armata H. Wang et al.

To note, hepatic levels of TG, ACC, and FAS were significantly increased in pdeficient mice in comparison to WT mice, indicating that the lack of this gene causes hepatic alterations in lipid metabolism. The most popular genes in the human genome. Despite numerous publications on SIRT1, our understanding of the molecular mechanism of how the SIRT1 gene is regulated by diet conditions and aging remains limited.

Hajrah NH 1. Epi: epididymal fat; SQ: subcutaneous fat. The P72R polymorphism of p53 predisposes to obesity and metabolic dysfunction. Food intake and body weights were recorded daily. There is a significant difference among these parameters when compared with the other two genotype containing samples Table 6. European Journal of Cancer 46 — Al-Massadi, O.

TCF7L2 regulates the expression of p53 and the p53 target gene p53INP1 to control activwtion survival of pancreatic beta cells. As cancer is in most cases an age-related disease, it seems paradoxical that p53 is so strongly conserved from early multicellular organisms to humans. Therefore, p53 induces lipolysis by directly activating ATGL transcription [ 60 ]. Serum insulin levels were measured using a previously described RIA technique Mesenchymal-epithelial transition in epithelial response to injury: The role of Foxc2.

Ribosomal protein-Mdm2-p53 pathway coordinates nutrient stress with lipid metabolism by regulating MCD and promoting fatty acid oxidation. Cancer Res. Therefore, psuppression-based approaches that beneficially reprogram adipocyte metabolic homeostasis in obesity may provide a new strategy for treating obesity and other metabolic diseases, including type II diabetes. Cell —

  • For example, p53 interacts with histone modifying enzymes and chromatin remodelers [e.

  • Buy or subscribe. Body weight, height, waist, and calf circumference were defined by regular procedures.

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Michael Czech. These data not only further demonstrate that non-canonical p53 pathways in metabolic regulation, but also provide a new explanation for the metabolic effect of metformin in adipocytes. The present study was a subgroup of the cross-sectional, population-based study adolescent obesity prevention policy August to February used for evaluating the prevalence of sarcopenia and its determinants among Iranian old subjects which described previously [ 6 ]. There is also evidence that senescent cells promote changes related to aging or age-related diseases 3456. Linear regression was applied to find the correlation between TP53 rs polymorphism, and biochemical and anthropometric parameters. The study is conducted in accordance to the approval obtained from the local ethics committee on biomedical research.

Obesity can be perceived as an accelerated form of adipose tissue senescence, linked to comorbidities similar to those attributed to aging e. Horn H. Related to this issue of systemic metabolism, the pKO cells have more lactate production. External link. Our findings appear to indicate that all the biochemical changes detected in WAT and liver are likely preceding changes in fat mass and body weight.

As described above, p53 affects adipogenesis dependent cell types in vitro. In addition to cell mide, mouse embryonic fibroblasts MEFs isolated from p53 knockout mice were differentiated into adipocytes. However, chronic p53 activation by nutrient stress obesity leads to hepatic steatosis, insulin resistance, and diabetes, pointing to the complexity of the homeostatic response 57 — Find articles by Yu Seong Chung.

These new results reinforce the hypothesis that the effects of hypothalamic p53 on body weight and metabolism occur only in a HFD setting. Iran J Public Health. Benoit, V. Issue Date : September

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Nature Reviews Molecular Zctivation Biology Results Basic characteristics Comparison of the sarcopenic, sarcopenic obesity, and healthy participants concerning basic characteristics were presented in Table 1. Diabetes 66— For post hoc identification, cells were loaded with biocytin by converting the perforated patch configuration to the whole-cell configuration at the end of the recording. Abdulkader M. Essential role of mouse telomerase in highly proliferative organs.

Author information Article notes Copyright and License information Disclaimer. In this model, when the mice were fed a diet containing doxycycline, the p53 expression in white adipose tissue was significantly reduced, specifically in comparison to the liver tissue Figure 7B—C. The p53 proto-oncogene can act study a suppressor of transformation. Your article has been reviewed by two peer reviewers, one of whom is a member of our Board of Reviewing Editors, and the evaluation has been overseen by David James as the Senior Editor. Interestingly, however, mice possessing the Ser18 to alanine mutation did not display significant changes in growth arrest or apoptosis, but rather displayed phenotypes of impaired glucose homeostasis and increased insulin resistance Armata et al. Qualitative regional differences in adipose tissue growth and cellularity in male Wistar rats fed ad libitum. Identification of ALDH4 as a pinducible gene and its protective role in cellular stresses.

Mechanistically, p53 seems to be involved in the regulation of the brown adipose phenotype by both protein—protein interaction and by transactivation of target genes. Mechanisms of Ageing and Development — Different regulatory mechanisms for the activation of each pathway have been identified, including upstream signaling, post-translational modifications, and downstream activated target genes Vousden and Prives, a ; Kruiswijk et al. WAT progenitor cells are differently developed according to location; subcutaneous white adipose tissues develop before birth but visceral white adipose tissues develop after birth [ 2627 ].

JNK in AgRP neurons is known to play an important role in the control of energy balance; study instance, JNK3 deficiency was associated with enhanced excitatory signaling by AgRP neurons in HFD-fed obese mice 61and in line with our results genetic activation of JNK1 signaling in AgRP neurons is sufficient to induce weight gain and adiposity in mice However, this mechanism has been challenged by studies in AMPK-deficient genetic mouse models Foretz et al. Diabetes 65— Agouti-related peptide, neuropeptide Y, and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus.

Trends Endocrinol. Lastly, the amount of Mdm2 is also important. Additionally, we discuss the emerging role of genetic variation in the p53 pathway single-nucleotide polymorphisms on the impact of p53 in metabolic disease and diabetes. Cellular Signalling 17 —

When hormones signal the need for energy, adipocttes acids and glycerol are released through lipolysis. In these baseline studies, we did not observe any obvious metabolic phenotypes, including body weight, overnight fasting glucose, and insulin, between the WT control and pKO mice data not shown. In addition, noncanonical functions of p53 in post-mitotic, noncancerous cells have been described more recently [ 567 ]. Liu S. TP53 mutations in human cancers: origins, consequences, and clinical use.

Dietrich, M. Data Data behind the article This data has been text mined from the article, or deposited into data resources. Blood glucose was measured using a Glucometer Arkray from the tail vein. Taking into account that the main neuronal population targeted by ghrelin is AgRP 4950we tested the ability of central ghrelin to induce food intake in AgRPp53 KO mice.

For post hoc identification, cells were loaded with biocytin by converting the perforated patch sthdy to the whole-cell configuration at the end of the recording. Serrano, M. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. After 2 weeks doxycycline feeding, the diet was replaced by regular food in animal facility, and proceeded to the experiments as indicated.

  • C Quantification of B.

  • Nevertheless, our data support metformin acts through a pdependent mechanism to affect adipocyte glucose consumption and lactate production Figure 6E-F. In recent studies, Burgdorf et al.

  • However, glucose uptakes were much higher in fat and muscle tissues, supporting increased glucose utilization in these tissues Figure 7Mwhich probably explains the hypoglycemia observed in fasted piAKO mice. This chronic inflammatory state can be maintained by passociated mechanisms.

  • Overall, our findings provide evidence that p53 in AgRP neurons is required for normal adaptations against diet-induced obesity. Metabolic regulation by p53 family members.

The present asipocytes was a subgroup of the cross-sectional, population-based study from August to February used for evaluating the prevalence of sarcopenia and its determinants among Iranian old subjects which described previously [ 6 ]. R Study design of high-fat diet feeding studies. Furthermore, the histology studies showed fat tissue from fasted piAKO mice had less morphological change comparing to WT control mice Figure 7N. Mutations in p53 may interrupt the fatty acid oxidation function Jiang et al. Diabetologia Denis, R.

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Xia Y. Adipose tissue-specific p53 knockout via Fabp4-Cre system in these mice also p53 activation in adipocytes of obese mice study in the reversal of the insulin resistant phenotype as well as normalized hepatic gluconeogenic enzyme expression which were increased in Ay and diet-induced obese micewithout modifying the visceral WAT weight. Nevertheless, these data clearly demonstrate LAL-mediated lipolysis plays a key role in lipolysis. Fuel metabolism in starvation. Gaulton K. As the adipose tissue becomes inflamed, production of inflammatory cytokines increases and production of adiponectin decreases, resulting in the inability to store surplus free fatty acids FFAs leading to further adipose tissue dysfunction Studies of adipose tissue have observed increases in the expression and activity of p53 in the adipocytes of obese mice Yahagi et al.

I agree, dismiss this banner. Consistent with a key role for p53 in metabolic shudy, our pharmacological and genetic approaches here establish hypothalamic p53 as a relevant player in the maintenance of energy homeostasis. Gee, J. This protocol incorporates centrifugation through a dense sucrose cushion to protect nuclei and strip away cytoplasmic contaminants. Get the most important science stories of the day, free in your inbox. Download asset Open asset.

Our ov was agreed by the ethics committee of the Shiraz University of Medical Sciences. Identification of candidate genes and proteins in aging skeletal muscle sarcopenia using gene expression and structural analysis. Obesity-associated adipocyte dysfunction is associated with features of premature aging such as p53 activation and increased adipose tissue inflammation.

Linear regression analysis adjusted for age was directed to discover the association between Activafion rs polymorphisms, and anthropometric, and biochemical parameters. Mutations in p53 may interrupt the fatty acid oxidation function Jiang et al. This indicates that hypothalamic ER stress is likely a consequence rather than the cause of the obese phenotype. Show results from All journals This journal.

Food intake and body weights were recorded daily. Recent studies indicated that hyperinsulinemia is leading to hypertension, type 2 diabetes, arthritis and increased tumor growth Valentino et al. No significant variances in regard to genotypes and alleles detected between sarcopenic and healthy individuals. Table 6 Phenotypic and Biochemical Characteristics of samples clustered according to rs Pro72Arg. Consent for publication Not applicable. By submitting a comment you agree to abide by our Terms and Community Guidelines.

Recent evidence strongly implicates p53 in the regulation of metabolism, linking p53 to metabolic abnormalities observed in aging, obesity, inflammation, and cancer 37 At the hypothalamic level, activation of GHS-R1a causes a cellular response in which hypothalamic SIRT1 is activated 2037 to deacetylate p53; this in turn leads to increased phosphorylation of AMPK and subsequent inactivation of the de novo fatty-acid biosynthetic pathway, with concomitant activation of fatty-acid oxidation Published online Sep 4. Zand H. Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. Table 1 p53 pathway SNPs and diabetes.

By inhibiting expression of the negative regulator of the obes dehydrogenase complex that is responsible for the transfer of cytosolic pyruvate to the mitochondria, p53 promotes OXPHOS by directing pyruvate to acetyl CoA rather than lactate Hence, determining the role of p53 in the regulation of adipogenesis and cellular metabolism could reveal an important association between obesity and cancer. All plasmid constructs were verified by DNA sequencing. Wei C. Nature Cell Biology 13 —

AgRP-specific ablation of p53 resulted in increased hypothalamic c-Jun N-terminal kinase JNK activity before the mice developed obesity, and central inhibition of JNK reversed the obese pp53 of these mice. Briefly, older adults were chosen by clustered, stratified, multistage sampling based on geographical locations. Figure 2—source data 1 An Excel sheet with numerical quantification data. Whether or not p53 is directly involved in mature adipocyte metabolic regulation remains unclear. Article PubMed Google Scholar Karlseder, J. Wang, X.

We found that chronic peripheral treatment with ghrelin increased hepatic TG content in WT but not in pdeficient mice Figure 3 Miice. Furthermore, young, pre-leukemic whole-body p53 knockout mice on a normal diet display no change in body weight, adlpocytes intake, locomotor activity, or energy expenditure [ 4554 adipocytes, ] when compared to wild-type controls. We are also offering, if you choose, to post the manuscript to bioRxiv if it is not already there along with this decision letter and a formal designation that the manuscript is "in revision at eLife ". The tumor suppressor p53 influences diabetes The first evidence linking p53 to the development of type 2 diabetes came inwhen Minamino and colleagues demonstrated that diet-induced insulin resistance in A y transgenic mice, which are susceptible to diabetes, is mediated by p53 Minamino et al. Ghrelin is the only known endogenous peptidic hormone that stimulates feeding 1 and adiposity 2 — 4. In aging Zbtb7c -KO mice, there was a significant decrease in body weight. Guardian of corpulence: A hypothesis on p53 signaling in the fat cell.

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