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P53 activation in adipocytes of obese mice lose weight – p53 Functions in Adipose Tissue Metabolism and Homeostasis

Some virulence effectors subvert the host autophagic machinery to escape the surveillance of autophagy.

Contradictory, Inoue et al. However, evidence supported by the majority of published studies paint a picture of p53 as a crucial regulator of adipose tissue metabolism and homeostasis, especially when nutritionally challenged. Pharmacological stimulation of p53 with low-dose doxorubicin ameliorates diet-induced nonalcoholic steatosis and steatohepatitis. REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. External link.

  • B, Expression of the RET-S receptor induces p53 expression and p53 activation as seen by serine 15 phosphorylation pS15—p

  • Neuron 37— Once you have made that decision, we will be able to accept the manuscript for publication.

  • Mechanisms and metabolic implications of regional differences among fat depots.

  • We performed additional experiments, adding 11 new data panels in Figure 7, providing a better overall metabolic profile.

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In the adipocytes of transparency, eLife publishes the most substantive revision requests and the accompanying author adipoctyes. Although most of these studies focused on the malignant transformation of cancer cells, it is clear that p53 activation is closely associated with general metabolic regulation as well Kung and Murphy, ; Krstic et al. To study the physiological relevance of p53 in adipocytes, we generated a conditional adipocyte-specific p53 knockout mouse model piAKO Figure 7A. Of note, this p53 up-regulation was not associated with canonical pathway activation in contrast to doxorubicin, a DNA replication inhibitor used widely as a p53 pathway activator for cell senescence, cell cycle arrest, and cell death Figure 1G.

Download PDF. Taking into account that AgRP neurons are the main target activatin ghrelin 495066we found that, contrary to control mice, ghrelin was unable to induce food intake and body weight gain in AgRPp53 KO mice. Michael Czech. A BCA protein assay kit was from Pierce. Cited 0 Views 1, Annotations Open annotations.

Next, we assessed the effect of AgRP neuron-specific ablation of p53 on the intrinsic electrophysiological properties of these neurons during Weigjt. Miki, T. Central role of p53 in the suntan response and pathologic hyperpigmentation. D, Forty-eight hours of total energy expenditure determined by indirect calorimetry. Two micrograms of total RNA were used for each reverse transcriptase reaction, and cDNA synthesis was performed using the SuperScript first-strand synthesis system Invitrogen and random primers as previously described Article Contents Materials and Methods.

  • Cell Cycle.

  • Trophic action of leptin on hypothalamic neurons that regulate feeding. Both factors differentiate p53 metabolic function from its traditional canonical pathway that are related to cell senescence, apoptosis, and death.

  • Furthermore, we try to evaluate studies exploring manipulation of p53 levels in adipose tissue depots and the impact on systemic energy metabolism in the context of insulin resistance and obesity.

  • Vousden KHPrives C. Prokesch A.

  • Gao, Y.

  • In keeping to the increased adiposity, histomorphological analysis revealed significantly larger white adipocytes Fig.

You are using a browser version with limited support for CSS. Martinez-Sanchez, N. Adenoviral vectors activatioon the tumor protein p53 1. As a tumor suppressor and the most frequently mutated gene in cancer, p53 is among the best-described molecules in medical research. Trends Neurosci. R Study design of high-fat diet feeding studies. This specific regulation is mediated through lysosomal acid lipase LALa downstream transcriptional target of p

Saleemuddin, A. Is the decreased glucose due to decreased hepatic glucose output in agreement with the concept that p53 activation in adipocytes of obese mice lose weight acids derived from adipocytes drive hepatic gluconeogenesis? The role of p53 in the ARC appears to be nucleus-specific, since no effect on body weight or food intake was detected when the same viral vector targeted the VMH Supplementary Fig. Although most of these studies focused on the malignant transformation of cancer cells, it is clear that p53 activation is closely associated with general metabolic regulation as well Kung and Murphy, ; Krstic et al. Taking into account that AgRP neurons are the main target for ghrelin 495066we found that, contrary to control mice, ghrelin was unable to induce food intake and body weight gain in AgRPp53 KO mice.

1. Introduction

In the case of the whole-body knockout mouse, these wejght could be explained by effects of p53 deficiency in other cells and tissues e. Lefterova M. Our current data demonstrate that global pnull mice challenged with HFD gain less weight and fat mass before they develop any sign of tumor incidence. Right: Mean SFA ratio and mean time constant of decay in instantaneous frequency.

Hence, despite existence of contradictory findings and a varying density of evidence, several functions of p53 in adipocytes and ATs have been emerging, positioning p53 as an essential regulatory hub in ATs. Lentivirus were packing used 3 rd generation packing system. Did the authors look at ATGL expression? Namba, T.

Byun, S. Zhao T. Cancer 9— In line with this, preclinical studies manipulating p53 in peripheral tissues showed important effects in the whole-body metabolism with pathological implications for obesity and type 2 diabetes 15202122232425 Taking into account that AgRP neurons are the main target for ghrelin 495066we found that, contrary to control mice, ghrelin was unable to induce food intake and body weight gain in AgRPp53 KO mice. Nemoto et al.

Introduction

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. Adopocytes, M. The interest in p53 has classically been focused in its anti-tumorigenic action, but has expanded into the field of metabolism by the findings that cancer cells must maintain an accelerated metabolic rate to cope with the energetic requirements of high replication. The Src-family kinase Lyn in immunoreceptor signaling. Dysregulation of the mTOR pathway in pdeficient mice.

Nevertheless, these data clearly demonstrate LAL-mediated lipolysis plays a key role in lipolysis. Tissues were dissected for processing. Sabio, G. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The administration of SP did not modify food intake or body weight gain in control mice Fig. Further reading.

  • By performing transcriptome analyses with concomitant functional annotation clustering of genes, we found genes that are commonly upregulated under starvation conditions in three major metabolic tissues: epididymal WAT, liver, and skeletal muscle.

  • Won, J. Biocytin-streptavidin labeling combined with GFP immunohistochemistry was performed as previously described

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  • Doreen Kuhlow.

  • Cartwright M.

View Metrics. Endocrinology— POMCp53 KO mice showed no differences in food intake, body weight, body composition, glucose tolerance, or insulin sensitivity when compared with their control littermates after 18 weeks on chow diet or HFD Fig. Methods 3715—26

Cancer Cell. However, we did not find any change in these markers Supplementary Fig. Opposing this finding, Ortega et al. Low access resistance perforated patch recordings using amphotericin B. Hypothalamic ER stress has also emerged as a relevant factor in the development of obesity 343536373839 Distinct roles for JNK and IKK activation in agouti-related peptide neurons in the development of obesity and insulin resistance. However, recent publications are demonstrating that p53 also exerts important functions in energy homeostasis 18 ,

Introduction

The impact of the p53 mutations on whole body metabolism was investigated in humanized p53 mice in which the mouse p53 locus was replaced by the human gene variant, harboring either a proline P72 or an arginine R72 on position 72 of the amino acid chain rs Endoplasmic reticulum stress plays a central role in development of leptin resistance. Gao, Y. Tamoxifen-inducible Cre-mediated recombination in adipocytes.

Quinones, M. Cavadas, C. Reactive oxygen species ROS are constantly produced during normal metabolism, especially through oxidative phosphorylation. Miki, T.

Minamino, T. It will be interesting to further study the connection between non-canonical and canonical p53 pathways and determine whether one can acgivation to the activation of the other. A new role of p53 in regulating lipid metabolism. Sign up for alerts Privacy notice. Animals were monitored in a custom cage indirect calorimetry, food intake, and locomotor activity monitoring system TSE LabMaster, TSE Systems, Germany as previously described 68 AgRPp53 KO mice exhibited reduced locomotor activity and energy expenditure, without changes in respiratory quotient Fig. Contreras, C.

Materials and Methods

Blinded by the light: the growing complexity of p To this end, we generated and characterized global pnull mice and mice lacking p53 specifically weiht BAT. Figure 1—source data 1 An Excel sheet with numerical quantification data. This specific regulation is mediated through lysosomal acid lipase LALa downstream transcriptional target of p Herein we sought to investigate the physiological role of endogenous p53 in BAT and its implication on BAT thermogenic activity and energy balance.

Alternative sections of paraffin were used for immunohistochemistry detection of UCP The phenotype obtained following deletion of p53 in AgRP neurons was difficult to predict since acute genetic ablation of AgRP in adult animals leads to anorexia, whereas its neonatal depletion reduces food intake and alters inter-organ communication, redirecting peripheral nutrient utilization toward increased fat oxidation 52 Furthermore, the histology studies showed fat tissue from fasted piAKO mice had less morphological change comparing to WT control mice Figure 7N. Gene expression levels were normalized to 36B4 and presented relative to the wild type Liu and Pilch, The regulation can be further demonstrated by examining the gene expression of p53 downstream target, LAL. CNS leptin and insulin action in the control of energy homeostasis.

Furthermore, p53 activation by nutlin-3a treatment in 3T3-L1 cells led to a reduced adipocyte phenotype and a concomitant downregulation of Carm1 mRNA and protein. Moreover, global analyses to assess p53 binding to the brown adipocyte genome i. Natl Acad. Issue Section:. Wade M.

  • The phenotype obtained following deletion of p53 in AgRP neurons was difficult to predict since acute genetic ablation of AgRP in adult animals leads to anorexia, whereas its neonatal depletion reduces food intake and alters inter-organ communication, redirecting peripheral nutrient utilization toward increased fat oxidation 52 ,

  • Finally, since the ARC is the primary hypothalamic area reached by circulating signals, we assessed the possibility that p53 in AgRP neurons might also act as a mediator of ghrelin actions. Neuron 37—

  • Ertunc M. The total density value was obtained by the sum of all image planes analyzed.

Instead, obsee found that p53 metabolic effects are mediated through its newly identified transcriptional target, LAL, which is an enzyme responsible for the breakdown of triglycerides and cholesteryl esters in lysosomes at pH 4. As shown in Figure 2Ap53 can be effectively eliminated after a 3 day doxycycline treatment. Finally, p53 in AgRP neurons regulates the ghrelin-induced food intake and body weight. Contreras, C.

However, when we challenged the mice with prolonged fasting 24 hr, started from 5 p. In wright present study, the lactate production of the pKO adipocytes was significantly increased, comparing to WT control cells Figure 2G. Please let us know if you would like to pursue this option. Overall, these results indicate that pregulated LAL expression is directly involved in lipolysis during nutrient starvation.

Stanford, K. Data availability All data generated or analyzed during this study are included in this published article and its Supplementary Information files or from the authors upon reasonable request. Ozcan, U. Publish with us For authors For Reviewers Submit manuscript. Despite the fact that lack of p53 in AgRP neurons activates hypothalamic ER stress, this effect does not seem to be the primary cause leading to energy imbalance, as 3 weeks of HFD in AgRPp53 KO did not cause differences in body weight or expression of ER stress markers in comparison to their control littermates.

  • This was suggested to be mediated through mild p53 activation, followed by decreased WAT macrophage infiltration, increased lipid oxidation, and thermogenic activity of adipose tissues [ ].

  • Alteration of circadian pattern of feeding has been associated with obesity 31 and p53 has been reported to interact with the circadian clock However, as shown in Figure 2Fthese findings did not result from gene expression changes in glucosephosphate dehydrogenase G6PD Jiang et al.

  • Tchkonia T.

  • No differences were found in body weight or food intake Figure 1A and B among the genotypes. Fischer M.

More specific mouse models are available by now, like systems based on obesd BAT-specific Ucp1 promoter [ ] or WAT-specific resistin Retn or Adipoq promoters []. Cahill G. J Neurosci. Briefly, we made an incision in the skin at the level of the interscapsular area and carefully held BAT fat using tweezers. Nature— AMP-activated protein kinase induces a pdependent metabolic checkpoint. The insulin resistant phenotype and p53 induction similar to that of Ay mice was also observed in mice with dietary obesity fed a high-fat, high-sucrose HFHS diet [ 71 ].

However, when fed normal chow, Mdm 2CF mice are phenotypically and metabolically comparable to wild-type mice. Puzio-Kuter A. Zand H. Kawagishi H. Several other factors linked to adipogenesis have been described, including transcriptional coactivators and corepressors [ 41 ] and signaling pathways [ 37 ]. Wang S.

Trends Neurosci. Minamino, T. Deletion of acctivation in AgRP neurons caused a dramatic obese phenotype characterized by increased adiposity, slight hyperphagia, and reduced energy expenditure in a setting of nutrient excess. In particular, p53 is shown to modulate the lysosomal acid lipase LAL expression which in turn regulates fatty acid availability for mitochondrial oxidation. 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.

Trophic action of leptin on hypothalamic neurons that regulate feeding. The quantification of relative lkse expression levels was normalized by tubulin and shown in bar graphs. Huang, S. To investigate the effects of the overexpression of p53 when diet is modulated, we overexpressed p53 in mice fed a chow diet. The administration of SP did not modify food intake or body weight gain in control mice Fig.

Given the potentially pleotropic effects of p53 not only on cell activity but also on multiple biological actions, we measured AgRP fiber density in the ARC and paraventricular nucleus PVH of mice fed a HFD for 13 weeks and found that the number of fibers were identical between both genotypes Supplementary Fig. Our study reveals the mechanism through which EPEC attenuates host autophagy activity. As a tumor suppressor and the most frequently mutated gene in cancer, p53 is among the best-described molecules in medical research. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. However, these studies were conducted in long-term, diet-induced obesity DIO mice models. In addition, p53 is increasingly being recognized as crucial player in nutrient sensing pathways.

CNS leptin and insulin action in the control of energy homeostasis. Diabetes 60— To investigate the effects of the overexpression of p53 when diet is modulated, we overexpressed p53 in mice fed a chow diet. The terminal differentiation phase is regulated by a complex transcriptional cascade [ 36 ]. Schupp M. Cancer Metab.

Advance article alerts. Finally, to assess whether heat dissipation was altered in pnull mice, we measured the surface temperature in the tail of the animals maintained at room temperature, but we weighg to detect any significant differences between WT and pnull mice Figure 2 Nsuggesting that heat dissipation is not involved in heat conservation. Uner, A. Cypess A. Species Raised Monoclonal or Polyclonal. Supplementary information. While we performed an unbiased sampling of the GFP-labeled AgRP neurons, the reason for this might be the heterogeneity of AgRP neurons and the existence of different neuronal subsets.

In this sense, we have previously shown that p53 is essential for the orexigenic and adipogenic un of ghrelin 28 Increased oxidative metabolism in the Li-Fraumeni syndrome. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. A crucial role for adipose tissue p53 in the regulation of insulin resistance.

N, Representative pictures of tail temperature in animals housed at room temperature. Liu J. To obtain activwtion best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. First and foremost, although one study reported impaired BAT development in postnatal p53 knockout embryos [ 45 ], data from mice with a p53 deletion specifically in Myf5 -positive precursor cells demonstrated that p53 expression in BAT progenitor cells is not necessary for normal development of BAT [ ].

The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare p53 activation in adipocytes of obese mice lose weight revised submission. The arcuate adipocyted of the hypothalamus ARC is critical for the regulation of energy balance since it receives direct signals hormones and nutrients from the periphery 1 and comprise two neuronal populations that modulate food intake, energy expenditure, and nutrient partitioning 2. We therefore evaluated the protein levels of UPR markers in our animal models. Cite this article as: eLife ;9:e doi: Cell Death Differ. Herein we sought to investigate the physiological role of endogenous p53 in BAT and its implication on BAT thermogenic activity and energy balance.

Schneeberger, M. Download references. J, Representative pictures and BAT interscapular temperature in animals housed at room temperature. Here, we provide compelling evidence that hypothalamic p53 is a key factor in the regulation of energy balance.

Importantly, these changes in BAT activity are not related with an alteration in heat dissipation. Adipokines in health and disease. After the procedure, the incision was closed with sutures, and mice were placed in a heated cage until they recovered from anesthesia. Minamino et al.

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Download references. Is the decreased glucose due to decreased hepatic glucose output in agreement with the concept that fatty acids derived from adipocytes drive hepatic gluconeogenesis? The phenotype obtained following deletion of p53 in AgRP neurons was difficult to predict miice acute genetic ablation of AgRP in adult animals leads to anorexia, whereas its neonatal depletion reduces food intake and alters inter-organ communication, redirecting peripheral nutrient utilization toward increased fat oxidation 52 E The effect of metformin on fasting-induced p53 phosphorylation was determined by immunoprecipitation and western blots. Ghrelin requires p53 to stimulate lipid storage in fat and liver. We have previously shown that central p53 plays an important role mediating ghrelin-induced food intake 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 ,

Brains were cryoprotected, frozen in smashed dry ice, and subsequently sectioned using a freezing microtome. Bouret, S. Using this working model, we first examined the role of p53 in glucose metabolism. Regulation of lipid metabolism by p53—fighting two villains with one sword. Metabolic cage studies showed piAKO mice had higher RER rate under fasting condition, suggesting they utilized more glucose as energy resource Fig. Related to this issue of systemic metabolism, the pKO cells have more lactate production.

Targets with a proven interaction between p53 and their promoters are in black letters, protein—protein interactions or pinduced genes without evidence of direct regulation are in grey. Fischer M. Martinez de Morentin, P.

Animals were monitored in a pose cage indirect calorimetry, food intake, and locomotor activity monitoring system Adipcytes LabMaster, TSE Systems, Germany as previously described 68 Both the basal and maximum respiration rates were lower in the pKO adipocytes than in the WT controls Figure 3Asuggesting that mitochondrial function was suppressed. The mechanism by which pathogens interact with host autophagy remains mostly unclear. Results Genetic inhibition of p53 in the ARC increases weight gain To analyze the role of p53 in the regulation of energy balance at the central level, we started with a virogenetic approach to inhibit p53 in two different hypothalamic nuclei involved in the control of energy homeostasis, namely, ARC and VMH. Controlled by multiple fine-tuned regulatory mechanisms, adipocytes have the ability to sense and coordinate responses to changes in nutrient availability during fasting and feeding, and they play central roles in lipid and glucose metabolism. Please let us know if you would like to pursue this option.

Data from different mouse models also paint a rather inconsistent picture that does not reflect the in vitro findings. Changes in body weight could not be explained by daily reductions in total food intake Figure 2 B. In addition, p53 is increasingly being recognized as crucial player in nutrient sensing pathways. A significance level of 0. In the first phase, mesenchymal stem cells commit to the adipogenic lineage determination phase and are then termed preadipocytes. SIRT1 and other sirtuins in metabolism. Semaphorin3E-induced inflammation contributes to insulin resistance in dietary obesity.

Overall, our findings point to a fundamental and specific role for p53 in AgRP neurons in the regulation of energy homeostasis. A positive correlation between p53 expression, inflammation e. Left: Original recording and corresponding plots of the instantaneous spike frequency.

In this report, we demonstrated that p53 plays a critical role in reprogramming adipocyte glucose and lipid metabolisms and that the down-regulation of p53 increases obese mice lose capacity and inhibits lipolysis activity simultaneously, which may result in Warburg-like metabolic effects in adipocytes and contribute to increased adipocyte metabolic flexibility and insulin sensitivity in obesity. Hausen, A. Metformin treatment may cause a pre-condition of AMPK-p53 pathway inhibition, however, the molecular details remains to be determined in future studies. Up to 10 animals per experimental group were used and 3 pictures per each image sections were analyzed. In attempting to understand the underlying mechanism 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. Key resources table.

Minamino, T. Show results from All journals This journal. Nevertheless, our data support metformin acts through a pdependent mechanism to affect adipocyte glucose consumption and lactate production Figure 6E-F. Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Abstract p53 is a well-known tumor suppressor that plays multiple biological roles, including the capacity to modulate metabolism at different levels. Biocytin-streptavidin labeling combined with GFP immunohistochemistry was performed as previously described Ghrelin requires p53 to stimulate lipid storage in fat and liver.

In the latter case, most studies used a system in which p53 ablation was driven by the Fabp4 promoter Fabp4-Cre mice crossed with p53 floxed mice. Fasshauer M. In keeping to the increased adiposity, histomorphological analysis revealed significantly larger white adipocytes Fig. Oxford University Press is a department of the University of Oxford.

Download asset Open asset. Related to this issue of systemic metabolism, the pKO cells have more lactate production. Cowley, M. Tornovsky-Babeay, S. Thank you for submitting your article "An AMPK-dependent, non-canonical p53 pathway plays a key role in adipocyte metabolic reprogramming" for consideration by eLife.

Figure 7. Different regulatory mechanisms for the activation of each pathway have been identified, including acctivation signaling, post-translational modifications, and downstream activated target genes Vousden and Prives, a ; Kruiswijk et al. Ghrelin induces adiposity in rodents. Herein we sought to investigate the physiological role of endogenous p53 in BAT and its implication on BAT thermogenic activity and energy balance. Alternative sections of paraffin were used for immunohistochemistry detection of UCP Genetic recovery of p53 in AgRP neurons decreases body weight gain. G Lactate levels were measured similarly as in B.

  • Genetic activation of p53 in the ARC ameliorates diet-induced obesity. Ann Med.

  • The functional efficiency of the viral vectors was demonstrated by decreased protein levels of phopho-p53 active form of p53 in the ARC Fig. Of note, this p53 up-regulation was not associated with canonical pathway activation in contrast to doxorubicin, a DNA replication inhibitor used widely as a p53 pathway activator for cell senescence, cell cycle arrest, and cell death Figure 1G.

  • In support of inflammation-induced p53 activity postulated by the authors, in vitro experiments showed that the anti-inflammatory effects of endogenously produced adiponectin or of rosiglitazone treatment reduced p53 expression in differentiated adipocytes.

  • Our studies suggest that a non-canonical p53 pathway plays a key role in the regulation of adipocyte metabolic flexibility.

  • Zand H.

A Three groups of WT C57 mice were either not treated Controlfasted for 24 hr Fastingor followed by refeeding for 24 hr Refeeding. Breast cancer type two susceptibility protein BRCA2 is an essential protein in genome maintenance, homologous recombination HRand replication fork protection. Here we show p53 protein expression can be up-regulated in adipocytes by nutrient starvation without activating cell senescence, apoptosis, or a death-related p53 canonical pathway. Cell Rep.

This means that the metabolic phenotype of pnull mice might be explained, at least partially, by the central effects of p Regulation of lipid metabolism by p53—fighting two villains with one sword. Wang Z. Article PubMed Google Scholar.

Received Jul 31; Accepted Aug Blinded by the light: the growing complexity of p Spalding K. Under a HFHS diet, p53 loss led to reduced body weight, reduced adiposity both in visceral WAT and subcutaneous WATlowered inflammation, and improved insulin sensitivity and glucose tolerance when compared to wild-type mice [ 87 ]. The p53 orchestra: Mdm2 and Mdmx set the tone.

  • Scheme 1.

  • This phenotype was associated with decreased temperature in the interscapular BAT Fig.

  • To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer.

  • Cell Metab. This protocol incorporates centrifugation through a dense sucrose cushion to protect nuclei and strip away cytoplasmic contaminants.

  • However, the p53 pathway downstream genes traditionally related to cell senescence, apoptosis, and death, such as Cdkn1aGadd45and Cdkn2abehaved differently. Waterson, M.

  • Update on liposarcoma: A review for cytopathologists. Identification and importance of brown adipose tissue in adult humans.

Finally, p53 in AgRP neurons addipocytes the ghrelin-induced food intake and body weight. This is a very interesting study that breaks new ground related to a new role of p53 in regulating adipocyte metabolism. However, the pathological implications as well as the potential metabolic role of p53 in the hypothalamus remain completely wright. The integrated intensity was then measured for each image. These inadvertent modifications of p53 levels in tissues other than adipose tissue may distort the data, especially in studies of the mechanisms of adipose tissue inflammation or systemic nutrient challenges. 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. In this report, we demonstrated that p53 plays a critical role in reprogramming adipocyte glucose and lipid metabolisms and that the down-regulation of p53 increases glycolysis capacity and inhibits lipolysis activity simultaneously, which may result in Warburg-like metabolic effects in adipocytes and contribute to increased adipocyte metabolic flexibility and insulin sensitivity in obesity.

Cell Metab. When p53 protein levels were measured in the mediobasal hypothalamus of mice fed a HFD during 2 and 4 weeks, before developing obesity, we did not find differences in p53 levels in comparison to mice fed a chow diet Supplementary Fig. Importantly, p53 knockout MEFs underwent spontaneous commitment to the adipogenic program and ectopic re-expression of p53 in knockout MEFs efficiently inhibited their spontaneous differentiation [ 5253 ]. By using diet-induced obese mice, primary adipocytes, and the 3T3L1 cell line, Vergoni et al. Furthermore, insulin resistance occurred in middle-aged mice, implying that chronic reduction of p53 activity is responsible for the development of insulin resistance under normal calorie intake. Census and evaluation of p53 target genes.

Cota, D. Since fasting can cause adipocytes to undergo significant reprogramming of cellular energy metabolism, these data suggest that p53 may be directly involved in adipocyte metabolic regulation. Does it cause lactic acidosis in animals?

Such regulation effects circulating glucose and fatty acid levels in fasting, thus controlling systemic metabolic control. Close banner Close. 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. Search Search articles by subject, keyword or author. All data generated or analyzed during this study are included in this published article and its Supplementary Information files or from the authors upon reasonable request. Yahagi, N.

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Role of p53 in preadipocyte differentiation. Herein, we show that mice lacking p53 adipoctes agouti-related peptide AgRPbut not proopiomelanocortin POMC or steroidogenic factor-1 SF1 neurons, are more prone to develop diet-induced obesity and show reduced brown adipose tissue BAT thermogenic activity. Cansell, C. Giordano A. Thus, p53 specifically located in AgRP neurons is essential for the orexigenic and adipogenic actions of ghrelin. In addition to the different WAT depots with distinct and linked metabolic functions, each of the depots is comprised of a number of cell types. Kanno S.

N -values and p -values are reported as exact numbers above the bar graphs. Our studies suggest that a non-canonical adipocytss pathway plays a key role in the regulation of adipocyte metabolic flexibility. The results from these working systems demonstrated a central role played by p53 in adipocyte energy metabolic reprogramming under challenging metabolic conditions. The incision was closed with sutures, and rats were kept warm until full recovery.

Cell Metab. It will be important to determine whether the pFoxo3a-Sirt1 axis is also functionally relevant in brown and white adipocytes, because Sirt1 can be pharmaceutically targeted and is an essential determinant in the conversion of white to beige adipocytes [ ]. Interestingly, while R72 mice are phenotypically similar to P72 mice when fed a normal chow diet [ 80 ], under HFD the R72 variant-carrying mice exhibit increased weight gain, concomitant with increased fat mass, adipose tissue immune cell infiltration, hepatic steatosis and fibrosis, and insulin resistance [ 81 ]. Nature Reviews Endocrinology

Pharmacological and genetic manipulation of p53 in brown fat at adult but not embryonic stages regulates thermogenesis and body weight in male mice. C, Quantitative evaluation of multiple Western blots showing significant reduction of p53 expression and activation in cells infected with Ad-DNp53RK, in relation with the apoptosis blockade. Obesity and metabolic syndrome in circadian Clock mutant mice. Schneeberger, M. Berkers, C.

J, Representative pictures and BAT interscapular temperature in animals housed at room temperature. Our results are in agreement with the latter study jn we found that pnull mice lose weight less weight when fed a HFD, showed increased energy expenditure, and had higher BAT UCP1 levels than their littermates. Additional in vitro experiments confirmed p53 induction upon treatment with palmitic acid [ 68 ]. Because the acute inhibition of p53 in the BAT of adult mice induces weight gain and decreases BAT thermogenic activity, we hypothesized that the specific overexpression of p53 in the BAT of obese mice might be sufficient to increase the BAT thermogenic activity and to ameliorate weight gain. Because this topic has been reviewed in [ 2930 ], we attempt to highlight more recent findings. After the pharmacological treatment or vehicle injection, mice were either culled to dissect the hypothalamus studies. Saltiel A.

Therefore, we next assessed whether mice lacking p53 in AgRP fed a HFD for 10 weeks, when body weight was already increased compared to their littermates, but we failed to detect any change in food intake along the circadian cycle Supplementary Fig. To confirm the integrity of the perforated patch recording, R a was monitored over the course of the experiment. Future studies are needed to rule out the relationship between these two pathways in adipocyte metabolism. A crucial role for adipose tissue p53 in the regulation of insulin resistance.

  • An effort to accurately recap the currently available literature about the role of p53 in adipose tissue biology is complicated by several factors see Scheme 1. Saleemuddin, A.

  • Figure 7—source data 1 An Excel sheet with numerical quantification data.

  • We found that the reduction in weight gain in animals treated with i.

  • For post hoc identification, cells were loaded with biocytin by converting iin perforated patch configuration to the whole-cell configuration at the end of the recording. Moreover, acyl-ghrelin levels were significantly increased in AgRPp53 KO3 mice, suggesting that these mice are overcompensating ghrelin resistance by increasing the circulating levels of active ghrelin.

  • Diabetes 63—

Peer Review File. Comparing blue bars in Figure 4D control vs. Cite this article as: eLife ;9:e doi: Coppari, R. Cota, D. Dividing lines indicate spliced bands from the same gel.

Jones R. Seale P. A crucial role for adipose tissue p53 in the regulation of insulin resistance. These cancer-unrelated functions of p53 are plausible with respect to the process of evolutionary selection, because cancer is a disease that appears, or becomes life-threatening, mainly after reproductive age. J Neurosci.

These acctivation findings could be due to differences in housing conditions e. Like with Mdm2, studying the physiological function of Mdm4 in whole body knockout mice has been impossible due to embryonic lethality. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Moreover, global analyses to assess p53 binding to the brown adipocyte genome i.

Furthermore, previous studies of human obrse with different types and degrees of obesity have revealed a direct correlation between autophagic activity and insulin sensitivity Kovsan et al. In addition to those genetic approaches, we assessed whether central pharmacological stimulation of p53 would mimic the findings obtained after genetic overexpression. Genes Dev. We will leave it to your decision if you wish to change this model cartoon or not. Lastly, previous research has established a tight association between obesity and cancer Deng et al. In contrast to the insight of p53 action in peripheral tissues, the metabolic role of p53 in the hypothalamus remains almost completely unknown.

This indicates that hypothalamic ER stress is likely a consequence rather than the cause of the mive phenotype. D, Nonfat mass. Patients with the Li Fraumeni syndrome, which is an autosomal dominant cancer predisposition disorder caused by some p53 mutations, have increased oxidative phosphorylation of skeletal muscle Targets with a proven interaction between p53 and their promoters are in black letters, protein—protein interactions or pinduced genes without evidence of direct regulation are in grey. In terms of differentiation, p53 suppresses the differentiation of white adipocytes, whereas potentiates brown adipocyte differentiation 23 — Vousden, K.

Given the potentially pleotropic effects of p53 moce only on cell activity but also on multiple biological actions, we measured AgRP fiber density in the ARC and paraventricular nucleus PVH of mice fed a HFD for 13 weeks and found that the number of fibers were identical between both genotypes Supplementary Fig. Therefore, we next assessed whether mice lacking p53 in AgRP fed a HFD for 10 weeks, when body weight was already increased compared to their littermates, but we failed to detect any change in food intake along the circadian cycle Supplementary Fig. Previous studies in non-adipocytes have suggested that glucose starvation causes p53 up-regulation associated with p53 phosphorylation through AMPK-dependent pathways Jones et al. Both factors differentiate p53 metabolic function from its traditional canonical pathway that are related to cell senescence, apoptosis, and death. Nevertheless, these data clearly demonstrate LAL-mediated lipolysis plays a key role in lipolysis.

Yahagi, N. Ozcan, L. For instance, in the light of results demonstrating that p53 regulates M2 macrophage polarization [ 86 ], it would be of special importance to investigate the function of p53 in adipose tissue-resident macrophages, as they are the most abundant immune cell type in obesity-related inflammation. Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. Unexpected evidence for active brown adipose tissue in adult humans. Metabolic regulation by p53 family members. Care of all animals was within institutional animal care committee guidelines, and all procedures were reviewed and approved by the Ethics Committee of the University of Santiago de Compostela, in accordance with European Union normative for the use of experimental animals.

Ghrelin induces adiposity in rodents. Ghrelin requires p53 to stimulate lipid storage in fat and liver. In comparison to 3T3-L1 cells, this cell line can be used to study earlier events of adipogenesis [ 51 ]. Hence, it is likely that p53 exerts its effects in adipocytes and in adipose tissue via regulation of single or multiple target genes and their respective pathways Figure 1.

Heart Circ. Respiratory quotient during light phase Gdark phase Hand mean over 24 hours I, right panel. Convertible visceral fat as a therapeutic target to curb obesity. Fat apoptosis through targeted activation of caspase 8: A new mouse model of inducible and reversible lipoatrophy. These results were largely consistent with data from adenoviral overexpression of p53 in BAT or from pharmacological p53 activation [ ]. Metabolic regulation by p53 family members. Brains were cryoprotected, frozen in smashed dry ice, and subsequently sectioned using a freezing microtome.

Further studies have shown that lipophagy can be induced by fasting Lettieri Barbato et al. Wctivation this end, we generated and characterized global pnull mice and mice lacking p53 specifically in BAT. Our studies of cell culture systems led us to hypothesize that disturbances in non-canonical p53 metabolic regulations in the early stages of HFD feeding may directly contribute to metabolic dysregulation and the pathological development of insulin resistance. Martinez de Morentin, P.

The inactivation of p53 in BAT was sufficient to induce a mild but significant body weight gain in adult mice fed a standard diet Figure 5 E. N -values and p -values are reported as exact numbers above the bar graphs. EMBO J. For instance, inducible BAT-specific cre-expressing mice Ucp1-CreER [ ] crossed with p53 -floxed mice, would present a more precise platform to interrogate the role of p53 in BAT maintenance and function, as well as in whole body energy homeostasis. A new role of p53 in regulating lipid metabolism. Trends Neurosci.

Furthermore, young, pre-leukemic whole-body p53 knockout mice on a normal diet display no change in body weight, food intake, locomotor activity, or energy expenditure [ 4554] when activahion to wild-type controls. Dilution Used. Tschaharganeh D. Gropp, E. In addition to those genetic approaches, we assessed whether central pharmacological stimulation of p53 would mimic the findings obtained after genetic overexpression. Obesity develops due to an imbalance between calorie intake and expenditure, which can be caused by a variety of factors ranging from behavioral to genetic, resulting in increased visceral adiposity and, in most cases, systemic low grade chronic inflammation [ 61 ].

Figure 5—source data 1 An Excel sheet with numerical quantification data. Adiipocytes, T. Consistent with this, HFD activated the p53 signaling pathway since it stimulated protein levels of the p53 downstream molecules pShc and Bax in the mediobasal hypothalamus of DIO mice Supplementary Fig. For each current pulse the number of action potentials was determined.

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