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Biomedical subjects

José M Mato

Publications and source records attributed to José M Mato.

At least 19 recordsLinked to original sources
PubMed2007

Inhibition of human betaine-homocysteine methyltransferase expression by S-adenosylmethionine and methylthioadenosine.

BHMT (betaine-homocysteine methyltransferase) remethylates homocysteine to form methionine. SAM (S-adenosylmethionine) inhibits BHMT activity, but whether SAM modulates BHMT gene expression is unknown. Transcriptional regulation of the human BHMT is also unknown. The present study examined regulation of the human BHMT gene by SAM and its metabolite, MTA (5'-methylthioadenosine). To facilitate these studies, we cloned the 2.7 kb 5'-flanking region of the human BHMT gene (GenBank accession number AY325901). Both SAM and MTA treatment of HepG2 cells resulted in a dose- and time-dependent decrease in BHMT mRNA levels, which paralleled their effects on the BHMT promoter activity. Maximal suppression was observed with the BHMT promoter construct -347/+33, which contains a number of NF-kappaB (nuclear factor kappaB) binding sites. SAM and MTA treatment increased NF-kappaB nuclear binding and NF-kappaB-driven luciferase activities, and increased nuclear binding activity of multiple histone deacetylase co-repressors to the NF-kappaB sites. Overexpression of p50 and p65 decreased BHMT promoter activity, while blocking NF-kappaB activation increased BHMT expression and promoter activity, and prevented SAM but not MTA's ability to inhibit BHMT expression. The NF-kappaB binding site at -301 is responsible, at least in part, for this effect. Lower BHMT expression can impair homocysteine metabolism, which can induce ER (endoplasmic reticulum) stress. Indeed, MTA treatment resulted in increased expression ER stress markers. In conclusion, SAM and MTA down-regulate BHMT expression in HepG2 cells in part by inducing NF-kappaB, which acts as a repressor for the human BHMT gene. While SAM's mechanism is NF-kappaB-dependent, MTA has both NF-kappaB-dependent and -independent mechanisms.

Adenosine↗
PubMed2007

Effect of hepatocyte growth factor on methionine adenosyltransferase genes and growth is cell density-dependent in HepG2 cells.

Hepatocyte growth factor (HGF) is a potent hepatocyte mitogen but its effect in liver cancer is conflicting. Methionine adenosyltransferase (MAT) is an essential enzyme encoded by two genes (MAT1A and MAT2A), while a third gene (MAT2beta) encodes for a subunit that regulates the MAT2A-encoded isoenzyme. MAT1A is silenced while MAT2A and MAT2beta are induced in hepatocellular carcinoma (HCC). The current work examined expression of HGF/c-met in HCC and whether HGF regulates MAT genes and growth in HepG2 cells. We found the mRNA levels of HGF and c-met are markedly increased in HCC. To study the influence of cell density, HepG2 cells were plated under high-density (HD) or low-density (LD) and treated with HGF (10 ng/ml). Cell density had a dramatic effect on MAT1A expression, being nearly undetectable at LD to a ninefold induction under HD. Cell density also determined the effect of HGF. At HD, HGF increased the mRNA levels of p21 and p27, while lowering the levels of MAT genes, cyclin A, and c-met. At LD, HGF increased the mRNA levels of cyclin A, MAT2A, MAT2beta, and c-met. Consistently, HGF inhibits growth under HD but stimulates growth under LD. HGF induced sustained high ERK activation under HD as compared to LD. In summary, HGF induces genes favoring growth and is mitogenic when HepG2 cells are plated under LD; however, the opposite occurs under HD. This involves cell density-dependent differences in HGF-induced ERK activation. This may explain why HGF is mitogenic only when there is loss of cell-cell contact in vivo.

Carcinoma, Hepatocellular↗
PubMed2006

Id2 leaves the chromatin of the E2F4-p130-controlled c-myc promoter during hepatocyte priming for liver regeneration.

The Id (inhibitor of DNA binding or inhibitor of differentiation) helix-loop-helix proteins are involved in the regulation of cell growth, differentiation and cancer. The fact that the molecular mechanisms of liver regeneration are not completely understood prompted us to study the fate of Id2 in proliferating liver. Id2 increases in liver regeneration after partial hepatectomy, following the early induction of its gene. Co-immunoprecipitation shows that Id2 forms a complex with E2F4, p130 and mSin3A in quiescent liver and all these components are present at the c-myc promoter as shown using ChIP (chromatin immunoprecipitation). Activation of c-myc during hepatocyte priming (G0-G1 transition) correlates with the dissociation of Id2 and HDAC (histone deacetylase), albeit p130 remains bound at least until 6 h. Moreover, as the G0-G1 transition progresses, Id2 and HDAC again bind the c-myc promoter concomitantly with the repression of this gene. The time course of c-myc binding to the Id2 promoter, as determined by ChIP assays is compatible with a role of the oncoprotein as a transcriptional inducer of Id2 in liver regeneration. Immunohistochemical analysis shows that Id2 also increases in proliferating hepatocytes after bile duct ligation. In this case, the pattern of Id2 presence in the c-myc promoter parallels that found in regenerating liver. Our results may suggest a control role for Id2 in hepatocyte priming, through a p130 dissociation-independent regulation of c-myc.

Animals↗
PubMed2006

A glycine N-methyltransferase knockout mouse model for humans with deficiency of this enzyme.

Three human cases having mutations in the glycine N-methyltransferase (GNMT) gene have been reported. This enzyme transfers a methyl group from S-adenosylmethionine (SAM) to glycine to form S-adenosylhomocysteine (SAH) and N-methylglycine (sarcosine) and is believed to be involved in the regulation of methylation. All three cases have mild liver disease but they seem otherwise unaffected. To study this further, gnmt deficient mice were generated for the first time. This resulted in the complete absence of GNMT protein and its activity in livers of homozygous mice. Compared to WT animals the absence of GNMT resulted in up to a 7-fold increase of free methionine and up to a 35-fold increase of SAM. The amount of SAH was significantly decreased (3 fold) in the homozygotes compared to WT. The ratio of SAM/SAH increased from 3 in WT to 300 in livers of homozygous transgenic mice. This suggests a possible significant change in methylation in the liver and other organs where GNMT is expressed.

Animals↗
PubMed2006

Molecular profiling of hepatocellular carcinoma in mice with a chronic deficiency of hepatic s-adenosylmethionine: relevance in human liver diseases.

S-adenosylmethionine arises as a central molecule in the preservation of liver homeostasis as a chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. In the present work, we have attempted a comprehensive analysis of proteins associated with hepatocarcinogenesis in MAT1A knock out mice using a combination of two-dimensional electrophoresis and mass spectrometry, to then apply the resulting information to identify hallmarks of human HCC. Our results suggest the existence of individual-specific factors that might condition the development of preneoplastic lesions. Proteomic analysis allowed the identification of 151 differential proteins in MAT1A-/- mice tumors. Among all differential proteins, 27 changed in at least 50% of the analyzed tumors, and some of these alterations were already detected months before the development of HCC in the KO liver. The expression level of genes coding for 13 of these proteins was markedly decreased in human HCC. Interestingly, seven of these genes were also found to be down-regulated in a pretumoral condition such as cirrhosis, while depletion of only one marker was assessed in less severe liver disorders.

Adult↗
PubMed2006

S-adenosylmethionine regulates cytoplasmic HuR via AMP-activated kinase.

BACKGROUND & AIMS: After liver injury, hepatic S-adenosylmethionine (SAM) content decreases, and the blockage this molecule imposes on hepatocyte proliferation is released, facilitating liver regeneration. This activity of SAM is important for normal liver function because mice deficient in hepatic SAM display abnormal liver regeneration and develop hepatocellular carcinoma. How SAM regulates hepatocyte growth is unclear, but because SAM blocks hepatocyte growth factor (HGF)-induced cyclin D1 expression and DNA synthesis without affecting HGF-induced extracellular signal-regulated kinase phosphorylation, the mitogen-activated protein kinase (MAPK) pathway is probably not the target. METHODS: The effects of SAM on AMPK, HuR localization were assessed in rat hepatocytes after HGF, AICAR, and SAM treatment. RESULTS: We show here that HGF and 5-aminoimidazole-4-carboxamide-riboside (AICAR), an activator of AMP-activated protein kinase (AMPK), induce the phosphorylation of AMPK in hepatocytes and that SAM blocks this process. We also show that HGF- and AICAR-induced AMPK activation stimulate the transport from nucleus to cytoplasm of HuR, an RNA-binding protein that increases the half-life of target mRNA such as cyclin A2, and that SAM blocks this process. We found that, in hepatocytes, AICAR increases HuR binding to cyclin A2 messenger RNA (mRNA) as well as the expression and stability of this mRNA and that SAM blocks these events. Consistently, we found that AICAR induces hepatocyte proliferation and that SAM blocks this effect. Finally, we found that liver AMPK phosphorylation, cytoplasmic HuR, and binding of HuR to HuR-target mRNA and the steady-state levels of these mRNA are increased in knockout mice deficient in hepatic SAM. CONCLUSIONS: Our results yield novel insights about the mechanism by which SAM inhibits cell-cycle progression in the liver.

AMP-Activated Protein Kinases↗
PubMed2006

Methionine adenosyltransferase and S-adenosylmethionine in alcoholic liver disease.

Methionine adenosyltransferase (MAT) is an essential enzyme that catalyzes the formation of the principal methyl donor S-adenosylmethionine (SAMe). Studies in the past decade have shown that SAMe is not only a methyl donor, but also a key metabolite that regulates hepatocyte growth, death and differentiation. Abnormalities in MAT and decreased SAMe levels occur in experimental animals and humans with alcoholic liver disease. Chronic hepatic SAMe deficiency can result in the spontaneous development of steatohepatitis and hepatocellular carcinoma. This paper reviews MAT genes and SAMe in relation to alcoholic liver disease and the molecular mechanisms by which SAMe regulates hepatocyte growth and apoptosis.

Animals↗
PubMed2005

Oxidation of specific methionine and tryptophan residues of apolipoprotein A-I in hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm with more than 500 000 new cases diagnosed yearly. Although major risk factors of HCC are currently known, the identification of biological targets leading to an early diagnosis of the disease is considered one of the priorities of clinical hepatology. In this work we have used a proteomic approach to identify markers of hepatocarcinogenesis in the serum of a knockout mice deficient in hepatic AdoMet synthesis (MAT1A(-/-)), as well as in patients with HCC. Three isoforms of apolipoprotein A-I (Apo A-I) with different pI were identified in murine serum. Isoform 1 is up-regulated in the serum of MAT1A(-/-) mice much earlier than any histological manifestation of liver disease. Further characterization of the differential isoform by electrospray MS/MS revealed specific oxidation of methionine 85 and 216 to methionine sulfoxide while the sequence of the analogous peptides on isoforms 2 and 3 showed the nonoxidized methionine residues. Enrichment of an acidic isoform of Apo A-I was also assessed in the serum of hepatitis B virus patients who developed HCC. Specific oxidation of methionine 112 to methionine sulfoxide and tryptophans 50 and 108 to formylkinurenine were identified selectively in the up-regulated isoform. Although it is not clear at present whether the occurrence of these modifications has a causal role or simply reflects secondary epiphenomena, this selectively oxidized Apo A-I isoform may be considered as a pathological hallmark that may help to the understanding of the molecular pathogenesis of HCC.

Animals↗
PubMed2005

Role of methionine adenosyltransferase and S-adenosylmethionine in alcohol-associated liver cancer.

Two genes (MAT1A and MAT2A) encode for the essential enzyme methionine adenosyltransferase (MAT), which catalyzes the biosynthesis of S-adenosylmethionine (SAMe), the principal methyl donor and, in the liver, a precursor of glutathione. MAT1A is expressed mostly in the liver, whereas MAT2A is widely distributed. MAT2A is induced in the liver during periods of rapid growth and dedifferentiation. In human hepatocellular carcinoma (HCC) MAT1A is replaced by MAT2A. This is important pathogenetically because MAT2A expression is associated with lower SAMe levels and faster growth, whereas exogenous SAMe treatment inhibits growth. Rats fed ethanol intragastrically for 9 weeks also exhibit a relative switch in hepatic MAT expression, decreased SAMe levels, hypomethylation of c-myc, increased c-myc expression, and increased DNA strand break accumulation. Patients with alcoholic liver disease have decreased hepatic MAT activity owing to both decreased MAT1A expression and inactivation of the MAT1A-encoded isoenzymes, culminating in decreased SAMe biosynthesis. Consequences of chronic hepatic SAMe depletion have been examined in the MAT1A knockout mouse model. In this model, the liver is more susceptible to injury. In addition, spontaneous steatohepatitis develops by 8 months, and HCC develops by 18 months. Accumulating evidence shows that, in addition to being a methyl donor, SAMe controls hepatocyte growth response and death response. Whereas transient SAMe depletion is necessary for the liver to regenerate, chronic hepatic SAMe depletion may lead to malignant transformation. It is interesting that SAMe is antiapoptotic in normal hepatocytes, but proapoptotic in liver cancer cells. This should make SAMe an attractive agent for both chemoprevention and treatment of HCC.

Animals↗
PubMed2004

WITHDRAWN: Silencing of human methionine adenosyltransferase 1A expression by methylation of the coding region.

Two genes (MAT1A and MAT2A) encode for the essential enzyme methionine adenosyltransferase (MAT). MAT1A is silenced in hepatocellular carcinoma (HCC), and absence of MAT1A leads to spontaneous development of HCC in mice. Here we investigated the role of methylation in regulating MAT1A expression. There are three MspI/HpaII sites from -1913 to +160 of the human MAT1A gene (numbered relative to the translational start site) at position -977, +10, and +88. Bisulfite treatment and DNA sequencing, and Southern blot analysis showed that methylation at +10 and +88, but not -977, correlated with lack of MAT1A expression. MAT1A promoter construct methylated at -977, +10 or +88 position has 0.7-fold, 3-fold, and 1.6-fold lower promoter activity, respectively. Methylation at -977 and +10 did not inhibit the promoter more than methylation at +10 alone; while methylation at +10 and +88 resulted in a 6-fold reduction of promoter activity. The promoter activity is not affected if these sites are mutated and cannot be methylated. Reactivation of MAT1A correlated with demethylation of +10 and +88. DNase I footprinting analysis using the probe containing nucleotides -346 to +160 and human liver nuclear extract or recombinant TATA binding protein (TBP) showed that HpaII methylation at +10 and +88 prevented TBP binding to the TATA box, but not if the sites were mutated. ChIP analysis confirmed TBP binding to MAT1A only in MAT1A expressing cells. Collectively our data support the novel finding that methylation of the MAT1A coding region can influence TBP binding to the TATA box and shut down gene transcription.

Journal Article↗
PubMed2004

Methylthioadenosine phosphorylase gene expression is impaired in human liver cirrhosis and hepatocarcinoma.

Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine and adenine salvage pathways. In mammals, the liver plays a central role in methionine metabolism, and this essential function is lost in the progression from liver cirrhosis to hepatocarcinoma. Deficient MTAP gene expression has been recognized in many transformed cell lines and tissues. In the present work, we have studied the expression of MTAP in human and experimental liver cirrhosis and hepatocarcinoma. We observe that MTAP gene expression is significantly reduced in human hepatocarcinoma tissues and cell lines. Interestingly, MTAP gene expression was also impaired in the liver of CCl4-cirrhotic rats and cirrhotic patients. We provide evidence indicating that epigenetic mechanisms, involving DNA methylation and histone deacetylation, may play a role in the silencing of MTAP gene expression in hepatocarcinoma. Given the recently proposed tumor suppressor activity of MTAP, our observations can be relevant to the elucidation of the molecular mechanisms of multistep hepatocarcinogenesis.

Aged↗
PubMed2004

Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A.

Methionine adenosyltransferase (MAT) is an essential enzyme because it catalyzes the formation of S-adenosylmethionine (SAMe), the principal biological methyl donor. Of the two genes that encode MAT, MAT1A is mainly expressed in adult liver and MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic SAMe content and spontaneously develop hepatocellular carcinoma. The current study examined the influence of chronic hepatic SAMe deficiency on liver regeneration. Despite having higher baseline hepatic staining for proliferating cell nuclear antigen, MAT1A knockout mice had impaired liver regeneration after partial hepatectomy (PH) as determined by bromodeoxyuridine incorporation. This can be explained by an inability to up-regulate cyclin D1 after PH in the knockout mice. Upstream signaling pathways involved in cyclin D1 activation include nuclear factor kappaB (NFkappaB), the c-Jun-N-terminal kinase (JNK), extracellular signal-regulated kinases (ERKs), and signal transducer and activator of transcription-3 (STAT-3). At baseline, JNK and ERK are more activated in the knockouts whereas NFkappaB and STAT-3 are similar to wild-type mice. Following PH, early activation of these pathways occurred, but although they remained increased in wild-type mice, c-jun and ERK phosphorylation fell progressively in the knockouts. Hepatic SAMe levels fell progressively following PH in wild-type mice but remained unchanged in the knockouts. In culture, MAT1A knockout hepatocytes have higher baseline DNA synthesis but failed to respond to the mitogenic effect of hepatocyte growth factor. Taken together, our findings define a critical role for SAMe in ERK signaling and cyclin D1 regulation during regeneration and suggest chronic hepatic SAMe depletion results in loss of responsiveness to mitogenic signals.

Adenosine Triphosphate↗
PubMed2004

5'-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes.

5'-methylthioadenosine (MTA) is a nucleoside generated from S-adenosylmethionine (AdoMet) during polyamine synthesis. Recent evidence indicates that AdoMet modulates in vivo the production of inflammatory mediators. We have evaluated the anti-inflammatory properties of MTA in bacterial lipopolysaccharide (LPS) challenged mice, murine macrophage RAW 264.7 cells, and isolated rat hepatocytes treated with pro-inflammatory cytokines. MTA administration completely prevented LPS-induced lethality. The life-sparing effect of MTA was accompanied by the suppression of circulating tumor necrosis factor-alpha (TNF-alpha), inducible NO synthase (iNOS) expression, and by the stimulation of IL-10 synthesis. These responses to MTA were also observed in LPS-treated RAW 264.7 cells. MTA prevented the transcriptional activation of iNOS by pro-inflammatory cytokines in isolated hepatocytes, and the induction of cyclooxygenase 2 (COX2) in RAW 264.7 cells. MTA inhibited the activation of p38 mitogen-activated protein kinase (MAPK), c-jun phosphorylation, inhibitor kappa B alpha (IkappaBalpha) degradation, and nuclear factor kappaB (NFkappaB) activation, all of which are signaling pathways related to the generation of inflammatory mediators. These effects were independent of the metabolic conversion of MTA into AdoMet and the potential interaction of MTA with the cAMP signaling pathway, central to the anti-inflammatory actions of its structural analog adenosine. In conclusion, these observations demonstrate novel immunomodulatory properties for MTA that may be of value in the management of inflammatory diseases.

Animals↗
PubMed2004

S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-x(S).

S-adenosylmethionine (SAMe) and its metabolite 5'-methylthioadenosine (MTA) are proapoptotic in HepG2 cells. In microarray studies, we found SAMe treatment induced Bcl-x expression. Bcl-x is alternatively spliced to produce two distinct mRNAs and proteins, Bcl-x(L) and Bcl-x(S). Bcl-x(L) is antiapoptotic, while Bcl-x(S) is proapoptotic. In this study we showed that SAMe and MTA selectively induced Bcl-x(S) in a time- and dose-dependent manner in HepG2 cells. There are three transcription start sites in the human Bcl-x gene which yield only Bcl-x(L) in control HepG2 cells. SAMe and MTA treatment did not affect promoter usage, but while one promoter yielded only Bcl-x(L), the other two yielded both Bcl-x(L) and Bcl-x(S), with Bcl-x(S) as the predominant messenger RNA (mRNA) species. Trichostatin A, 3-deaza-adenosine, cycloleucine, and okadaic acid had no effect on Bcl-x(S) induction by SAMe or MTA. Calyculin A and tautomycin, on the other hand, blocked SAMe and MTA-mediated Bcl-x(S) induction and apoptosis in a dose-dependent manner. SAMe and MTA increased protein phosphatase 1 (PP1) catalytic subunit mRNA and protein levels and dephosphorylation of serine-arginine proteins, with the latter blocked by calyculin A. The effects of SAMe and MTA on Bcl-x(S), PP1 expression, and apoptosis were also seen in 293 cells, but not in primary hepatocytes. Induction of Bcl-x(S) by ceramide in HepG2 cells also resulted in apoptosis. In conclusion, we have uncovered a highly novel action of SAMe and MTA, namely the ability to affect the cellular phosphorylation state and alternative splicing of genes, in this case resulting in the induction of Bcl-x(S) leading to apoptosis.

Acetylation↗
PubMed2004

Methylthioadenosine.

5'-Methylthioadenosine (MTA) is a naturally occurring sulfur-containing nucleoside present in all mammalian tissues. MTA is produced from S-adenosylmethionine mainly through the polyamine biosynthetic pathway, where it behaves as a powerful inhibitory product. This compound is metabolized solely by MTA-phosphorylase, to yield 5-methylthioribose-1-phosphate and adenine, a crucial step in the methionine and purine salvage pathways, respectively. Abundant evidence has accumulated over time suggesting that MTA can affect cellular processes in many ways. MTA has been shown to influence numerous critical responses of the cell including regulation of gene expression, proliferation, differentiation and apoptosis. Although most of these responses have been observed at the pharmacological level, their specificity makes it tempting to speculate that endogenous MTA could play a regulatory role in the cell. Finally, observations carried out in models of liver damage and cancer demonstrate a therapeutic potential for MTA that deserves further consideration.

Adenine↗
PubMed2004

Abnormal hepatic methionine and glutathione metabolism in patients with alcoholic hepatitis.

BACKGROUND: Abnormal methionine metabolism occurs in animals fed ethanol and in end-stage cirrhotic patients. Expected consequences of these abnormalities include reduced hepatic S-adenosylmethionine and glutathione (GSH) levels, impaired transmethylation, and reduced homocysteine catabolism, resulting in the often-observed hyperhomocystinemia in cirrhotic patients. These parameters have not been examined simultaneously in patients with less advanced alcoholic liver disease. METHODS: Six patients hospitalized for alcoholic hepatitis were studied. Plasma was analyzed for homocysteine, methionine, and GSH levels. Liver biopsies diagnosed acute alcoholic hepatitis and underlying fibrosis. Liver specimens were processed for messenger RNA (mRNA) levels and various metabolites and were compared with those of six normal controls. RESULTS: Three patients had cirrhosis, and three had only portal fibrosis. Plasma levels of homocysteine and methionine were increased in two of the three patients with cirrhosis but not in the patients with fibrosis. All patients had markedly lower plasma GSH levels (mean +/- SD: 0.27 +/- 0.19 microM, which is at least 10-fold lower than the normal range). Hepatic S-adenosylmethionine levels were reduced by 50%, whereas methionine, GSH, and cysteine levels were reduced by 70-80%. The mRNA levels of most enzymes involved in methionine metabolism and GSH synthesis were decreased, whereas albumin expression was unchanged. Despite the well known induction of cytochrome P450 2E1 in chronic alcoholics, its mRNA levels were nearly 70% lower in these patients. CONCLUSIONS: In alcoholic hepatitis, abnormal hepatic gene expression in methionine and GSH metabolism occurs and often contributes to decreased hepatic methionine, S-adenosylmethionine, cysteine, and GSH levels. It may be important to replenish these thiols in patients hospitalized with alcoholic hepatitis.

Adult↗
PubMed2003

Gene expression profile of omental adipose tissue in human obesity.

The aim of the present study was to gain insight into the pathophysiology of obesity by comparing the pattern of gene expression of omental adipose tissue of obese and lean volunteers using DNA microarrays. Omental adipose tissue biopsies were obtained by laparoscopic surgery from six male patients (44.2+/-6.3 yr). RNA was extracted and pooled for the obese (BMI: 37.3+/-2.5 kg/m2) and lean (BMI: 23.4+/-0.8 kg/m2) groups. From the total number of genes analyzed (1,152 well-characterized human genes), 41% were expressed at sufficient levels in human adipose tissue for detection in the microarray experiments, finding that 89 genes were up-regulated while 64 were down-regulated at least twofold in the omental adipose tissue obtained from obese patients. We found a general tendency to blunt lipolysis inducer genes and a global down-regulation of genes encoding growth factors. Moreover, an up-regulation in the expression of several mitogen-activated protein kinases (MAPKs) was observed. The down-regulation of genes involved in lipolysis activation may be involved in the etiopathogenesis of obesity. In addition, down-regulation of growth factors and the up-regulation of MAPKs may indicate an attempt to restrain adipocyte proliferation and differentiation. Furthermore, obesity is accompanied by an altered expression in omental adipose tissue of genes involved not only in energy homeostasis but also in quite diverse biological functions, such as immune response. The genomic approach underlines the importance of adipose tissue beyond energy metabolism.

Adipose Tissue↗