FABP4 Dynamics in Obesity: Discrepancies in Adipose Tissue and Liver Expression Regarding Circulating Plasma Levels

Background FABP4 is predominantly expressed in adipose tissue, and its circulating levels are linked with obesity and a poor atherogenic profile. Objective In patients with a wide BMI range, we analyze FABP4 expression in adipose and hepatic tissues in the settings of obesity and insulin resistance. Associations between FABP4 expression in adipose tissue and the FABP4 plasma level as well as the main adipogenic and lipolytic genes expressed in adipose tissue were also analyzed. Methods The expression of several lipogenic, lipolytic, PPAR family and FABP family genes was analyzed by real time PCR. FABP4 protein expression in total adipose tissues and its fractions were determined by western blot. Results In obesity FABP4 expression was down-regulated (at both mRNA and protein levels), with its levels mainly predicted by ATGL and inversely by the HOMA-IR index. The BMI appeared as the only determinant of the FABP4 variation in both adipose tissue depots. FABP4 plasma levels showed a significant progressive increase according to BMI but no association was detected between FABP4 circulating levels and SAT or VAT FABP4 gene expression. The gene expression of FABP1, FABP4 and FABP5 in hepatic tissue was significantly higher in tissue from the obese IR patients compared to the non-IR group. Conclusion The inverse pattern in FABP4 expression between adipose and hepatic tissue observed in morbid obese patients, regarding the IR context, suggests that both tissues may act in a balanced manner. These differences may help us to understand the discrepancies between circulating plasma levels and adipose tissue expression in obesity.This work was supported by Fondo de Investigacion Sanitaria (FIS) 07/1024, 08/1195, CB06/03/0018, CP07/0095 and PI081655, 10/00967, 11/00085 from the Spanish Instituto de Salud Carlos III (ISCIII), Ministerio de Sanidad y Consumo; with the participation of the European Regional Development Fund (ERDF) SAF-2009-10461 from the Ministerio de Economia y Competitividad (MICINN), the Servicio Andaluz de Salud (PI325/2008) and Fundación Mutua Madrileña, Spain (BP). LGS and VCM are supported by fellowships from the Juan de la Cierva programme (JdlC) (JCI200904086 and JCI-2010-06395). CIBERs are an ISCIII Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Control of cell cycle progression by the last MAPK Hog1

Exposure of yeast to increases in extracellular osmolarity activates the stress-activated Hog1 MAP kinase, which is essential for cell survival upon osmotic stress. Activation of the Hog1 MAPK results in cell growth arrest, suggesting a possible role of the MAP kinase in the control of the cell cycle. Our results have shown that Hog1 activation resulted in accumulation of cells in the G1/S and G2/M transitions. At G1, Hog1 regulates the cell cycle progression by a dual mechanism that involves downregulation of G1 cyclin expression and direct targeting of the CDK-inhibitor protein Sic1. The MAPK interacts with Sic1, and phosphorylates a single residue of Sic1, which, in combination with the downregulation of cyclin expression, results in Sic1 stabilization and inhibition of cell cycle progression. Consistently, sic1_ cells, or cells containing a SIC1 allele mutated in the Hog1 phosphorylation site, are unable to arrest at G1 phase after Hog1 activation, and become sensitive to osmostress. Together, our data indicate that Sic1 is the molecular target for Hog1 that is required to modulate cell cycle progression in response to stress at G1. On the other hand, activation of the Hog1 MAPK also results in an increase of cells in the G2 phase. Arrested cells displayed down regulation of the Clb2-Cdc28 kinase activity and consequently enlarged buds, defects in spindle formation and orientation. These effects were prevented by deletion of the SWE1 gene. Thus, swe1Ä cells failed to arrest at G2, which resulted in a premature entry into mitosis and mislocalization of nuclei. Consistently, swe1Ä cells were osmosensitive. Swe1 degradation was reduced in response to activation of Hog1. Swe1 accumulation is mediated by the activity of the complex Hsl1-Hsl7. Hog1 phosphorylates a single residue at the regulatory domain of Hsl1, which leads to the mislocalization of Hsl7 from the bud neck, and consequent Swe1 accumulation. In addition, Hog1 downregulates G2 cyclin expression, reinforcing the inhibition of cell cycle progression at G2/M. These results indicate that Hog1 imposes a delay in critical phases of cell cycle progression necessary for proper cellular adaptation to new extracellular conditions

Role and regulation of CDK2 and p27 in adipose tissue and obesity

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Role and regulation of CDK2 and p27 in adipose tissue and obesity

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Effects of Maresin 1 (MaR1) on Colonic Inflammation and Gut Dysbiosis in Diet-Induced Obese Mice

The aim of this study was to characterize the effects of Maresin 1 (MaR1), a DHA-derived pro-resolving lipid mediator, on obesity-related colonic inflammation and gut dysbiosis in diet-induced obese (DIO) mice. In colonic mucosa of DIO mice, the MaR1 treatment decreased the expression of inflammatory genes, such as Tnf-α and Il-1β. As expected, the DIO mice exhibited significant changes in gut microbiota composition at the phylum, genus, and species levels, with a trend to a higher Firmicutes/Bacteroidetes ratio. Deferribacteres and Synergistetes also increased in the DIO animals. In contrast, these animals exhibited a significant decrease in the content of Cyanobacteria and Actinobacteria. Treatment with MaR1 was not able to reverse the dysbiosis caused by obesity on the most abundant phyla. However, the MaR1 treatment increased the content of P. xylanivorans, which have been considered to be a promising probiotic with healthy effects on gut inflammation. Finally, a positive association was found between the Deferribacteres and Il-1β expression, suggesting that the increase in Deferribacteres observed in obesity could contribute to the overexpression of inflammatory cytokines in the colonic mucosa. In conclusion, MaR1 administration ameliorates the inflammatory state in the colonic mucosa and partially compensates changes on gut microbiota caused by obesity

Effects of Maresin 1 (MaR1) on Colonic Inflammation and Gut Dysbiosis in Diet-Induced Obese Mice

The aim of this study was to characterize the effects of Maresin 1 (MaR1), a DHA-derived pro-resolving lipid mediator, on obesity-related colonic inflammation and gut dysbiosis in diet-induced obese (DIO) mice. In colonic mucosa of DIO mice, the MaR1 treatment decreased the expression of inflammatory genes, such as Tnf-α and Il-1β. As expected, the DIO mice exhibited significant changes in gut microbiota composition at the phylum, genus, and species levels, with a trend to a higher Firmicutes/Bacteroidetes ratio. Deferribacteres and Synergistetes also increased in the DIO animals. In contrast, these animals exhibited a significant decrease in the content of Cyanobacteria and Actinobacteria. Treatment with MaR1 was not able to reverse the dysbiosis caused by obesity on the most abundant phyla. However, the MaR1 treatment increased the content of P. xylanivorans, which have been considered to be a promising probiotic with healthy effects on gut inflammation. Finally, a positive association was found between the Deferribacteres and Il-1β expression, suggesting that the increase in Deferribacteres observed in obesity could contribute to the overexpression of inflammatory cytokines in the colonic mucosa. In conclusion, MaR1 administration ameliorates the inflammatory state in the colonic mucosa and partially compensates changes on gut microbiota caused by obesity

GLUT12 expression in brain of mouse models of Alzheimer's Disease

The brain depends on glucose as a source of energy. This implies the presence of glucose transporters, being GLUT1 and GLUT3 the most relevant. Expression of GLUT12 is found in mouse and human brain at low levels. We previously demonstrated GLUT12 upregulation in the frontal cortex of aged subjects that was even higher in aged Alzheimer’s disease (AD) patients. However, the cause and the mechanism through which this increase occurs are still unknown. Here, we aimed to investigate whether the upregulation of GLUT12 in AD is related with aging or Aβ deposition in comparison with GLUT1, GLUT3, and GLUT4. In the frontal cortex of two amyloidogenic mouse models (Tg2576 and APP/PS1) GLUT12 levels were increased. Contrary, expression of GLUT1 and GLUT3 were decreased, while GLUT4 did not change. In aged mice and the senescence-accelerated model SAMP8, GLUT12 and GLUT4 were upregulated in comparison with young animals. GLUT1 and GLUT3 did not show significant changes with age. The effect of βamyloid (Aβ) deposition was also evaluated in Aβ peptide i.c.v. injected mice. In the hippocampus, GLUT12 expression increased whereas GLUT4 was not modified. Consistent with the results in the amyloidogenic models, GLUT3 and GLUT1 were downregulated. In summary, Aβ increases GLUT12 protein expression in the brain pointing out a central role of the transporter in AD pathology and opening new perspectives for the treatment of this neurodegenerative disease

Maresin 1 activates brown adipose tissue and promotes browning of white adipose tissue in mice

Objective: Maresin 1 (MaR1) is a docosahexaenoic acid-derived proresolving lipid mediator with insulin-sensitizing and anti-steatosis properties. Here, we aim to unravel MaR1 actions on brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning. Methods: MaR1 actions were tested in cultured murine brown adipocytes and in human mesenchymal stem cells (hMSC)-derived adipocytes. In vivo effects of MaR1 were tested in diet-induced obese (DIO) mice and lean WT and Il6 knockout (Il6 / ) mice. Results: In cultured differentiated murine brown adipocytes, MaR1 reduces the expression of inflammatory genes, while stimulates glucose uptake, fatty acid utilization and oxygen consumption rate, along with the upregulation of mitochondrial mass and genes involved in mitochondrial biogenesis and function and the thermogenic program. In Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6)-depleted brown adipocytes using siRNA, the stimulatory effect of MaR1 on thermogenic genes was abrogated. In DIO mice, MaR1 promotes BAT remodeling, characterized by higher expression of genes encoding for master regulators of mitochondrial biogenesis and function and iBAT thermogenic activation, together with increased M2 macrophage markers. In addition, MaR1-treated DIO mice exhibit a better response to cold-induced BAT activation. Moreover, MaR1 induces a beige adipocyte signature in inguinal WAT of DIO mice and in hMSC-derived adipocytes. MaR1 potentiates Il6 expression in brown adipocytes and BAT of cold exposed lean WT mice. Interestingly, the thermogenic properties of MaR1 were abrogated in Il6 / mice. Conclusions: These data reveal MaR1 as a novel agent that promotes BAT activation and WAT browning by regulating thermogenic program in adipocytes and M2 polarization of macrophages. Moreover, our data suggest that LGR6 receptor is mediating MaR1 actions on brown adipocytes, and that IL-6 is required for the thermogenic effects of MaR1