Publications by authors named "Mouaadh Abdelkarim"

10 Publications

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Low expression of brown and beige fat genes in subcutaneous tissues in obese patients.

Arch Med Sci 2019 Sep 25;15(5):1113-1122. Epub 2018 Jun 25.

Department of Physiology, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia.

Introduction: The molecular mechanisms behind obesity pathogenesis remain largely undefined. Impairment in the browning process of subcutaneous tissues proposed to contribute to obesity pathogenesis. In the current study, we aimed to assess whether the expression of brown fat genes in subcutaneous tissues in obese patients is altered as compared to non-obese patients.

Material And Methods: Participants were recruited from patients undergoing general surgeries. At the same site of surgery, biopsies were taken from the abdominal subcutaneous tissues from each participant, along with a venous blood sample. The expression of BAT genes was measured using a real-time PCR method. Serum FGF21 was measured using an ELISA kit, and the serum blood lipid profile was measured using the Dimension VistaTM 1500 System.

Results: A total of 58 surgical patients was involved. A low expression of BAT genes was observed in the groups with higher body mass index (BMI) (< 30 kg/m) as compared to the groups with lower BMI (> 30 kg/m). The expression of CIDEA and CITED1 was significantly higher in the patients with normal weight as compared to obese ( = 0.01 and = 0.02, respectively). A significant negative correlation was found between the expression of BAT genes and BMI in patients with BMI < 35 kg/m. However, the strongest negative correlation was observed in the expression of CIDEA ( = -0.5, = 0.004), followed by TBX1 ( = -0.4, = 0.01), CITED1, and ZIC1 ( = -0.4, = 0.03). Whereas the correlation of UCP1 with BMI remained insignificant ( = -0.29, = 0.08). When including patients with BMI > 35 kg/m, the correlation decreased and became insignificant ( = 0.08). No significant correlation was found between the expression of BAT genes and blood lipid profiles ( > 0.05). Serum FGF21 was positively and significantly correlated to the expression of UCP1 ( = 0.56, = 0.02) and TBX1 ( = 0.62, = 0.01), however, this correlation was missing in patients with severe obesity.

Conclusions: Our data suggested that brown and beige genes expression in abdominal subcutaneous tissues is dysregulated in patients with obesity. Further studies are needed to investigate the role of browning of subcutaneous tissues in regulating body weight and metabolism in human.
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http://dx.doi.org/10.5114/aoms.2018.76684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764296PMC
September 2019

Gene Polymorphism Is Associated with Obesity and Blood Lipids Profiles in Saudi Population.

J Clin Med 2018 Jun 8;7(6). Epub 2018 Jun 8.

Department of Physiology, Faculty of Medicine, King Saud University, Riyadh 11461, Saudi Arabia.

Aims: The PR domain containing 16 () gene and the Phosphodiesterase 4D () gene are both an essential regulators in the thermogenesis process in the brown adipose tissues (BAT). The influence of polymorphisms in those genes on obesity and blood lipids profile is unknown particularly in the Saudi population, so the current study is aiming to explore that.

Methods: A case control format was used that involved 89 obese individual and 84 non-obese (control). The () and () polymorphisms were genotyped using KASP™ (Competitive Allele-Specific PCR) method.

Results: The distributions of the AA, GG, and AG genotypes of () polymorphism were 0.19, 0.26 and 0.54, respectively. While the distribution of the mutated allele A was 0.7 in the obese group comparing to 0.34 in the non-obese group. Participants with the mutated genotypes, AA and AG, of () polymorphism were significantly more likely to be obese as compared to participants with wild type genotype (OR = 21, 95% CI = 5.4190 to 84.4231, value < 0.0001 and OR = 44.6, 95% CI = 11.5984 to 172.0157, value < 0.0001, respectively). The wild type GG genotype of this polymorphism was associated with higher blood cholesterol, HDL and LDL but lower blood triglyceride compared with the mutated genotypes ( = 0.003, = 0.008, = 0.02 and = 0.003, respectively). In contrast, () polymorphism was not associated with risk of obesity and had no effects on blood lipids profile.

Conclusions: We found that the PRDM16 polymorphism () is a risk factor for obesity and influence blood lipids profiles significantly in Saudi population. While the () polymorphism didn’t show significant effect on risk of obesity or blood lipids profiles.
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http://dx.doi.org/10.3390/jcm7060141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025268PMC
June 2018

The supramammillary nucleus and the claustrum activate the cortex during REM sleep.

Sci Adv 2015 Apr 3;1(3):e1400177. Epub 2015 Apr 3.

UMR 5292 CNRS/U1028 INSERM, Centre de Recherche en Neurosciences de Lyon (CRNL), Team "Physiopathologie des réseaux neuronaux responsables du cycle veille-sommeil," Université Claude Bernard Lyon 1, Faculté de Médecine RTH Laennec, 7 Rue Guillaume Paradin, 69372 Lyon Cedex 08, France.

Evidence in humans suggests that limbic cortices are more active during rapid eye movement (REM or paradoxical) sleep than during waking, a phenomenon fitting with the presence of vivid dreaming during this state. In that context, it seemed essential to determine which populations of cortical neurons are activated during REM sleep. Our aim in the present study is to fill this gap by combining gene expression analysis, functional neuroanatomy, and neurochemical lesions in rats. We find in rats that, during REM sleep hypersomnia compared to control and REM sleep deprivation, the dentate gyrus, claustrum, cortical amygdaloid nucleus, and medial entorhinal and retrosplenial cortices are the only cortical structures containing neurons with an increased expression of Bdnf, FOS, and ARC, known markers of activation and/or synaptic plasticity. Further, the dentate gyrus is the only cortical structure containing more FOS-labeled neurons during REM sleep hypersomnia than during waking. Combining FOS staining, retrograde labeling, and neurochemical lesion, we then provide evidence that FOS overexpression occurring in the cortex during REM sleep hypersomnia is due to projections from the supramammillary nucleus and the claustrum. Our results strongly suggest that only a subset of cortical and hippocampal neurons are activated and display plasticity during REM sleep by means of ascending projections from the claustrum and the supramammillary nucleus. Our results pave the way for future studies to identify the function of REM sleep with regard to dreaming and emotional memory processing.
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http://dx.doi.org/10.1126/sciadv.1400177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640625PMC
April 2015

Comprehensive molecular characterization of human adipocytes reveals a transient brown phenotype.

J Transl Med 2015 Apr 30;13:135. Epub 2015 Apr 30.

Laboratory of Genetic Medicine & Immunology, Weill Cornell Medical College in Qatar, P.O. Box 24144, Doha, Qatar.

Background: Functional brown adipose tissue (BAT), involved in energy expenditure, has recently been detected in substantial amounts in adults. Formerly overlooked BAT has now become an attractive anti-obesity target.

Methods And Results: Molecular characterization of human brown and white adipocytes, using a myriad of techniques including high-throughput RNA sequencing and functional assays, showed that PAZ6 and SW872 cells exhibit classical molecular and phenotypic markers of brown and white adipocytes, respectively. However, the pre-adipocyte cell line SGBS presents a versatile phenotype. A transit expression of classical brown markers such as UCP1 and PPARγ peaked and declined at day 28 post-differentiation initiation. Conversely, white adipocyte markers, including Tcf21, showed reciprocal behavior. Interestingly, leptin levels peaked at day 28 whereas the highest adiponectin mRNA levels were detected at day 14 of differentiation. Phenotypic analysis of the abundance and shape of lipid droplets were consistent with the molecular patterns. Accordingly, the oxidative capacity of SGBS adipocytes peaked on differentiation day 14 and declined progressively towards differentiation day 28.

Conclusions: Our studies have unveiled a new phenotype of human adipocytes, providing a tool to identify molecular gene expression patterns and pathways involved in the conversion between white and brown adipocytes.
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http://dx.doi.org/10.1186/s12967-015-0480-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438513PMC
April 2015

PAZ6 cells constitute a representative model for human brown pre-adipocytes.

Front Endocrinol (Lausanne) 2012 2;3:13. Epub 2012 Feb 2.

Department of Infectology, The Scripps Research Institute-Florida Jupiter, FL, USA.

The role of brown adipose tissue (BAT) in human metabolism and its potential as an anti-obesity target organ have recently received much renewed attention. Following radiological detection of substantial amounts of BAT in adults by several independent research groups, an increasing number of studies are now dedicated to uncover BAT's genetic, developmental, and environmental determinants. In contrast to murine BAT, human BAT is not present as a single major fat depot in a well-defined location. The distribution of BAT in several areas in the body significantly limits its availability to research. A human brown adipocyte cell line is therefore critical in broadening the options available to researchers in the field. The human BAT-cell line PAZ6 was created to address such a need and has been well characterized by several research groups around the world. In the present review, we discuss their findings and propose potential applications of the PAZ6 cells in addressing the relevant questions in the BAT field, namely for future use in therapeutic applications.
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http://dx.doi.org/10.3389/fendo.2012.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355992PMC
July 2012

Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity.

Diabetes 2011 Jul 18;60(7):1861-71. Epub 2011 May 18.

University of Lille Nord de France, INSERM UMR1011, UDSL, Institut Pasteur de Lille, Lille, France.

Objective: Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed.

Research Design And Methods: Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity.

Results: FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism.

Conclusions: Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis.
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http://dx.doi.org/10.2337/db11-0030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121443PMC
July 2011

The farnesoid X receptor regulates adipocyte differentiation and function by promoting peroxisome proliferator-activated receptor-gamma and interfering with the Wnt/beta-catenin pathways.

J Biol Chem 2010 Nov 17;285(47):36759-67. Epub 2010 Sep 17.

Université Lille Nord de France, F-59000 Lille, France.

The bile acid receptor farnesoid X receptor (FXR) is expressed in adipose tissue, but its function remains poorly defined. Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipocyte differentiation and function. The aim of this study was to analyze the role of FXR in adipocyte function and to assess whether it modulates PPARγ action. Therefore, we tested the responsiveness of FXR-deficient mice (FXR(-/-)) and cells to the PPARγ activator rosiglitazone. Our results show that genetically obese FXR(-/-)/ob/ob mice displayed a resistance to rosiglitazone treatment. In vitro, rosiglitazone treatment did not induce normal adipocyte differentiation and lipid droplet formation in FXR(-/-) mouse embryonic fibroblasts (MEFs) and preadipocytes. Moreover, FXR(-/-) MEFs displayed both an increased lipolysis and a decreased de novo lipogenesis, resulting in reduced intracellular triglyceride content, even upon PPARγ activation. Retroviral-mediated FXR re-expression in FXR(-/-) MEFs restored the induction of adipogenic marker genes during rosiglitazone-forced adipocyte differentiation. The expression of Wnt/β-catenin pathway and target genes was increased in FXR(-/-) adipose tissue and MEFs. Moreover, the expression of several endogenous inhibitors of this pathway was decreased early during the adipocyte differentiation of FXR(-/-) MEFs. These findings demonstrate that FXR regulates adipocyte differentiation and function by regulating two counteracting pathways of adipocyte differentiation, the PPARγ and Wnt/β-catenin pathways.
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http://dx.doi.org/10.1074/jbc.M110.166231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978604PMC
November 2010

Inhibition of adipocyte differentiation by RORalpha.

FEBS Lett 2009 Jun 18;583(12):2031-6. Epub 2009 May 18.

Institut Pasteur de Lille, Département d'Athérosclérose, Lille F-59019, France.

Here we show that gene expression of the nuclear receptor RORalpha is induced during adipogenesis, with RORalpha4 being the most abundantly expressed isoform in human and murine adipose tissue. Over-expression of RORalpha4 in 3T3-L1 cells impairs adipogenesis as shown by the decreased expression of adipogenic markers and lipid accumulation, accompanied by decreased free fatty acid and glucose uptake. By contrast, mouse embryonic fibroblasts from staggerer mice, which carry a mutation in the RORalpha gene, differentiate more efficiently into mature adipocytes compared to wild-type cells, a phenotype which is reversed by ectopic RORalpha4 restoration.
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http://dx.doi.org/10.1016/j.febslet.2009.05.019DOI Listing
June 2009

FXR-deficiency confers increased susceptibility to torpor.

FEBS Lett 2007 Nov 12;581(27):5191-8. Epub 2007 Oct 12.

Institut Pasteur de Lille, Département d'Athérosclérose, Lille F-59019, France.

The role of the nuclear receptor FXR in adaptive thermogenesis was investigated using FXR-deficient mice. Despite elevated serum bile acid concentrations and increased mRNA expression profiles of thermogenic genes in brown adipose tissue, FXR-deficiency did not alter energy expenditure under basal conditions. However, FXR-deficiency accelerated the fasting-induced entry into torpor in a leptin-dependent manner. FXR-deficient mice were also extremely cold-intolerant. These altered responses may be linked to a more rapid decrease in plasma concentrations of metabolic fuels (glucose, triglycerides) thus impairing uncoupling protein 1-driven thermogenesis. These results identify FXR as a modulator of energy homeostasis.
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http://dx.doi.org/10.1016/j.febslet.2007.09.064DOI Listing
November 2007

The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice.

J Biol Chem 2006 Apr 30;281(16):11039-49. Epub 2006 Jan 30.

Institut Pasteur de Lille, Département d'Athérosclérose, Lille, F-59019, France.

The farnesoid X receptor (FXR) is a bile acid (BA)-activated nuclear receptor that plays a major role in the regulation of BA and lipid metabolism. Recently, several studies have suggested a potential role of FXR in the control of hepatic carbohydrate metabolism, but its contribution to the maintenance of peripheral glucose homeostasis remains to be established. FXR-deficient mice display decreased adipose tissue mass, lower serum leptin concentrations, and elevated plasma free fatty acid levels. Glucose and insulin tolerance tests revealed that FXR deficiency is associated with impaired glucose tolerance and insulin resistance. Moreover, whole-body glucose disposal during a hyperinsulinemic euglycemic clamp is decreased in FXR-deficient mice. In parallel, FXR deficiency alters distal insulin signaling, as reflected by decreased insulin-dependent Akt phosphorylation in both white adipose tissue and skeletal muscle. Whereas FXR is not expressed in skeletal muscle, it was detected at a low level in white adipose tissue in vivo and induced during adipocyte differentiation in vitro. Moreover, mouse embryonic fibroblasts derived from FXR-deficient mice displayed impaired adipocyte differentiation, identifying a direct role for FXR in adipocyte function. Treatment of differentiated 3T3-L1 adipocytes with the FXR-specific synthetic agonist GW4064 enhanced insulin signaling and insulin-stimulated glucose uptake. Finally, treatment with GW4064 improved insulin resistance in genetically obese ob/ob mice in vivo. Although the underlying molecular mechanisms remain to be unraveled, these results clearly identify a novel role of FXR in the regulation of peripheral insulin sensitivity and adipocyte function. This unexpected function of FXR opens new perspectives for the treatment of type 2 diabetes.
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http://dx.doi.org/10.1074/jbc.M510258200DOI Listing
April 2006