Biomedical subjects

Naima Moustaid-Moussa

Publications and source records attributed to Naima Moustaid-Moussa.

8 recordsLinked to original sources

PubMed2006

Phenotypic characterization of polygenic type 2 diabetes in TALLYHO/JngJ mice.

The TALLYHO/JngJ (TH) strain is a newly established, polygenic mouse model for type 2 diabetes (T2D) and obesity, and we have previously reported some key physiological features of this model after the overt onset of diabetes. In the present work, we conducted a comprehensive phenotypic characterization of TH in order to completely characterize this new and relevant model for human T2D and obesity. We monitored the development of obesity and diabetes starting at 4 weeks of age by measuring body weight, glucose tolerance, and plasma levels of insulin, glucose, and triglyceride. Additionally, histological alterations in the pancreas and glucose uptake and glucose transporter 4 (GLUT4) content in soleus muscle were also examined. Compared with age- and sex-matched C57BL/6J (B6) mice, both male and female TH mice were significantly heavier, hyperleptinemic, and hyperinsulinemic at 4 weeks of age, without glucose intolerance or hyperglycemia. TH mice maintained higher body weights throughout the study period of 16 weeks. The hyperinsulinemia in TH mice worsened with age, but to a lesser degree in females than in males. Both the male and the female TH mice had enlarged pancreatic islets. Male TH mice showed impaired glucose tolerance at 8 weeks that became more prominent at 16 weeks. Plasma glucose levels continuously increased with age in male TH mice resulting in frank diabetes, while female TH mice remained normoglycemic throughout the study. Impaired glucose tolerance and hyperglycemia in male TH mice were accompanied by impaired 2-deoxyglucose uptake in the soleus muscle at basal and insulin-stimulated states, but without any reduction in GLUT4 content. Interestingly, male TH mice exhibited a drastic elevation in plasma triglyceride levels in the pre-diabetic stage that was maintained throughout the study. These findings suggest that obesity and insulin resistance are an inherent part of the TH phenotype and glucose intolerance is evident preceding progression to overt diabetes in male TH mice.

Animals↗

PubMed2005

Differential regulation of hepatic gene expression by starvation versus refeeding following a high-sucrose or high-fat diet.

OBJECTIVES: The objective of this work was to determine the effects of starvation versus refeeding following a high-sucrose diet (HS) or high-fat diet (HF) on fatty acid metabolism in mice. METHODS: The mice were fed an AIN-76 control diet (CD), a modified HS, or an HF. The three dietary groups were subdivided into three groups each: those fed experimental diets for 12 wk, mice starved for 48 h after 12 wk on an experimental diet, and those with the same starvation treatment but with 72 h of refeeding after starvation, respectively. RESULTS: Serum total cholesterol levels of CD and HF groups decreased and then increased under starvation and refeeding states, respectively. Refeeding HS and HF increased serum levels of low-density lipoprotein (LDL) cholesterol compared with refeeding of the CD group. Starvation significantly increased hepatic levels of total cholesterol in the HS and HF groups compared with the CD group. Hepatic acyl coenzyme A (CoA) synthetase (ACS) levels in the CD and HS groups but not the HF group increased and then decreased under starved and refed states, respectively; an opposite regulation was observed in the HF group. Levels of hepatic acetyl-CoA carboxylase (ACC) in the HS and HF groups were significantly increased by refeeding. Hepatic levels of carnitine palmitoyltransferase-I mRNA were significantly enhanced by starvation and refeeding in the HS group but decreased in CD and then increased in the HF group. CONCLUSIONS: Changes in dietary energy nutrients, fasting, and refeeding affect hepatic ACS, CPT-I, and ACC mRNA expression, and these results will serve to enhance our understanding of the molecular mechanisms underlying regulation of fatty acid metabolism.

Acetyl-CoA Carboxylase↗

PubMed2005

Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance.

The renin-angiotensin system with its active metabolite angiotensin (Ang) II has been related not only to hypertension but also to obesity and insulin resistance. Recent evidence obtained in vitro suggests that the type 2 Ang II receptor (AT2R) mediates the trophic action of Ang II on adipocyte differentiation and lipogenesis. We used AT2R(y/-) mice to delineate a potential role of AT2R in adipose tissue development and metabolism. AT2R(y/-) mice had a normal adiposity but displayed a striking adipose tissue phenotype characterized by small adipocytes and an increase in cell number. In muscle, the expression of several genes involved in lipid metabolism, including fatty acid translocase, uncoupling protein-3, peroxisome proliferator-activated receptors (alpha, delta), and carnitine palmitoyl transferase-1, was increased in AT2R-deficient mice. In response to high-fat feeding, these mice were protected against obesity and obesity-related glucose intolerance, as assessed by glucose tolerance tests. Moreover, lipid oxidation assessed by indirect calorimetry was higher in AT2R-deficient mice than in wild-type mice, irrespective of the diet. This suggests that AT2R-dependent signaling exerts a direct or indirect negative control on lipid utilization in muscles. These data support the idea that AT2R-dependent Ang II signaling increases adipose cell mass and glucose intolerance and thus could participate to the deleterious effects of a high-fat diet.

Adipocytes↗

PubMed2004

Expression of interleukin-6 is greater in preadipocytes than in adipocytes of 3T3-L1 cells and C57BL/6J and ob/ob mice.

Inflammation plays a major role in the development of chronic diseases such as cardiovascular disease and Type 2 diabetes. Further, it was demonstrated that obese animals and humans have significantly higher levels of circulating proinflammatory cytokines, such as interleukin-6 (IL-6). The aim of this study was to determine whether adipose tissue could be a major source of circulating IL-6 in leptin-deficient obese (ob/ob) mice by comparing the expression of IL-6 in different tissues of ob/ob mice. Our secondary goal was to determine whether preadipocytes are the source of adipose tissue IL-6. The ob/ob mice had higher levels of plasma IL-6 (P < 0.05) and adipose tissue IL-6 mRNA (P < 0.05) compared with lean mice. Interestingly, IL-6 mRNA levels of liver and spleen were not different between ob/ob and lean mice, whereas adipose tissue IL-6 mRNA levels were higher in the ob/ob mice compared with lean mice (P < 0.05). In addition, we showed that IL-6 secretion from the adipose tissue stromal vascular fraction cells was higher than that from fully differentiated adipocytes (P < 0.001). We further demonstrated that 3T3-L1 preadipocytes had significantly higher levels of lipopolysaccharide (LPS)-stimulated IL-6 mRNA and IL-6 secretion than differentiated 3T3-L1 adipocytes. Taken together, these data suggest that adipose tissue and preadipocytes from the adipose tissue stromal vascular fraction may contribute significantly to the increased plasma IL-6 levels in ob/ob mice.

3T3-L1 Cells↗

PubMed2004

Gene expression profiling in human preadipocytes and adipocytes by microarray analysis.

Uncontrolled expansion of adipose tissue leads to obesity, a public health epidemic affecting >30% of adult Americans. Adipose mass increases in part through the recruitment and differentiation of an existing pool of preadipocytes (PA) into adipocytes (AD). Most studies investigating adipogenesis used primarily murine cell lines; much less is known about the relevant processes that occur in humans. Therefore, characterization of genes associated with adipocyte development is key to understanding the pathogenesis of obesity and developing treatments for this disorder. To address this issue, we performed large-scale analyses of human adipose gene expression using microarray technology. Differential gene expression between PA and AD was analyzed in 6 female patients using human cDNA microarray slides and data analyzed using the Stanford Microarray Database. Statistical analysis for the gene expression was performed using the SAS mixed models. Compared with PA, several genes involved in lipid metabolism were overexpressed in AD, including fatty acid binding protein, adipose differentiation-related protein, lipoprotein lipase, perilipin, and adipose most abundant transcript 1. Novel genes expressed in adipocytes included E2F5 transcriptional factor and SMARC (SWI/SNF-related, matrix associated, actin-dependent regulator of chromatin). PA predominantly expressed genes encoding extracellular matrix components such as fibronectin, matrix metalloprotein, and novel proteins such as lysyl oxidase. Despite the high differential expression of some of these genes, many did not differ significantly likely due to high variability and limited statistical power. A comprehensive list of differential gene expression is presented according to cellular function. In conclusion, these studies offer an overview of the gene expression profiles in PA and AD and identify new genes with potentially important functions in adipose tissue development and obesity that merit further investigation.

Adipocytes↗

PubMed2004

The human fatty acid synthase gene and de novo lipogenesis are coordinately regulated in human adipose tissue.

Despite its potential importance in obesity and related disorders, little is known about regulation of lipogenesis in human adipose tissue. To investigate this area at the molecular and mechanistic levels, we studied lipogenesis and the regulation of 1 of its core enzymes, fatty acid synthase (FAS), in human adipose tissue in response to hormonal and nutritional manipulation. As a paradigm for lipogenic genes, we cloned the upstream region of the human FAS gene, compared its sequence to that of FAS orthologs from other species, and identified important regulatory elements that lie upstream of the FAS coding region. Lipogenesis, as assessed by glucose incorporation into lipids, was increased by insulin and more so by the combination of insulin and dexamethasone (Dex, a potent glucocorticoid analogue). In parallel, FAS expression, activity, and gene transcription rate were also significantly increased by these treatments. We also showed that linoleic acid, a representative PUFA, attenuated the actions of insulin and Dex on fatty acid and lipid synthesis as well as FAS activity and expression. Using reporter assays, we determined that the regions responsible for hormonal regulation of the FAS gene lie in the proximal portion of the gene's 5'-flanking region, within which we identified an insulin response element similar to the E-box sequence we identified previously in the rat FAS gene. In summary, we demonstrated that lipogenesis occurs in human adipose tissue and can be induced by insulin, further enhanced by glucocorticoids, and suppressed by PUFA in a hormone-dependent manner.

Adipose Tissue↗

PubMed2003

Characterization of the long pentraxin PTX3 as a TNFalpha-induced secreted protein of adipose cells.

Exposure of preadipocytes to long-chain fatty acids induces the expression of several markers of adipocyte differentiation. In an attempt to identify novel genes and proteins that are regulated by fatty acids in preadipocytes, we performed a substractive hybridization screening and identified PTX3, a protein of the pentraxin family. PTX3 mRNA expression is transient during adipocyte differentiation of clonal cell lines and is absent in fully differentiated cells. Stable overexpression of PTX3 in preadipocytes has no effect on adipocyte differentiation. In line with this, PTX3 mRNA is expressed in the stromal-vascular fraction of adipose tissue, but not in the adipocyte fraction; however, in 3T3-F442A adipocytes, the PTX3 gene can be reinduced by tumor necrosis factor alpha (TNFalpha) in a dose-dependent manner. This effect is accompanied by PTX3 protein secretion from both 3T3-F442A adipocytes and explants of mouse adipose tissue. PTX3 mRNA levels are found to be higher in adipose tissue of genetically obese mice versus control mice, consistent with their increased TNFalpha levels. In conclusion, PTX3 appears as a TNFalpha-induced protein that provides a new link between chronic low-level inflammatory state and obesity.

3T3 Cells↗

PubMed2002

Angiotensin II increases leptin secretion by 3T3-L1 and human adipocytes via a prostaglandin-independent mechanism.

We previously reported that angiotensin II (Ang II) increases adipocyte fatty acid synthesis and triglyceride content. Triglyceride stores or adiposity correlate positively with the amount of circulating leptin. Ang II was proposed to increase adipocyte differentiation and growth by promoting prostaglandin (PG) production. The purpose of this study was to determine whether Ang II increases leptin secretion via a PG-dependent mechanism. Physiologic doses of Ang II significantly increased leptin secretion by 3T3-L1 adipocytes and human adipocytes. Elevation of PG secretions was elicited at physiologic concentrations of Ang II (P < 0.05). Secretions of 6-keto PGF(1alpha), a stable derivative of PGI(2), and PGE(2) were induced by physiologic concentrations of Ang II in a time-responsive fashion (P < 0.05). Inhibition of PG synthesis by indomethacin and aspirin significantly suppressed basal as well as Ang II-induced PG levels, but did not significantly affect basal and Ang II-induced leptin secretion. In conclusion, although Ang II stimulates both leptin and PG secretion by adipocytes, regulation of leptin secretion by Ang II in adipocytes is not mediated by a PG-dependent mechanism.

3T3 Cells↗