Leptin deficiency leads to a unique natural history of NASH in rats
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ABSTRACT:
ORGANISM(S): Rattus norvegicus Macaca fascicularis
PROVIDER: GSE124002 | GEO | 2019/12/31
REPOSITORIES: GEO
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Project description:Gallstone disease is a major contributor to health care costs in the United States. Approximately 12 % of the U.S. population has gallstones. As a result, more than 700,000 cholecystectomies are performed in this country each year. Many of these patients are obese and have a positive family history; but surprisingly, little is known about the link between obesity, genetics and gallstone formation. Obese individuals have been shown to have supersaturated bile, larger gallbladder fasting volumes and impaired gallbladder emptying. We have recently demonstrated that leptin plays a role in gallbladder motility. In an effort to understand the genetic basis for these observations, we tested the hypothesis that leptin would alter gallbladder gene expression. Methods: Affymetrix oligonucleotide microarrays 430 2.0 were used to compare gallbladder gene expression profiles from 12 week old control saline-treated leptin-deficient (Lep ob) and from leptin-treated Lep ob female mice. Analyses were performed on pooled RNA (n=4) from the gallbladders of 12 saline-treated Lep ob mice and from 12 Lep ob mice which were administered daily IP 5 ug/g of recombinant murine leptin for 4 weeks. Resulting data were analyzed utilizing Gene Chip Operating Software or MAS 5.0. Results: Of the genes analyzed 314 were upregulated and 108 were downregulated by leptin administration. Numerous genes related to gallstone pathogenesis, gallbladder absorption/secretion, inflammatory cytokines, and insulin resistance were altered by leptin. Keywords: comparitive response to leptin
2005-12-31 | GSE3293 | GEO
Project description:Gallstone disease is a major contributor to health care costs in the United States. Approximately 12 % of the U.S. population has gallstones. As a result, more than 700,000 cholecystectomies are performed in this country each year. Many of these patients are obese and have a positive family history; but surprisingly, little is known about the link between obesity, genetics and gallstone formation. Obese individuals have been shown to have supersaturated bile, larger gallbladder fasting volumes and impaired gallbladder emptying. We have recently demonstrated that leptin plays a role in gallbladder motility. In an effort to understand the genetic basis for these observations, we tested the hypothesis that leptin would alter gallbladder gene expression. Methods: Affymetrix oligonucleotide microarrays 430 2.0 were used to compare gallbladder gene expression profiles from 12 week old control saline-treated leptin-deficient (Lep ob) and from leptin-treated Lep ob female mice. Analyses were performed on pooled RNA (n=4) from the gallbladders of 12 saline-treated Lep ob mice and from 12 Lep ob mice which were administered daily IP 5 ug/g of recombinant murine leptin for 4 weeks. Resulting data were analyzed utilizing Gene Chip Operating Software or MAS 5.0. Results: Of the genes analyzed 314 were upregulated and 108 were downregulated by leptin administration. Numerous genes related to gallstone pathogenesis, gallbladder absorption/secretion, inflammatory cytokines, and insulin resistance were altered by leptin. Experiment Overall Design: Female B6.V-lepob obese mice (n=24) aged 7 weeks were obtained from The Jackson Laboratory (Bar Harbor, ME). Upon arrival, mice were placed on a standard chow diet and were allowed to acclimate for 1 week before starting the experiment. For leptin treatments, mice received daily intraperitoneal injections of either recombinant mouse leptin (R&D Systems, Minneapolis, MN) (n=12) at a dose of 5 µg/g body weight or with saline as a control (n=12) for 4 weeks. At 12 weeks of age, mice were fasted overnight with free access to water. The following morning the mice underwent cholecystectomy. Three gallbladders were pooled to create 4 pools in each treatment and total RNA was isolated. Affymetrix murine 430 2.0 arrays were utilized to examine altered gallbladder gene expression as a result of leptin administration. The resulting data was analyzed utlizing Gene Chip Operating Software or MAS 5.0.
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Project description:In mammals, expansion of adipose tissue mass induces accumulation of adipose tissue macrophages (ATMs). We isolated CD11c- (FB) and CD11c+ (FBC) perigonadal ATMs from SVCs of lean (C57BL/6J Lep +/+) and obese leptin-deficient (C57BL/6J Lep ob/ob) mice. We used expression microarrays to generate transcription profiles of perigonadal ATMs from lean (C57BL/6J Lep +/+) and obese (C57BL/6J Lep ob/ob) mice. Profiling purified FBs and FBCs, we identified 521 transcripts whose expression was differentially (nominal p-value < 0.01) expressed between FBs from lean and obese mice and 1509 genes whose expression was differentially (nominal p-value <0.01) expressed between FBC from lean and obese mice
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Project description:We applied RNA sequencing to study the hepatic gene expression profile of Lep(ob/ob) mice fed the Amylin liver NASH (AMLN) diet for 14 weeks and then treated for 2 weeks with vehicle (n=10), obeticholic acid (OCA) (n=9), or INT-787 (n=9). INT-787, which is equipotent to OCA but more hydrophilic, modulated a substantially greater number of genes associated with FXR signaling, lipid metabolism, and stellate cell activation relative to OCA.
2024-04-11 | GSE263273 | GEO
Project description:In mammals, expansion of adipose tissue mass induces accumulation of adipose tissue macrophages (ATMs). We isolated CD11c- (FB) and CD11c+ (FBC) perigonadal ATMs from SVCs of lean (C57BL/6J Lep +/+) and obese leptin-deficient (C57BL/6J Lep ob/ob) mice. We used expression microarrays to generate transcription profiles of perigonadal ATMs from lean (C57BL/6J Lep +/+) and obese (C57BL/6J Lep ob/ob) mice. Profiling purified FBs and FBCs, we identified 521 transcripts whose expression was differentially (nominal p-value < 0.01) expressed between FBs from lean and obese mice and 1509 genes whose expression was differentially (nominal p-value <0.01) expressed between FBC from lean and obese mice RNA was isolated from sorted FBC (F4/80+, CD11b+, CD11c+) cells and FB ( F4/80+, CD11b+, CD11c-) cells and using RNeasy micro-kits (Qiagen), using a PicoPure RNA isolation kit then amplified two-rounds. Labeled cRNA Mouse Genome 430 2.0 arrays (purified FB and FBC adipose tissue macrophages. There was a total of sixteen samples. FB and FBC populations were isolated from 4 lean and 4 obese mice.
2013-12-18 | E-GEOD-53403 | biostudies-arrayexpress
Project description:We hypothesize that gene expression in the lungs of these differentially-treated mice are divergent thus contributing to the disparity in their phenotypes. More specifically, (1) Effects of Leptin-treatment of ob/ob postnatal mice lungs are known to be volume-dependent from 2 to 10 wks of age, and are independent of the hypometabolism associated with leptin deficiency. ; (2) Leptin is critical to postnatal lung remodeling, particularly related to enlarged alveolar surface area. In order to test these hypotheses at the gene expression level, we utilized microarray analysis to examine transcriptional differences between lungs of leptin or saline-treated ob/ob postnatal mice. Keywords: leptin, ob, lung
2008-06-01 | GSE10915 | GEO
Project description:We hypothesize that gene expression in the lungs of these differentially-treated mice are divergent thus contributing to the disparity in their phenotypes. More specifically, (1) Effects of Leptin-treatment of ob/ob postnatal mice lungs are known to be volume-dependent from 2 to 10 wks of age, and are independent of the hypometabolism associated with leptin deficiency. ; (2) Leptin is critical to postnatal lung remodeling, particularly related to enlarged alveolar surface area. In order to test these hypotheses at the gene expression level, we utilized microarray analysis to examine transcriptional differences between lungs of leptin or saline-treated ob/ob postnatal mice. Experiment Overall Design: This study utilizes microarray analysis to test these hypotheses. Three sets of lungs were harvested from both treatments (Leptin or Saline) at around 1 mo. postnatal. RNA was isolated and used for global gene expression profiling (Affymetrix Mouse 430A array). Statistically significant gene expression was determined as a minimum 6 counts of 9 pairwise comparisons, minimum 1.5-fold change, and p < 0.05.
2008-06-18 | E-GEOD-10915 | biostudies-arrayexpress
Project description:The purpose of this study was to identify leptin target genes and subsequent pathways correlated with leptin-mediated weight loss. We utilized the microarray technology to compare two types of leptin administration: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We report here the impact of central and peripheral administration of leptin on food intake, body weight and body fat composition in ob/ob mice. We also report hepatic gene expression changes caused by central versus peripheral leptin administration. Keywords: comparison Leptin deficient (ob/ob) mice were continuously administered leptin over 12-days using central (intracerebroventricular) or peripheral (subcutaneous) route of administration. Liver RNA was extracted and hybridized to Illumina microarrays and gene expression data was analyzed. The global gene expression profiles were compared after the central and peripheral leptin treatments in ob/ob mice and C57BL6 mice were used for the baseline gene expression.
2010-11-10 | E-GEOD-20878 | biostudies-arrayexpress
Project description:Although mitochondrial dysfunctions are implicated in the pathogenesis of obesity, the molecular mechanisms underlying obesity-related metabolic abnormalities are still not well established. To acquire a comprehensive picture of mitochondrial molecular changes within metabolically active tissues, we focused on hepatic and muscle whole cellular transcriptome and mitochondrial proteome alterations in 16 and 48 weeks old high fat diet (HFD)-feed wild type C57BL/6J and hyperphagic, genetically modified mice with leptin dysfunction (ob/ob and db/db). On transcriptome level, the most discriminative hepatic alterations distinguished between genetically modified and wild type mice, and between overnight fasted and non-fasted mice, while the muscle transcriptional alterations related mainly to the fasting state. The fractions of uniquely different proteins were consistently higher in hyperphagic than in HFD-fed mice and in fasted than non-fasted mice . The liver samples revealed overall higher number of differentially expressed RNAs and proteins than muscle samples. Differentially expressed genes and proteins in the liver, but not in the muscle, could be assigned to several Gene Ontology terms, including oxidation-reduction and several metabolic processes. Thus, altered expression of genes and proteins accompanied the state of obesity and was quantitatively different in the liver and muscle. Our parallel microarray- and quantitative mitochondrial mass spectrometry-based study performed on hepatic and muscle samples identified a higher number of differentially expressed proteins than any other studies investigating obesity-related proteomes. However, even with our integrated transcriptomic and proteomic approach still many details and dynamics of a chain of metabolic events leading to obesity-related mitochondrial dysfunctions remain unresolved . 48 samples each of liver and muscle (total samples: 96). Samples splitted equally according to 3 criterions: age (24 young/24 old), fasting status (24 fasted/24 non fasted), and strain+diet (12 each: B6.V-Lep ob/J+D12450B, B6.BKS(D)-Lep rdb/J+D12450B, C57BL/6J+D12450B, C57BL/6J+D12492). Overall 3 replicates for each strain+diet/age/fasting_status combination. Low fat diet = D12450B; high fat diet = D12492.
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Project description:Ob/ob mice were given 0, 12.5 or 25 ng/hr leptin through an osmotic pump. After 12 days, livers RNA was prepared and illumina microarrays were done. We tested whether leptin can ameliorate diabetes independent of weight loss by defining the lowest dose at which leptin treatment of ob/ob mice reduces plasma [glucose] and [insulin]. We found that a leptin dose of 12.5 ng/hour significantly lowers blood glucose and that 25 ng/hour of leptin normalizes plasma glucose and insulin without significantly reducing body weight, thus establishing that leptin exerts its most potent effects on glucose metabolism. To find possible mediators of this effect, we profiled liver mRNA using microarrays and identified IGF Binding Protein 2 as being regulated by leptin with a similarly high potency. Over-expression of IGFBP2 by an adenovirus reversed diabetes in insulin resistant ob/ob, Ay/a and diet-induced obese mice (DIO), as well as insulin deficient streptozotocin-treated mice. Hyperinsulinemic clamp studies showed a three-fold improvement in hepatic insulin sensitivity following IGFBP2 treatment in ob/ob mice. These results show that IGFBP2 can regulate glucose metabolism, a finding with potential implications for the pathogenesis and treatment of diabetes.
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