Leptin treatment has vasculo-protective effects in lipodystrophic mice
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ABSTRACT:
PROVIDER: PRJNA880772 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21590465_1.fastq.gz | Fastqsanger.gz | |||
| SRR21590465_2.fastq.gz | Fastqsanger.gz | |||
| SRR21590466_1.fastq.gz | Fastqsanger.gz | |||
| SRR21590466_2.fastq.gz | Fastqsanger.gz | |||
| SRR21590467_1.fastq.gz | Fastqsanger.gz |
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Project description:Lipodystrophy syndromes (LD) are characterized by loss of adipose tissue, metabolic complications such as dyslipidemia, insulin resistance and fatty liver disease, as well as accelerated atherosclerosis. As a result of adipose tissue deficiency, the systemic concentration of the adipokine leptin is reduced. A current promising therapeutic option for patients with LD is treatment with recombinant leptin (metreleptin) resulting in reduced risk of mortality. Here, we investigate the effects of leptin on endothelial-to-mesenchymal transition (EndMT), which impairs the functional properties of endothelial cells and promotes atherogenesis in LD. Leptin treatment reduced inflammation, TGF-β2-induced expression of mesenchymal genes and prevented impairment of endothelial barrier function. Treatment of lipodystrophic and atherosclerosis prone animals (Ldlr-/-; aP2-nSrebp1c-Tg) with leptin reduced macrophage accumulation in atherosclerotic lesions, vascular plaque protrusion and the number of endothelial cells with mesenchymal gene expression, confirming a reduction in EndMT in LD after leptin treatment. Treatment with leptin inhibited LD-mediated induction of the pro-atherosclerotic cytokine growth/differentiation factor 15 (GDF15). Inhibition of GDF15 reduced EndMT induction triggered by plasma from LD patients. Our study reveals that in addition to the effects on adipose tissue function, leptin treatment exerts beneficial effects protecting endothelial function and identity in LD by reducing GDF15.
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Project description:Leptin monotherapy (i.e. without the use of administered insulin and/or any other molecule) corrects ID-induced metabolic aberrancies and promotes survival of insulin deficient rodents. These results generated great interest in the possibility of treating insulin deficient patients with leptin and/or molecule(s) underlying its beneficial effects. Hence, with the goal of identifying circulating molecule(s) underlying the advantageous effect of leptin we performed quantitative proteomic analysis of plasma and identified S100A9 as a putative peripheral mediator of leptin action. Here, to identify circulating molecule(s) underlying the advantageous effect of leptin we compared the results obtained by quantitative proteomic analysis of plasma between 2 groups of mice: streptozotocin (STZ)-treated mice that underwent intracerebroventricular (icv) leptin treatment for 12 days (STZ-Leptin) and ii) STZ-treated mice that underwent icv leptin treatment for 10 days and were withdrawn from leptin treatment for the following two days (STZ-Leptin-STOP). STZ treatment led to a massive loss of pancreatic insulin-producing β-cells, diminished pancreatic Proinsulin mRNA level, and caused severe insulinopenia, and hyperglycemia. icv leptin administration normalized hyperglycemia. However, two days after leptin delivery was halted hyperglycemia reappeared. We hypothesized that change in plasmatic protein(s) content could underlie re-emergence of hyperglycemia following decrease of leptin action.
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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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Project description:Ob/ob mice are characterized by a defect in leptin synthesis. In this study, the contribution of leptin deficiency to the deregulation of miRNA expression in ob/ob mice was determined by comparing leptin infused ob/ob mice to saline control.
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Project description:Lipodystrophy syndromes (LDs) are characterized by loss of adipose tissue, metabolic complications such as dyslipidemia, insulin resistance, and fatty liver disease, as well as accelerated atherosclerosis. As a result of adipose tissue deficiency, the systemic concentration of the adipokine leptin is reduced. A current promising therapeutic option for patients with LD is treatment with recombinant leptin (metreleptin), resulting in reduced risk of mortality. Here, we investigate the effects of leptin on endothelial to mesenchymal transition (EndMT), which impair the functional properties of endothelial cells and promotes atherogenesis in LD. Leptin treatment reduced inflammation and TGF-β2-induced expression of mesenchymal genes and prevented impairment of endothelial barrier function. Treatment of lipodystrophic- and atherosclerosis-prone animals (Ldlr-/-; aP2-nSrebp1c-Tg) with leptin reduced macrophage accumulation in atherosclerotic lesions, vascular plaque protrusion, and the number of endothelial cells with mesenchymal gene expression, confirming a reduction in EndMT in LD after leptin treatment. Treatment with leptin inhibited LD-mediated induction of the proatherosclerotic cytokine growth/differentiation factor 15 (GDF15). Inhibition of GDF15 reduced EndMT induction triggered by plasma from patients with LD. Our study reveals that in addition to the effects on adipose tissue function, leptin treatment exerts beneficial effects protecting endothelial function and identity in LD by reducing GDF15.
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Project description:Concentrations of leptin decline during food restriction. This study was designed to test the hypothesis that some of the effects of maternal food restriction on placental development are mediated by the loss of leptin. Mice were randomized to 3 treatment groups on day 1.5 of pregnancy: (1) ad libitum fed (control) (2) 50% food restriction (restricted) (3) 50% food restriction with leptin replacement (1µg/g body weight/day) (leptin). On day 11.5 placentas were collected, and two placentas from each mother were pooled for microarray analysis.
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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. 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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