Genetic regulator of mitochondrial metabolism and insulin resistance [ncRNA-Seq]
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ABSTRACT:
PROVIDER: PRJNA680249 | ENA |
REPOSITORIES: ENA
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Project description:Mitochondrial energy metabolism and function are key processes underlying the pathophysiology of insulin resistance and predisposition to type 2 diabetes. This is because mitochondria produce most of the energy required by the cell. Impaired energy production, use of energy stores and mitochondrial dysfunction are major features in metabolic diseases. Nevertheless, it remains uncertain how mitochondrial dysfunction can cause, contribute to, or result in insulin resistance and metabolic diseases. Furthermore there is growing evidence from genetic and genome wide-association studies that genetic variation in mtDNA contributes to these common metabolic diseases (Wallace, 2005), however there has been essentially no in vivo functional validation for these findings. Therefore we generated a mouse model homozygous for a polymorphism in the Mrpp3 gene identified in the French Canadian population responsible for 22% of mitochondrial epitranscriptome variation, with likely consequences on metabolism. We investigated the in vivo effects of the polymorphism on mitochondrial function and metabolism in mice fed normal and high fat diet. We identify that the polymorphism reduces the efficiency of mitochondrial RNA processing and this is most pronounced in the pancreas that results in insulin resistance. The MRPP3 protein containing the Asn434Ser polymorphism associates specifically with the calcium antiporter LETM1 preventing effective release of calcium from mitochondria and consequently impairs insulin release from the pancreatic islet cells of these mice. Reduction in insulin secretion and enlarged pancreatic islet size results in lower circulating levels of insulin that causes insulin resistance and liver steatosis. Our findings reveal for the first time the link between mitochondrial gene regulation and insulin resistance via calcium signaling.
2021-09-24 | GSE161978 | GEO
Project description:Genetic regulator of mitochondrial metabolism and insulin resistance
| PRJNA680312 | ENA
Project description:Genetic regulator of mitochondrial metabolism and insulin resistance [RNA-Seq]
| PRJNA680321 | ENA
Project description:Mitochondrial energy metabolism and function are key processes underlying the pathophysiology of insulin resistance and predisposition to type 2 diabetes. This is because mitochondria produce most of the energy required by the cell. Impaired energy production, use of energy stores and mitochondrial dysfunction are major features in metabolic diseases. Nevertheless, it remains uncertain how mitochondrial dysfunction can cause, contribute to, or result in insulin resistance and metabolic diseases. Furthermore there is growing evidence from genetic and genome wide-association studies that genetic variation in mtDNA contributes to these common metabolic diseases (Wallace, 2005), however there has been essentially no in vivo functional validation for these findings. Therefore we generated a mouse model homozygous for a polymorphism in the Mrpp3 gene identified in the French Canadian population responsible for 22% of mitochondrial epitranscriptome variation, with likely consequences on metabolism. We investigated the in vivo effects of the polymorphism on mitochondrial function and metabolism in mice fed normal and high fat diet. We identify that the polymorphism reduces the efficiency of mitochondrial RNA processing and this is most pronounced in the pancreas that results in insulin resistance. The MRPP3 protein containing the Asn434Ser polymorphism associates specifically with the calcium antiporter LETM1 preventing effective release of calcium from mitochondria and consequently impairs insulin release from the pancreatic islet cells of these mice. Reduction in insulin secretion and enlarged pancreatic islet size results in lower circulating levels of insulin that causes insulin resistance and liver steatosis. Our findings reveal for the first time the link between mitochondrial gene regulation and insulin resistance via calcium signaling.
2021-09-24 | GSE162020 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-09-24 | GSE162021 | GEO
Project description:A major target of insulin signaling is the FoxO family of Forkhead transcription factors, which translocate from the nucleus to the cytoplasm following insulin-stimulated phosphorylation. Here we show that the Forkhead transcription factors FoxK1 and FoxK2 are also downstream targets of insulin action, but that following insulin stimulation, they translocate from the cytoplasm to nucleus, reciprocal to the translocation of FoxO1. FoxK1/FoxK2 translocation to the nucleus is dependent on the Akt-mTOR pathway, while its localization to the cytoplasm in the basal state is dependent on GSK3. Knockdown of FoxK1 and FoxK2 in liver cells results in upregulation of genes related to apoptosis and down-regulation of genes involved in cell cycle and lipid metabolism. This is associated with decreased cell proliferation and altered mitochondrial fatty acid metabolism. Thus, FoxK1/K2 are reciprocally regulated to FoxO1 following insulin stimulation and play a novel role in the control of apoptosis, metabolism and mitochondrial function.
2019-02-25 | GSE110574 | GEO
Project description:The brain is the most cholesterol-rich organ in the body, most of which comes from in situ synthesis. Here we demonstrate that in insulin-deficient diabetic mice, there is a reduction in expression of the major transcriptional regulator of cholesterol metabolism, SREBP-2, and its downstream genes in the hypothalamus and other areas of the brain, leading to a reduction in brain cholesterol synthesis and synaptosomal cholesterol content. These changes are due, at least in part, to direct effects of insulin to regulate these genes in neurons and glial cells and can be corrected by intracerebroventricular injections of insulin. Knockdown of SREBP-2 in cultured neurons causes a decrease in markers of synapse formation and reduction of SREBP-2 in the hypothalamus of mice using shRNA results in increased feeding and weight gain. Thus, insulin and diabetes can alter brain cholesterol metabolism, and this may play an important role in the neurologic and metabolic dysfunction observed in diabetes and other disease states. Hypothalamus was compared between streptozotocin (STZ)-induced diabetic, ob/ob, and control mice, with 5-6 replicates per goup.
2014-10-03 | E-GEOD-62013 | biostudies-arrayexpress
Project description:The brain is the most cholesterol-rich organ in the body, most of which comes from in situ synthesis. Here we demonstrate that in insulin-deficient diabetic mice, there is a reduction in expression of the major transcriptional regulator of cholesterol metabolism, SREBP-2, and its downstream genes in the hypothalamus and other areas of the brain, leading to a reduction in brain cholesterol synthesis and synaptosomal cholesterol content. These changes are due, at least in part, to direct effects of insulin to regulate these genes in neurons and glial cells and can be corrected by intracerebroventricular injections of insulin. Knockdown of SREBP-2 in cultured neurons causes a decrease in markers of synapse formation and reduction of SREBP-2 in the hypothalamus of mice using shRNA results in increased feeding and weight gain. Thus, insulin and diabetes can alter brain cholesterol metabolism, and this may play an important role in the neurologic and metabolic dysfunction observed in diabetes and other disease states.
2014-10-03 | GSE62013 | GEO
Project description:FoxK1/2 – New Components in Insulin Regulation of Cellular and Mitochondrial Metabolism
| PRJNA434000 | ENA
Project description:ncRNA has been shown to be important for various biological processes including transcriptional regulation and protein complex formation. Mitochondoria were purified from the livers of normal mice and three metabolic model mice, and the RNA contained therein was analyzed by the next-generation sequencing method. Differential expression patterns of RNA species were detected in normal and three models, and some ncRNA were significantly up- or down-regulated in the metabolic models.
2023-10-02 | GSE158914 | GEO