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Diabetes and Insulin in Regulation of Brain Cholesterol Metabolism

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE62013 | GEO | 2014/10/03

SECONDARY ACCESSION(S): PRJNA262937

REPOSITORIES: GEO

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Diabetes and Insulin in Regulation of Brain Cholesterol Metabolism

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

Mus musculus

Project description:Diabetes and Insulin in Regulation of Brain Cholesterol Metabolism

| PRJNA262937 | ENA

E-GEOD-62013

Project description:Diabetes and Insulin in Regulation of Brain Cholesterol Metabolism

2014-10-28 | E-GEOD-62013 | ExpressionAtlas

Depletion of PARP-2 in HepG2 cells

Project description:Poly(ADP-ribose) polymerase-2 (PARP-2) is acknowledged as a DNA repair enzyme; however, recently metabolic properties had been attributed to it. Hereby, we examined the metabolic consequences of PARP-2 ablation in liver. Microarray analysis of PARP-2 knockdown HepG2 cells revealed the dysregulation of lipid and cholesterol metabolism genes. Induction of cholesterol biosynthesis genes stemmed from the enhanced expression of sterol-regulatory element binding protein (SREBP)-1. We revealed that PARP-2 is a suppressor of the SREBP-1 promoter, therefore ablation of PARP-2 induces SREBP-1 expression and consequently cholesterol synthesis. PARP-2-/- mice had higher SREBP-1 expression that was translated into enhanced hepatic and serum cholesterol levels. PARP-2 silencing was performed employing shPARP-2 (small hairpin) and scPARP-2 (scrambled) shRNA by lentiviral delivery (Sigma) using 40 MOI lentiviruses coding shRNA sequence against PARP-2.

2013-12-31 | E-GEOD-43981 | biostudies-arrayexpress

Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2

Project description:Background: Fibroblast growth factor-19 (FGF19) is an intestinal hormone that mediates postprandial metabolic responses in the liver. The unusual orphan nuclear receptor, Small Heterodimer Partner (SHP), acts as a co-repressor for many transcriptional factors and has been implicated in diverse biological pathways including FGF19-mediated repression of bile acid synthesis. To explore global functions of SHP in mediating FGF19 action, we identify genome-wide SHP binding sites in hepatic chromatin in mice treated with vehicle or FGF19 by ChIP-seq analysis. Results: The overall pattern of SHP binding sites between these two groups is similar, but SHP binding is enhanced at the sites by addition of FGF19. SHP binding is detected preferentially in promoter regions that are enriched in motifs for unexpected non-nuclear receptors. We observe global co-localization of SHP sites with published sites for SREBP-2, a master transcriptional activator of cholesterol biosynthesis. FGF19 increases functional interaction between endogenous SHP and SREBP-2 and inhibits SREBP-2 target genes, and these effects were blunted in SHP-knockout mice. Furthermore, FGF19-induced phosphorylation of SHP at Thr-55 is shown to be important for its functional interaction with SREBP-2 and reduction of liver/serum cholesterol levels. Conclusion: This study reveals SHP as a global transcriptional partner of SREBP-2 in regulation of sterol biosynthetic gene networks and provides a potential mechanism for cholesterol-lowering action of FGF19. Genome-wide SHP binding profiles in hepatic chromatin in mice under treatment of FGF19 or vehicle were generated using high throughput sequencing followed by chromatin immunoprecipitation.

2015-11-12 | E-GEOD-74913 | biostudies-arrayexpress

Depletion of PARP-2 in HepG2 cells

2013-12-31 | GSE43981 | GEO

Peripheral Insulin Regulates A Broad Network of Gene Expression in Brain

Project description:The brain is now recognized as an insulin sensitive tissue, however, the role of insulin on gene expression in the brain is largely unknown. Here, we show that increases in peripheral insulin within the physiological range regulate expression of a broad network of gene expression, with the most robust effect in the hypothalamus followed by the hippocampus then nucleus accumbens. In hypothalamus, insulin regulates many genes involved in neurotransmission, including up-regulating expression of GABA-A receptor components, differentially modulating glutamate receptors, and suppressing multiple neuropeptides. Insulin also strongly modulates brain metabolism by suppressing genes involved in the glycolysis and pentose phosphate pathways while increasing expression of genes regulating pyruvate dehydrogenase complex, long-chain fatty acyl-CoA and cholesterol biosynthesis, rerouting carbon substrates to the biogenesis of plasma membrane for neuronal and glial function and synaptic remodeling. Thus, peripheral insulin acutely and potently regulates expression of genes involved in neurotransmission, neuromodulation and brain metabolism.

2021-06-07 | GSE132352 | GEO

Gpnmb secreted from liver promotes lipogenesis in white adipose tissue and aggravates obesity and insulin resistance

Project description:Metabolism in mammals is regulated by the complex interplay among different organs. Fatty acid synthesis is increased in white adipose tissue (WAT) when it is inhibited in liver. Here we identify glycoprotein nonmetastatic melanoma protein B (Gpnmb) as one liver-WAT cross-talk factor in lipogenesis. Hepatic SREBP pathway inhibition leads to increased transcription of the Gpnmb and promotes the processing of the membrane protein to a secreted form. Gpnmb stimulates lipogenesis in WAT and exacerbates diet-induced obesity and insulin resistance. In humans, Gpnmb is tightly associated with body mass index and is a strong risk factor for obesity. Gpnmb inhibition by a neutralizing antibody or liver specific knockdown improves metabolic parameters including weight gain reduction and increased insulin sensitivity, likely by promoting the beiging of WAT. These results suggest that Gpnmb is a liver-secreted factor regulating lipogenesis in WAT, and that Gpnmb inhibition may provide a therapeutic strategy for obesity and diabetes. Hepatic SREBP pathway inhibition, such as liver-specific ablation of Scap (L-Scap-/-), decreases fatty acid synthesis in liver. Meanwhile, the fatty acid synthesis in white adipose tissue of L-Scap-/- is compensatorily increased. The microarray analysis using the liver RNAs of L-Scap-/- and wild type (WT) mice is performed to identify the up-regulated genes encoding secreted factors in L-Scap-/-.

2019-04-04 | GSE129283 | GEO

Repeated hypoglycemia in diabetic mice induce hypothalamic mitochondrial and synaptic activity deregulations characteristic of neurodegenerative diseases

Project description:Repeated exposures to insulin-induced hypoglycemia in diabetic patients progressively impair the counter-regulatory response (CRR) that restores normoglycemia. This defect is characterized by reduced secretion of glucagon and other counter-regulatory hormones. Evidence indicates that glucose responsive neurons located in the hypothalamus, orchestrate the CRR. Here, we aimed at identifying the changes in hypothalamic gene and protein expression that underlie impaired CRR. High fat diet fed and low dose streptozocin-treated C57BL6N mice were exposed to one (acute hypoglycemia, AH) or multiple (recurrent hypoglycemia, RH) insulin-induced hypoglycemic episodes. Single nuclei RNA sequencing (snRNAseq) data were obtained from the hypothalamus and cortex of AH and RH mice. Proteomic data were also obtained from hypothalamic synaptosomal fractions. The present study shows that repeated moderate hypoglycemia in diabetic mice lead, in the hypothalamus, to multiple cellular physiology changes, affecting all cell types and their interactions, which show striking features of neurodegenerative diseases. It also shows that repeated hypoglycemic episodes affect very differently the hypothalamus and the cortex.

2023-11-13 | PXD040183 | Pride

Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2

2015-11-12 | GSE74913 | GEO

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