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Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE117560 | GEO | 2021/06/11

REPOSITORIES: GEO

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Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway [I]

Project description:To evaluate gene expression changes in response to low-density-lipoprotein related protein 1 (LRP1) depletion in endothelial cells, we performed mRNA-sequencing analysis with microvascular endothelial cells isolated from the lung, heart and liver LRP1 endothelial knockout mice and their littermate control wild type mice.

2021-06-11 | GSE117554 | GEO

Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway [II]

Project description:To evaluate gene expression changes in response to low-density-lipoprotein related protein 1 (LRP1) depletion in endothelial cells, we performed mRNA-sequencing analysis with microvascular endothelial cells isolated from the liver LRP1 endothelial knockout mice and their littermate control wild type mice.

2021-06-11 | GSE117555 | GEO

Endothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin.

Project description:The vascular endothelium is present within metabolic organs and actively regulates energy metabolism. Here we show osteocalcin, recognized as a bone-secreted metabolic hormone, is expressed in mouse primary endothelial cells isolated from heart, lung and liver. In human osteocalcin promoter-driven green fluorescent protein transgenic mice, green fluorescent protein signals are enriched in endothelial cells lining aorta, small vessels and capillaries and abundant in aorta, skeletal muscle and eye of adult mice. The depletion of lipoprotein receptor-related protein 1 induces osteocalcin through a Forkhead box O -dependent pathway in endothelial cells. Whereas depletion of osteocalcin abolishes the glucose-lowering effect of low-density lipoprotein receptor-related protein 1 depletion, osteocalcin treatment normalizes hyperglycemia in multiple mouse models. Mechanistically, osteocalcin receptor-G protein-coupled receptor family C group 6 member A and insulin-like-growth-factor-1 receptor are in the same complex with osteocalcin and required for osteocalcin-promoted insulin signaling pathway. Therefore, our results reveal an endocrine/paracrine role of endothelial cells in regulating insulin sensitivity, which may have therapeutic implications in treating diabetes and insulin resistance through manipulating vascular endothelium.

| S-EPMC8421392 | biostudies-literature

Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway

Project description:Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway

| PRJNA482452 | ENA

Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway [I]

Project description:Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway [I]

| PRJNA482455 | ENA

Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway [II]

Project description:Endothelium-specific depletion of LRP1 improves glucose homeostasis through the osteocalcin-IGF1R pathway [II]

| PRJNA482461 | ENA

Inflammation Improves Glucose Homeostasis through IKK?-XBP1s Interaction.

Project description:It is widely believed that inflammation associated with obesity has an important role in the development of type 2 diabetes. I?B kinase beta (IKK?) is a crucial kinase that responds to inflammatory stimuli such as tumor necrosis factor ? (TNF-?) by initiating a variety of intracellular signaling cascades and is considered to be a key element in the inflammation-mediated development of insulin resistance. We show here, contrary to expectation, that IKK?-mediated inflammation is a positive regulator of hepatic glucose homeostasis. IKK? phosphorylates the spliced form of X-Box Binding Protein 1 (XBP1s) and increases the activity of XBP1s. We have used three experimental approaches to enhance the IKK? activity in the liver of obese mice and observed increased XBP1s activity, reduced ER stress, and a significant improvement in insulin sensitivity and consequently in glucose homeostasis. Our results reveal a beneficial role of IKK?-mediated hepatic inflammation in glucose homeostasis.

| S-EPMC5908236 | biostudies-literature

Hexosamine Pathway Activation Improves Protein Homeostasis through the Integrated Stress Response.

Project description:Activation of the hexosamine pathway (HP) through gain-of-function mutations in its rate-limiting enzyme glutamine fructose-6-phosphate amidotransferase (GFAT-1) ameliorates proteotoxicity and increases lifespan in Caenorhabditis elegans. Here, we investigate the role of the HP in mammalian protein quality control. In mouse neuronal cells, elevation of HP activity led to phosphorylation of both PERK and eIF2? as well as downstream ATF4 activation, identifying the HP as a modulator of the integrated stress response (ISR). Increasing uridine 5'-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) levels through GFAT1 gain-of-function mutations or supplementation with the precursor GlcNAc reduces aggregation of the polyglutamine (polyQ) protein Ataxin-3. Blocking PERK signaling or autophagy suppresses this effect. In C. elegans, overexpression of gfat-1 likewise activates the ISR. Consistently, co-overexpression of gfat-1 and proteotoxic polyQ peptides in muscles reveals a strong protective cell-autonomous role of the HP. Thus, the HP has a conserved role in improving protein quality control through modulation of the ISR.

| S-EPMC7033349 | biostudies-literature

Repression of Adipose Tissue Fibrosis through a PRDM16-GTF2IRD1 Complex Improves Systemic Glucose Homeostasis.

Project description:Adipose tissue fibrosis is a hallmark of malfunction that is linked to insulin resistance and type 2 diabetes; however, what regulates this process remains unclear. Here we show that the PRDM16 transcriptional complex, a dominant activator of brown/beige adipocyte development, potently represses adipose tissue fibrosis in an uncoupling protein 1 (UCP1)-independent manner. By purifying the PRDM16 complex, we identified GTF2IRD1, a member of the TFII-I family of DNA-binding proteins, as a cold-inducible transcription factor that mediates the repressive action of the PRDM16 complex on fibrosis. Adipocyte-selective expression of GTF2IRD1 represses adipose tissue fibrosis and improves systemic glucose homeostasis independent of body-weight loss, while deleting GTF2IRD1 promotes fibrosis in a cell-autonomous manner. GTF2IRD1 represses the transcription of transforming growth factor β-dependent pro-fibrosis genes by recruiting PRDM16 and EHMT1 onto their promoter/enhancer regions. These results suggest a mechanism by which repression of obesity-associated adipose tissue fibrosis through the PRDM16 complex leads to an improvement in systemic glucose homeostasis.

| S-EPMC5765755 | biostudies-literature

High glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway.

Project description:Diabetes mellitus (DM) is associated with higher risk of tendinopathy, which reduces tolerance to exercise and functional activities and affects lifestyle and glycemic control. Expression of tendon-related genes and matrix metabolism in tenocytes are essential for maintaining physiological functions of tendon. However, the molecular mechanisms involved in diabetic tendinopathy remain unclear. We hypothesized that high glucose (HG) alters the characteristics of tenocyte. Using in vitro 2-week culture of tenocytes, we found that expression of tendon-related genes, including Egr1, Mkx, TGF-β1, Col1a2, and Bgn, was significantly decreased in HG culture and that higher glucose consumption occurred. Down-regulation of Egr1 by siRNA decreased Scx, Mkx, TGF-β1, Col1a1, Col1a2, and Bgn expression. Blocking AMPK activation with Compound C reduced the expression of Egr1, Scx, TGF-β1, Col1a1, Col1a2, and Bgn in the low glucose condition. In addition, histological examination of tendons from diabetic mice displayed larger interfibrillar space and uneven glycoprotein deposition. Thus, we concluded that high glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway and the expression of downstream tendon-related genes in tenocytes. The findings render a molecular basis of the mechanism of diabetic tendinopathy and may help develop preventive and therapeutic strategies for the pathology.

| S-EPMC5339827 | biostudies-literature

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