General Information:

Id: 1,092
Diseases: Diabetes mellitus, type II - [OMIM]
Insulin resistance
Obesity - [OMIM]
Mammalia
article
Reference: de Luca C and Olefsky JM(2008) Inflammation and insulin resistance FEBS Lett. 582: 97-105 [PMID: 18053812]

Interaction Information:

Comment In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter to the plasma membrane, and impaired skeletal muscle insulin signaling results in decreased glucose disposal.
Formal Description
Interaction-ID: 6917

complex/PPI

Insulin

increases_activity of

gene/protein

SLC2A4

in skeletal muscle
Comment In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter to the plasma membrane, and impaired skeletal muscle insulin signaling results in decreased glucose disposal.
Formal Description
Interaction-ID: 6923

gene/protein

SLC2A4

increases_activity of

process

glucose import

in skeletal muscle
Comment In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter to the plasma membrane, and impaired skeletal muscle insulin signaling results in decreased glucose disposal.
Formal Description
Interaction-ID: 6925

disease

Insulin resistance

decreases_activity of

process

glucose import

in skeletal muscle
Comment In the liver, insulin inhibits the expression of key gluconeogenic enzymes and, therefore, insulin resistance in liver leads to elevated hepatic glucose production.
Formal Description
Interaction-ID: 6926

complex/PPI

Insulin

decreases_activity of

process

gluconeogenesis

in liver
Comment In the liver, insulin inhibits the expression of key gluconeogenic enzymes and, therefore, insulin resistance in liver leads to elevated hepatic glucose production.
Formal Description
Interaction-ID: 6928

disease

Insulin resistance

increases_activity of

process

gluconeogenesis

in liver
Comment Adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid (FFA) efflux out of adipocytes.
Formal Description
Interaction-ID: 6929

complex/PPI

Insulin

decreases_activity of

gene/protein

LIPE

in adipose tissue
Comment Adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid (FFA) efflux out of adipocytes.
Formal Description
Interaction-ID: 6931

complex/PPI

Insulin

decreases_quantity of

drug/chemical compound

Fatty acid

in blood
Comment Adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid (FFA) efflux out of adipocytes.
Formal Description
Interaction-ID: 6932

disease

Insulin resistance

increases_quantity of

drug/chemical compound

Fatty acid

in blood
Comment Increased circulating FFA can result in decreased insulin sensitivity in skeletal muscle due to an increase in intracellular lipid products, including fatty acyl-CoA and ceramide. These lipid intermediates can activate the serine/threonine kinase, protein kinase C-theta (PKC-theta), which then inhibits the insulin signaling cascade.
Formal Description
Interaction-ID: 6933

affects_quantity of

drug/chemical compound

Lipid

intracellular, in skeletal muscle
Comment Increased circulating FFA can result in decreased insulin sensitivity in skeletal muscle due to an increase in intracellular lipid products, including fatty acyl-CoA and ceramide. These lipid intermediates can activate the serine/threonine kinase, protein kinase C-theta (PKC-theta), which then inhibits the insulin signaling cascade.
Formal Description
Interaction-ID: 6960

drug/chemical compound

Lipid

increases_activity of

gene/protein

PRKCQ

in skeletal muscle
Drugbank entries Show/Hide entries for PRKCQ
Comment Increased circulating FFA can result in decreased insulin sensitivity in skeletal muscle due to an increase in intracellular lipid products, including fatty acyl-CoA and ceramide. These lipid intermediates can activate the serine/threonine kinase, protein kinase C-theta (PKC-theta), which then inhibits the insulin signaling cascade.
Formal Description
Interaction-ID: 6962

gene/protein

PRKCQ

decreases_activity of

in skeletal muscle
Drugbank entries Show/Hide entries for PRKCQ
Comment Increased circulating FFA can result in decreased insulin sensitivity in skeletal muscle due to an increase in intracellular lipid products, including fatty acyl-CoA and ceramide. These lipid intermediates can activate the serine/threonine kinase, protein kinase C-theta (PKC-theta), which then inhibits the insulin signaling cascade.
Formal Description
Interaction-ID: 6963

gene/protein

PRKCQ

increases_activity of

disease

Insulin resistance

in skeletal muscle
Drugbank entries Show/Hide entries for PRKCQ
Comment The insulin signaling cascade branches off into two main pathways, the first is the phosphatidylinositol 3-kinase (PI3K)-AKT (also called protein kinase B (PKB)) pathway which is largely responsible for insulin action on glucose uptake, as well as other metabolic actions of insulin, including the suppression of gluconeogenesis. The second pathway is the Ras-mitogen activated protein kinase (MAPK) pathway which mediates gene expression, but also interacts with the PI3K-AKT pathway to control cell growth and differentiation.
Formal Description
Interaction-ID: 6964
Comment The insulin signaling cascade branches off into two main pathways, the first is the phosphatidylinositol 3-kinase (PI3K)-AKT (also called protein kinase B (PKB)) pathway which is largely responsible for insulin action on glucose uptake, as well as other metabolic actions of insulin, including the suppression of gluconeogenesis. The second pathway is the Ras-mitogen activated protein kinase (MAPK) pathway which mediates gene expression, but also interacts with the PI3K-AKT pathway to control cell growth and differentiation.
Formal Description
Interaction-ID: 6966
Comment The insulin signaling cascade branches off into two main pathways, the first is the phosphatidylinositol 3-kinase (PI3K)-AKT (also called protein kinase B (PKB)) pathway which is largely responsible for insulin action on glucose uptake, as well as other metabolic actions of insulin, including the suppression of gluconeogenesis. The second pathway is the Ras-mitogen activated protein kinase (MAPK) pathway which mediates gene expression, but also interacts with the PI3K-AKT pathway to control cell growth and differentiation.
Formal Description
Interaction-ID: 6967
Comment The insulin signaling cascade branches off into two main pathways, the first is the phosphatidylinositol 3-kinase (PI3K)-AKT (also called protein kinase B (PKB)) pathway which is largely responsible for insulin action on glucose uptake, as well as other metabolic actions of insulin, including the suppression of gluconeogenesis. The second pathway is the Ras-mitogen activated protein kinase (MAPK) pathway which mediates gene expression, but also interacts with the PI3K-AKT pathway to control cell growth and differentiation.
Formal Description
Interaction-ID: 6968
Comment The insulin signaling cascade branches off into two main pathways, the first is the phosphatidylinositol 3-kinase (PI3K)-AKT (also called protein kinase B (PKB)) pathway which is largely responsible for insulin action on glucose uptake, as well as other metabolic actions of insulin, including the suppression of gluconeogenesis. The second pathway is the Ras-mitogen activated protein kinase (MAPK) pathway which mediates gene expression, but also interacts with the PI3K-AKT pathway to control cell growth and differentiation.
Formal Description
Interaction-ID: 6971

affects_activity of

process

gene expression

Comment The insulin signaling cascade branches off into two main pathways, the first is the phosphatidylinositol 3-kinase (PI3K)-AKT (also called protein kinase B (PKB)) pathway which is largely responsible for insulin action on glucose uptake, as well as other metabolic actions of insulin, including the suppression of gluconeogenesis. The second pathway is the Ras-mitogen activated protein kinase (MAPK) pathway which mediates gene expression, but also interacts with the PI3K-AKT pathway to control cell growth and differentiation.
Formal Description
Interaction-ID: 6973
Comment The insulin signaling cascade branches off into two main pathways, the first is the phosphatidylinositol 3-kinase (PI3K)-AKT (also called protein kinase B (PKB)) pathway which is largely responsible for insulin action on glucose uptake, as well as other metabolic actions of insulin, including the suppression of gluconeogenesis. The second pathway is the Ras-mitogen activated protein kinase (MAPK) pathway which mediates gene expression, but also interacts with the PI3K-AKT pathway to control cell growth and differentiation.
Formal Description
Interaction-ID: 6974

affects_activity of

process

cell growth

Comment The insulin signaling cascade branches off into two main pathways, the first is the phosphatidylinositol 3-kinase (PI3K)-AKT (also called protein kinase B (PKB)) pathway which is largely responsible for insulin action on glucose uptake, as well as other metabolic actions of insulin, including the suppression of gluconeogenesis. The second pathway is the Ras-mitogen activated protein kinase (MAPK) pathway which mediates gene expression, but also interacts with the PI3K-AKT pathway to control cell growth and differentiation.
Formal Description
Interaction-ID: 6975

affects_activity of

Comment Activation of the insulin receptor leads to tyrosine phosphorylation of IRS1 thereby initiating signal transduction.
Formal Description
Interaction-ID: 6980

complex/PPI

Insulin receptor

increases_phosphorylation of

gene/protein

IRS1

at Tyr residues of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment Activation of the insulin receptor leads to tyrosine phosphorylation of IRS1 thereby initiating signal transduction.
Formal Description
Interaction-ID: 6981

protein modification

IRS1-phosTyr

increases_activity of

Comment When IRS1 is alternatively phosphorylated on serine 307, its downstream signaling ability is diminished. Serine kinases that phosphorylate serine 307 include I kappa B kinase beta (Ikkb) in the NFkappaB pathway and C-jun N-terminal kinase 1 (Jnk1) in the JNK/AP-1 pathway.
Formal Description
Interaction-ID: 6982

gene/protein

IKBKB

increases_phosphorylation of

gene/protein

IRS1

at Ser307 of IRS1
Drugbank entries Show/Hide entries for IKBKB or IRS1
Comment When IRS1 is alternatively phosphorylated on serine 307, its downstream signaling ability is diminished. Serine kinases that phosphorylate serine 307 include I kappa B kinase beta (Ikkb) in the NFkappaB pathway and C-jun N-terminal kinase 1 (Jnk1) in the JNK/AP-1 pathway.
Formal Description
Interaction-ID: 6983

gene/protein

MAPK8

increases_phosphorylation of

gene/protein

IRS1

at Ser307 of IRS1
Drugbank entries Show/Hide entries for MAPK8 or IRS1
Comment When IRS1 is alternatively phosphorylated on serine 307, its downstream signaling ability is diminished. Serine kinases that phosphorylate serine 307 include I kappa B kinase beta (Ikkb) in the NFkappaB pathway and C-jun N-terminal kinase 1 (Jnk1) in the JNK/AP-1 pathway.
Formal Description
Interaction-ID: 6984

protein modification

IRS1-phosSer307

decreases_activity of

Comment Socs1 and Socs3, which are induced in inflammation, promote the ubiquitylation and subsequent degradation of IRS1.
Formal Description
Interaction-ID: 6985

increases_activity of

gene/protein

SOCS1

Comment Socs1 and Socs3, which are induced in inflammation, promote the ubiquitylation and subsequent degradation of IRS1.
Formal Description
Interaction-ID: 6999

increases_activity of

gene/protein

SOCS3

Comment Socs1 and Socs3, which are induced in inflammation, promote the ubiquitylation and subsequent degradation of IRS1.
Formal Description
Interaction-ID: 7001

gene/protein

SOCS1

increases_ubiquitination/sumoylation of

gene/protein

IRS1

Drugbank entries Show/Hide entries for IRS1
Comment Socs1 and Socs3, which are induced in inflammation, promote the ubiquitylation and subsequent degradation of IRS1.
Formal Description
Interaction-ID: 7003

gene/protein

SOCS3

increases_ubiquitination/sumoylation of

gene/protein

IRS1

Drugbank entries Show/Hide entries for IRS1
Comment Socs1 and Socs3, which are induced in inflammation, promote the ubiquitylation and subsequent degradation of IRS1.
Formal Description
Interaction-ID: 7004

gene/protein

SOCS1

decreases_quantity of

gene/protein

IRS1

via increased degradation of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment Socs1 and Socs3, which are induced in inflammation, promote the ubiquitylation and subsequent degradation of IRS1.
Formal Description
Interaction-ID: 7005

gene/protein

SOCS3

decreases_quantity of

gene/protein

IRS1

via increased degradation of IRS1
Drugbank entries Show/Hide entries for IRS1
Comment The activated insulin receptor can phosphorylate tyrosine residues on Src homology 2 containing protein (Shc) which then binds to the Son of sevenless (SOS)-growth factor receptor-bound protein 2 (Grb2) complex which then triggers the Ras-MAPK signaling cascade.
Formal Description
Interaction-ID: 7008

complex/PPI

Insulin receptor

increases_phosphorylation of

gene/protein

SHC

at Tyr residues of SHC
Drugbank entries Show/Hide entries for SHC
Comment The activated insulin receptor can phosphorylate tyrosine residues on Src homology 2 containing protein (Shc) which then binds to the Son of sevenless (SOS)-growth factor receptor-bound protein 2 (Grb2) complex which then triggers the Ras-MAPK signaling cascade.
Formal Description
Interaction-ID: 7009

protein modification

SHC-phosTyr

affects_activity of

gene/protein

GRB2

Drugbank entries Show/Hide entries for GRB2
Comment The activated insulin receptor can phosphorylate tyrosine residues on Src homology 2 containing protein (Shc) which then binds to the Son of sevenless (SOS)-growth factor receptor-bound protein 2 (Grb2) complex which then triggers the Ras-MAPK signaling cascade.
Formal Description
Interaction-ID: 7011

complex/PPI

SHC-GRB2 complex

increases_activity of

Comment An additional mediator of insulin action is the heterotrimeric G protein, G-alpha-q/11. Phosphorylation of G-alpha-q/11 by the insulin receptor activates PI3K, thus, stimulating GLUT4-mediated glucose uptake. This signaling pathway is inhibited by G-protein-coupled receptor kinase-2 (Grk2) which binds and inhibits the G-alpha subunit of G-alpha-q/11.
Formal Description
Interaction-ID: 7013

complex/PPI

Insulin receptor

increases_phosphorylation of

complex/PPI

G-alpha-q/11 complex

Comment An additional mediator of insulin action is the heterotrimeric G protein, G-alpha-q/11. Phosphorylation of G-alpha-q/11 by the insulin receptor activates PI3K, thus, stimulating GLUT4-mediated glucose uptake. This signaling pathway is inhibited by G-protein-coupled receptor kinase-2 (Grk2) which binds and inhibits the G-alpha subunit of G-alpha-q/11.
Formal Description
Interaction-ID: 7041

complex/PPI

Insulin receptor

increases_activity of

complex/PPI

G-alpha-q/11 complex

via phosphorylation
Comment An additional mediator of insulin action is the heterotrimeric G protein, G-alpha-q/11. Phosphorylation of G-alpha-q/11 by the insulin receptor activates PI3K, thus, stimulating GLUT4-mediated glucose uptake. This signaling pathway is inhibited by G-protein-coupled receptor kinase-2 (Grk2) which binds and inhibits the G-alpha subunit of G-alpha-q/11.
Formal Description
Interaction-ID: 7042

complex/PPI

G-alpha-q/11 complex

increases_activity of

complex/PPI

Phosphatidylinositol 3-kinase

Comment An additional mediator of insulin action is the heterotrimeric G protein, G-alpha-q/11. Phosphorylation of G-alpha-q/11 by the insulin receptor activates PI3K, thus, stimulating GLUT4-mediated glucose uptake. This signaling pathway is inhibited by G-protein-coupled receptor kinase-2 (Grk2) which binds and inhibits the G-alpha subunit of G-alpha-q/11.
Formal Description
Interaction-ID: 7043

complex/PPI

Phosphatidylinositol 3-kinase

increases_activity of

process

glucose import

Comment An additional mediator of insulin action is the heterotrimeric G protein, G-alpha-q/11. Phosphorylation of G-alpha-q/11 by the insulin receptor activates PI3K, thus, stimulating GLUT4-mediated glucose uptake. This signaling pathway is inhibited by G-protein-coupled receptor kinase-2 (Grk2) which binds and inhibits the G-alpha subunit of G-alpha-q/11.
Formal Description
Interaction-ID: 7044

gene/protein

GRK2

decreases_activity of

complex/PPI

G-alpha-q/11 complex

Comment The proto-oncogene product, Cbl, is recruited to the insulin receptor by the adapter protein Cbl associated protein (CAP) and the CAP/Cbl complex can mediate cell surface translocation of GLUT4 independent of PI3K activity.
Formal Description
Interaction-ID: 7060

complex/PPI

Insulin receptor

increases_activity of

complex/PPI

CAP-CBL complex

Comment The proto-oncogene product, Cbl, is recruited to the insulin receptor by the adapter protein Cbl associated protein (CAP) and the CAP/Cbl complex can mediate cell surface translocation of GLUT4 independent of PI3K activity.
Formal Description
Interaction-ID: 7061

complex/PPI

CAP-CBL complex

increases_activity of

gene/protein

SLC2A4

via translocation of GLUT4 to the membrane
Comment The proto-oncogene product, Cbl, is recruited to the insulin receptor by the adapter protein Cbl associated protein (CAP) and the CAP/Cbl complex can mediate cell surface translocation of GLUT4 independent of PI3K activity.
Formal Description
Interaction-ID: 7062

complex/PPI

CAP-CBL complex

increases_activity of

process

glucose import

via translocation of GLUT4 to the membrane
Comment Elevated levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin resistant states.
Formal Description
Interaction-ID: 7063

cooccurs with

disease

Insulin resistance

Comment Elevated levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin resistant states.
Formal Description
Interaction-ID: 7064

cooccurs with

disease

Insulin resistance

Comment Elevated levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin resistant states.
Formal Description
Interaction-ID: 7065

phenotype

increased circulating interleukin-8 level

cooccurs with

disease

Insulin resistance

Comment The inflammatory marker C-reactive protein (CRP), a non-specific acute phase reactant, is commonly elevated in human insulin resistant states.
Formal Description
Interaction-ID: 7066

phenotype

increased circulating C-reactive protein level

cooccurs with

disease

Insulin resistance

Comment The inflammatory marker C-reactive protein (CRP), a non-specific acute phase reactant, is commonly elevated in human insulin resistant states.
Formal Description
Interaction-ID: 7067

increases_activity of

phenotype

increased circulating C-reactive protein level

Comment Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity.
Formal Description
Interaction-ID: 7068

gene/protein

RETN

affects_activity of

disease

Insulin resistance

Comment Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity.
Formal Description
Interaction-ID: 7069

gene/protein

RETN

affects_activity of

Comment Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity.
Formal Description
Interaction-ID: 7070

gene/protein

LEP

affects_activity of

disease

Insulin resistance

Comment Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity.
Formal Description
Interaction-ID: 7071

gene/protein

LEP

affects_activity of

Comment Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity.
Formal Description
Interaction-ID: 7072

gene/protein

ADIPOQ

affects_activity of

disease

Insulin resistance

Comment Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity.
Formal Description
Interaction-ID: 7073

gene/protein

ADIPOQ

affects_activity of

Comment Hepatic inflammation can occur in obesity whereby inflammatory pathway activation could be the result of steatosis and/or increased hepatocyte stress pathway responses. This can result in hepatocyte-autonomous inflammation. Kupffer cells (liver-resident macrophage-like cells) can also become activated, releasing locally acting cytokines which further exacerbates inflammation and hepatic insulin resistance.
Formal Description
Interaction-ID: 7075

disease

Obesity

increases_activity of

phenotype

liver inflammation

Comment Hepatic inflammation can occur in obesity whereby inflammatory pathway activation could be the result of steatosis and/or increased hepatocyte stress pathway responses. This can result in hepatocyte-autonomous inflammation. Kupffer cells (liver-resident macrophage-like cells) can also become activated, releasing locally acting cytokines which further exacerbates inflammation and hepatic insulin resistance.
Formal Description
Interaction-ID: 7076

disease

Obesity

increases_activity of

tissue/cell line

Kupffer cell

Comment Hepatic inflammation can occur in obesity whereby inflammatory pathway activation could be the result of steatosis and/or increased hepatocyte stress pathway responses. This can result in hepatocyte-autonomous inflammation. Kupffer cells (liver-resident macrophage-like cells) can also become activated, releasing locally acting cytokines which further exacerbates inflammation and hepatic insulin resistance.
Formal Description
Interaction-ID: 7077

tissue/cell line

Kupffer cell

is localized in

tissue/cell line

liver

Comment Hepatic inflammation can occur in obesity whereby inflammatory pathway activation could be the result of steatosis and/or increased hepatocyte stress pathway responses. This can result in hepatocyte-autonomous inflammation. Kupffer cells (liver-resident macrophage-like cells) can also become activated, releasing locally acting cytokines which further exacerbates inflammation and hepatic insulin resistance.
Formal Description
Interaction-ID: 7078

tissue/cell line

Kupffer cell

increases_activity of

Comment Hepatic inflammation can occur in obesity whereby inflammatory pathway activation could be the result of steatosis and/or increased hepatocyte stress pathway responses. This can result in hepatocyte-autonomous inflammation. Kupffer cells (liver-resident macrophage-like cells) can also become activated, releasing locally acting cytokines which further exacerbates inflammation and hepatic insulin resistance.
Formal Description
Interaction-ID: 7081

increases_activity of

disease

Insulin resistance

in liver
Comment Overnutrition and obesity are often accompanied by elevations in tissue and circulating FFA concentrations, and saturated FFAs can directly activate pro-inflammatory responses in vascular endothelial cells, adipocytes and myeloid-derived cells. The result of these obesity-induced physiologic events is the development of systemic inflammation.
Formal Description
Interaction-ID: 7082

disease

Obesity

increases_activity of

Comment Overnutrition and obesity are often accompanied by elevations in tissue and circulating FFA concentrations, and saturated FFAs can directly activate pro-inflammatory responses in vascular endothelial cells, adipocytes and myeloid-derived cells. The result of these obesity-induced physiologic events is the development of systemic inflammation.
Formal Description
Interaction-ID: 7083

increases_activity of

in vascular endothelial cells, in adipose tissue, in myeloid-derived cells
Comment Tnf (a.k.a. Tnf-alpha) is a pro-inflammatory cytokine secreted predominantly by monocytes and macrophages. Activation of the Tnf receptor results in stimulation of NF-kappa-B signaling via Ikkb.
Formal Description
Interaction-ID: 7084

gene/protein

TNF

increases_activity of

gene/protein

TNFRSF1A

Drugbank entries Show/Hide entries for TNF or TNFRSF1A
Comment Tnf (a.k.a. Tnf-alpha) is a pro-inflammatory cytokine secreted predominantly by monocytes and macrophages. Activation of the Tnf receptor results in stimulation of NF-kappa-B signaling via Ikkb.
Formal Description
Interaction-ID: 7085

gene/protein

TNFRSF1A

increases_activity of

gene/protein

IKBKB

Drugbank entries Show/Hide entries for TNFRSF1A or IKBKB
Comment Tnf (a.k.a. Tnf-alpha) is a pro-inflammatory cytokine secreted predominantly by monocytes and macrophages. Activation of the Tnf receptor results in stimulation of NF-kappa-B signaling via Ikkb.
Formal Description
Interaction-ID: 7086

gene/protein

IKBKB

increases_activity of

Drugbank entries Show/Hide entries for IKBKB
Comment By activating Ikkb, Tnf stimulation leads to serine phosphorylation of Irs1 which attenuates its ability to transduce insulin mediated cellular events.
Formal Description
Interaction-ID: 7087

gene/protein

IKBKB

increases_phosphorylation of

gene/protein

IRS1

at Ser residues of IRS1
Drugbank entries Show/Hide entries for IKBKB or IRS1
Comment By activating Ikkb, Tnf stimulation leads to serine phosphorylation of Irs1 which attenuates its ability to transduce insulin mediated cellular events.
Formal Description
Interaction-ID: 7088

gene/protein

IKBKB

decreases_activity of

gene/protein

IRS1

via phosphorylation at Ser residues of IRS1
Drugbank entries Show/Hide entries for IKBKB or IRS1
Comment Treatment of cultured 3T3-L1 adipocytes with Tnf leads to reduced expression of the insulin receptor, IRS1 and Glut4 genes, as well as a decrease in insulin stimulated glucose uptake.
Formal Description
Interaction-ID: 7089

gene/protein

TNF

decreases_expression of

gene/protein

INSR

in adipose tissue
Drugbank entries Show/Hide entries for TNF or INSR
Comment Treatment of cultured 3T3-L1 adipocytes with Tnf leads to reduced expression of the insulin receptor, IRS1 and Glut4 genes, as well as a decrease in insulin stimulated glucose uptake.
Formal Description
Interaction-ID: 7090

gene/protein

TNF

decreases_expression of

gene/protein

IRS1

in adipose tissue
Drugbank entries Show/Hide entries for TNF or IRS1
Comment Treatment of cultured 3T3-L1 adipocytes with Tnf leads to reduced expression of the insulin receptor, IRS1 and Glut4 genes, as well as a decrease in insulin stimulated glucose uptake.
Formal Description
Interaction-ID: 7091

gene/protein

TNF

decreases_expression of

gene/protein

SLC2A4

in adipose tissue
Drugbank entries Show/Hide entries for TNF
Comment Treatment of cultured 3T3-L1 adipocytes with Tnf leads to reduced expression of the insulin receptor, IRS1 and Glut4 genes, as well as a decrease in insulin stimulated glucose uptake.
Formal Description
Interaction-ID: 7092

gene/protein

TNF

decreases_activity of

process

glucose import

in adipose tissue
Drugbank entries Show/Hide entries for TNF
Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7093

gene/protein

TNF

decreases_expression of

gene/protein

LIPE

in adipose tissue
Drugbank entries Show/Hide entries for TNF
Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7095

gene/protein

TNF

decreases_expression of

gene/protein

ACSL

in adipose tissue
Drugbank entries Show/Hide entries for TNF
Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7096

gene/protein

TNF

decreases_expression of

gene/protein

ADIPOQ

in adipose tissue
Drugbank entries Show/Hide entries for TNF
Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7097

gene/protein

TNF

decreases_expression of

gene/protein

CEBP

in adipose tissue
Drugbank entries Show/Hide entries for TNF
Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7098

gene/protein

TNF

decreases_expression of

gene/protein

PPARG

in adipose tissue
Drugbank entries Show/Hide entries for TNF or PPARG
Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7099

gene/protein

TNF

decreases_expression of

gene/protein

RXR

in adipose tissue
Drugbank entries Show/Hide entries for TNF
Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7100

gene/protein

SLC2A4

affects_activity of

Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7101

gene/protein

LIPE

affects_activity of

Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7102

gene/protein

ACSL

affects_activity of

Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7103

gene/protein

ADIPOQ

affects_activity of

Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7104

gene/protein

CEBP

affects_activity of

Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7105

gene/protein

PPARG

affects_activity of

Drugbank entries Show/Hide entries for PPARG
Comment A Tnf-induced decrease in 3T3-L1 adipocyte genes has been found, including GLUT4, Hormone Sensitive Lipase (HSL), long-chain fatty acyl CoA synthetase, adiponectin (ADIPOQ), the transcription factor CCAAT/enhancer binding protein-alpha (C/EBP), and the nuclear receptors Pparg and retinoic acid x receptor (RXR). These genes all contribute to glucose homeostasis, both directly and indirectly.
Formal Description
Interaction-ID: 7106

gene/protein

RXR

affects_activity of

Comment Jnk1 (encoded by Mapk8) contributes to the development of insulin resistance in obese and diabetic states.
Formal Description
Interaction-ID: 7188

gene/protein

MAPK8

affects_activity of

disease

Insulin resistance

Drugbank entries Show/Hide entries for MAPK8
Comment Jnk1 knockout led to decreased IRS1 phospho-Ser307 in liver.
Formal Description
Interaction-ID: 7189

gene/protein

MAPK8

affects_phosphorylation of

gene/protein

IRS1

in liver; at Ser307 of IRS1
Drugbank entries Show/Hide entries for MAPK8 or IRS1
Comment The anti-inflammatory compounds, salicylate and its derivative aspirin,inhibit the activity of Ikkb, thus preventing Irs1 serine307 phosphorylation and this presumably accounts for their insulin-sensitizing effects.
Formal Description
Interaction-ID: 7190

drug/chemical compound

Sodium salicylate

decreases_activity of

gene/protein

IKBKB

Drugbank entries Show/Hide entries for IKBKB
Comment The anti-inflammatory compounds, salicylate and its derivative aspirin,inhibit the activity of Ikkb, thus preventing Irs1 serine307 phosphorylation and this presumably accounts for their insulin-sensitizing effects.
Formal Description
Interaction-ID: 7193

drug/chemical compound

Aspirin

decreases_activity of

gene/protein

IKBKB

Drugbank entries Show/Hide entries for IKBKB
Comment The anti-inflammatory compounds, salicylate and its derivative aspirin,inhibit the activity of Ikkb, thus preventing Irs1 serine307 phosphorylation and this presumably accounts for their insulin-sensitizing effects.
Formal Description
Interaction-ID: 7195

drug/chemical compound

Sodium salicylate

decreases_activity of

disease

Insulin resistance

Comment The anti-inflammatory compounds, salicylate and its derivative aspirin,inhibit the activity of Ikkb, thus preventing Irs1 serine307 phosphorylation and this presumably accounts for their insulin-sensitizing effects.
Formal Description
Interaction-ID: 7196

drug/chemical compound

Aspirin

decreases_activity of

disease

Insulin resistance

Comment Nitric oxide (NO) is an endogenous signaling molecule produced by nitric oxide synthase. NO acts as a signal transduction molecule for a number of physiological processes and is involved in many pathophysiologic states, including insulin resistance.
Formal Description
Interaction-ID: 7226

drug/chemical compound

NO

affects_activity of

disease

Insulin resistance

Comment Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes inducible nitric oxide synthase (iNOS).
Formal Description
Interaction-ID: 7229

increases_activity of

disease

Insulin resistance

Comment Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes inducible nitric oxide synthase (iNOS).
Formal Description
Interaction-ID: 7230

gene/protein

Proinflammatory cytokine

increases_activity of

disease

Insulin resistance

Comment Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes inducible nitric oxide synthase (iNOS).
Formal Description
Interaction-ID: 7238

increases_activity of

disease

Insulin resistance

Comment Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes inducible nitric oxide synthase (iNOS).
Formal Description
Interaction-ID: 7239

increases_expression of

gene/protein

NOS2

Drugbank entries Show/Hide entries for NOS2
Comment Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes inducible nitric oxide synthase (iNOS).
Formal Description
Interaction-ID: 7240

gene/protein

Proinflammatory cytokine

increases_expression of

gene/protein

NOS2

Drugbank entries Show/Hide entries for NOS2
Comment Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes inducible nitric oxide synthase (iNOS).
Formal Description
Interaction-ID: 7241

increases_expression of

gene/protein

NOS2

Drugbank entries Show/Hide entries for NOS2
Comment In the insulin signaling pathway, NO can reduce Akt activity by causing s-nitrosylation of a specific cysteine residue.
Formal Description
Interaction-ID: 7242

drug/chemical compound

NO

decreases_activity of

gene/protein

AKT1

Drugbank entries Show/Hide entries for AKT1
Comment Increased iNOS activity also results in the degradation of Irs1 in cultured skeletal muscle cells.
Formal Description
Interaction-ID: 7244

gene/protein

NOS2

decreases_quantity of

gene/protein

IRS1

via increased degradation of IRS1 if NPS2 activity is increased
Drugbank entries Show/Hide entries for NOS2 or IRS1
Comment Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes. Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NF-kappa-B activation by reducing IKK activity.
Formal Description
Interaction-ID: 7245

gene/protein

IL10

decreases_activity of

Comment Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes. Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NF-kappa-B activation by reducing IKK activity.
Formal Description
Interaction-ID: 7272

gene/protein

TNF

increases_activity of

Drugbank entries Show/Hide entries for TNF
Comment Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes. Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NF-kappa-B activation by reducing IKK activity.
Formal Description
Interaction-ID: 7273

increases_activity of

complex/PPI

NF-kappaB complex

Comment Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes. Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NF-kappa-B activation by reducing IKK activity.
Formal Description
Interaction-ID: 7274

complex/PPI

NF-kappaB complex

increases_activity of

Comment Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes. Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NF-kappa-B activation by reducing IKK activity.
Formal Description
Interaction-ID: 7276

gene/protein

IL10

decreases_activity of

Comment In human studies, it has been shown that there is a greater incidence of insulin resistance in subjects with reduced serum levels of IL-10.
Formal Description
Interaction-ID: 7277

increases_activity of

disease

Insulin resistance

Comment A major conceptual advance in the field of obesity-induced inflammation and insulin resistance was made by the discovery of bone marrow-derived macrophages in adipose tissue of obese mice and humans.
Formal Description
Interaction-ID: 7278

disease

Obesity

increases_quantity of

tissue/cell line

macrophage

in adipose tissue
Comment Adipose tissue macrophages are responsible for nearly all adipose tissue Tnf expression and a significant portion of Nos2 and Il6 expression.
Formal Description
Interaction-ID: 7281

tissue/cell line

adipose tissue macrophage

increases_quantity of

gene/protein

TNF

in adipose tissue
Drugbank entries Show/Hide entries for TNF
Comment Inactivation of myeloid-Ikkb activity prevents systemic insulin resistance, most likely by interrupting local paracrine effects between resident macrophages and insulin target tissues.
Formal Description
Interaction-ID: 7288

gene/protein

IKBKB

affects_activity of

disease

Insulin resistance

Drugbank entries Show/Hide entries for IKBKB
Comment Newly recruited adipose tissue macrophages are pro-inflammatory, as indicated by increased expression of Il6, Nos2 and Ccr2, while resident adipose tissue macrophages are antiinflammatory.
Formal Description
Interaction-ID: 7291

tissue/cell line

recruited adipose tissue macrophage

increases_activity of

in adipose tissue
Comment Macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the 'classically activated' pro-inflammatory macrophage, to the M2 state or the 'alternatively activated' non-inflammatory cell. The M2 classification involves cells that express arginase and the anti-inflammatory cytokine Il-10 and have a high capacity to repair damaged tissue. M1 cells express inflammatory cytokines and the cell surface marker Cd11c. Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance.
Formal Description
Interaction-ID: 7302

tissue/cell line

M1 macrophage

increases_activity of

Comment Cbl-associated protein (CAP), known as a positive regulator of glucose transport into cells, plays a role in obesity-related inflammation due to its function in maintaining normal macrophage activity.
Formal Description
Interaction-ID: 7303

gene/protein

SORBS1

increases_activity of

process

glucose import

Comment Cbl-associated protein (CAP), known as a positive regulator of glucose transport into cells, plays a role in obesity-related inflammation due to its function in maintaining normal macrophage activity.
Formal Description
Interaction-ID: 7304

gene/protein

SORBS1

increases_activity of

if inflammatory response is obesity-related
Comment Sorbs1 -/- mice show reduced activity of both Ikkb and Jnk, decreased Mcp1 protein levels, reduced macrophage infiltration and lower white blood cell counts.
Formal Description
Interaction-ID: 7307

gene/protein

SORBS1

affects_activity of

gene/protein

IKBKB

Drugbank entries Show/Hide entries for IKBKB
Comment Sorbs1 -/- mice show reduced activity of both Ikkb and Jnk, decreased Mcp1 protein levels, reduced macrophage infiltration and lower white blood cell counts.
Formal Description
Interaction-ID: 7309

gene/protein

SORBS1

affects_activity of

gene/protein

MAPK8

Drugbank entries Show/Hide entries for MAPK8
Comment Sorbs1 -/- mice show reduced activity of both Ikkb and Jnk, decreased Mcp1 protein levels, reduced macrophage infiltration and lower white blood cell counts.
Formal Description
Interaction-ID: 7311

gene/protein

SORBS1

affects_quantity of

gene/protein

CCL2

Drugbank entries Show/Hide entries for CCL2
Comment Pparg is a nuclear receptor required for adipogenesis. It is also the target for the insulin-sensitizing TZD class of drugs, which promote adipogenesis and cause systemic insulin sensitivity.
Formal Description
Interaction-ID: 7312

gene/protein

PPARG

affects_activity of

Drugbank entries Show/Hide entries for PPARG
Comment Pparg is a nuclear receptor required for adipogenesis. It is also the target for the insulin-sensitizing TZD class of drugs, which promote adipogenesis and cause systemic insulin sensitivity.
Formal Description
Interaction-ID: 7314

drug/chemical compound

Thiazolidinedione

increases_activity of

Comment Pparg is a nuclear receptor required for adipogenesis. It is also the target for the insulin-sensitizing TZD class of drugs, which promote adipogenesis and cause systemic insulin sensitivity.
Formal Description
Interaction-ID: 7315

drug/chemical compound

Thiazolidinedione

decreases_activity of

disease

Insulin resistance

Comment Pparg is a nuclear receptor required for adipogenesis. It is also the target for the insulin-sensitizing TZD class of drugs, which promote adipogenesis and cause systemic insulin sensitivity.
Formal Description
Interaction-ID: 7316

drug/chemical compound

Thiazolidinedione

affects_activity of

gene/protein

PPARG

Drugbank entries Show/Hide entries for PPARG
Comment In addition to adipocytes, Pparg is also expressed in macrophages where it negatively regulates a large set of inflammatory pathway genes by a unique transrepression mechanism.
Formal Description
Interaction-ID: 7317

gene/protein

PPARG

decreases_activity of

in macrophages
Drugbank entries Show/Hide entries for PPARG
Comment Jnk1 signaling in macrophages is a key component of macrophage function and a mediator of the macrophage inflammatory response which ultimately leads to insulin resistance.
Formal Description
Interaction-ID: 7319

gene/protein

MAPK8

affects_activity of

in macrophages
Drugbank entries Show/Hide entries for MAPK8
Comment Jnk1 also plays an important role in non-hematopoietic cells in the development of obesity and the associated insulin resistance.
Formal Description
Interaction-ID: 7321

gene/protein

MAPK8

affects_activity of

disease

Obesity

Drugbank entries Show/Hide entries for MAPK8
Comment Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system. Tlr4 is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria. Tlr4 stimulation results in the activation of both Ikkb/NF-kappa-B and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1.
Formal Description
Interaction-ID: 7322

drug/chemical compound

Lipopolysaccharide

increases_activity of

gene/protein

TLR4

Drugbank entries Show/Hide entries for TLR4
Comment Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system. Tlr4 is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria. Tlr4 stimulation results in the activation of both Ikkb/NF-kappa-B and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1.
Formal Description
Interaction-ID: 7323

gene/protein

TLR4

increases_activity of

Drugbank entries Show/Hide entries for TLR4
Comment Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system. Tlr4 is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria. Tlr4 stimulation results in the activation of both Ikkb/NF-kappa-B and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1.
Formal Description
Interaction-ID: 7324

gene/protein

TLR4

increases_activity of

process

JNK cascade

Drugbank entries Show/Hide entries for TLR4
Comment Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system. Tlr4 is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria. Tlr4 stimulation results in the activation of both Ikkb/NF-kappa-B and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1.
Formal Description
Interaction-ID: 7325

gene/protein

TLR4

increases_expression of

gene/protein

IL1B

Drugbank entries Show/Hide entries for TLR4 or IL1B
Comment Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system. Tlr4 is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria. Tlr4 stimulation results in the activation of both Ikkb/NF-kappa-B and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1.
Formal Description
Interaction-ID: 7326

gene/protein

TLR4

increases_expression of

gene/protein

IL6

Drugbank entries Show/Hide entries for TLR4 or IL6
Comment Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system. Tlr4 is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria. Tlr4 stimulation results in the activation of both Ikkb/NF-kappa-B and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1.
Formal Description
Interaction-ID: 7327

gene/protein

TLR4

increases_expression of

gene/protein

TNF

Drugbank entries Show/Hide entries for TLR4 or TNF
Comment Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system. Tlr4 is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria. Tlr4 stimulation results in the activation of both Ikkb/NF-kappa-B and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1.
Formal Description
Interaction-ID: 7329

gene/protein

TLR4

increases_expression of

gene/protein

CCL2

Drugbank entries Show/Hide entries for TLR4 or CCL2
Comment FFA activate the NF-kappa-B signaling pathway in primary macrophages from wildtype mice but not in macrophages derived from Tlr4 deficient (Tlr4-/-) mice.
Formal Description
Interaction-ID: 7347

drug/chemical compound

Fatty acid

increases_activity of

in wild-type mice
Comment FFA activate the NF-kappa-B signaling pathway in primary macrophages from wildtype mice but not in macrophages derived from Tlr4 deficient (Tlr4-/-) mice.
Formal Description
Interaction-ID: 7352

drug/chemical compound

Fatty acid

NOT increases_activity of

in TLR4-/- mice
Comment Obese mice have increased Tlr4 expression in adipose tissue compared to lean controls.
Formal Description
Interaction-ID: 7353

disease

Obesity

increases_expression of

gene/protein

TLR4

in adipose tissue
Drugbank entries Show/Hide entries for TLR4
Comment The induction of ER stress induces insulin resistance via JNK-mediated serine phosphorylation of IRS1 in cultured liver cells.
Formal Description
Interaction-ID: 7354

increases_activity of

disease

Insulin resistance

via JNK-mediated Ser phosphorylation of IRS1
Comment The induction of ER stress induces insulin resistance via JNK-mediated serine phosphorylation of IRS1 in cultured liver cells.
Formal Description
Interaction-ID: 7356

increases_activity of

gene/protein

MAPK8

Drugbank entries Show/Hide entries for MAPK8
Comment Newly recruited adipose tissue macrophages are pro-inflammatory, as indicated by increased expression of Il6, Nos2 and Ccr2, while resident adipose tissue macrophages are antiinflammatory.
Formal Description
Interaction-ID: 13444

tissue/cell line

resident adipose tissue macrophage

decreases_activity of

in adipose tissue
Comment In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter to the plasma membrane, and impaired skeletal muscle insulin signaling results in decreased glucose disposal.
Formal Description
Interaction-ID: 16691

disease

Insulin resistance

decreases_activity of

complex/PPI

Insulin

in skeletal muscle
Comment Adipose tissue macrophages are responsible for nearly all adipose tissue Tnf expression and a significant portion of Nos2 and Il6 expression.
Formal Description
Interaction-ID: 45977

tissue/cell line

adipose tissue macrophage

increases_quantity of

gene/protein

NOS2

in adipose tissue
Drugbank entries Show/Hide entries for NOS2
Comment Adipose tissue macrophages are responsible for nearly all adipose tissue Tnf expression and a significant portion of Nos2 and Il6 expression.
Formal Description
Interaction-ID: 45978

tissue/cell line

adipose tissue macrophage

increases_quantity of

gene/protein

IL6

in adipose tissue
Drugbank entries Show/Hide entries for IL6
Comment Macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the 'classically activated' pro-inflammatory macrophage, to the M2 state or the 'alternatively activated' non-inflammatory cell. The M2 classification involves cells that express arginase and the anti-inflammatory cytokine Il-10 and have a high capacity to repair damaged tissue. M1 cells express inflammatory cytokines and the cell surface marker Cd11c. Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance.
Formal Description
Interaction-ID: 45979

tissue/cell line

M2 macrophage

NOT increases_activity of

Comment Macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the 'classically activated' pro-inflammatory macrophage, to the M2 state or the 'alternatively activated' non-inflammatory cell. The M2 classification involves cells that express arginase and the anti-inflammatory cytokine Il-10 and have a high capacity to repair damaged tissue. M1 cells express inflammatory cytokines and the cell surface marker Cd11c. Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance.
Formal Description
Interaction-ID: 45980

gene/protein

IL10

is_expressed_in

tissue/cell line

M2 macrophage

Comment Macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the 'classically activated' pro-inflammatory macrophage, to the M2 state or the 'alternatively activated' non-inflammatory cell. The M2 classification involves cells that express arginase and the anti-inflammatory cytokine Il-10 and have a high capacity to repair damaged tissue. M1 cells express inflammatory cytokines and the cell surface marker Cd11c. Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance.
Formal Description
Interaction-ID: 45981

gene/protein

ITGAX

is_expressed_in

tissue/cell line

M1 macrophage

Comment Macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the 'classically activated' pro-inflammatory macrophage, to the M2 state or the 'alternatively activated' non-inflammatory cell. The M2 classification involves cells that express arginase and the anti-inflammatory cytokine Il-10 and have a high capacity to repair damaged tissue. M1 cells express inflammatory cytokines and the cell surface marker Cd11c. Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance.
Formal Description
Interaction-ID: 45982

disease

Obesity

increases_quantity of

tissue/cell line

M1 macrophage

in adipose tissue
Comment Macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the 'classically activated' pro-inflammatory macrophage, to the M2 state or the 'alternatively activated' non-inflammatory cell. The M2 classification involves cells that express arginase and the anti-inflammatory cytokine Il-10 and have a high capacity to repair damaged tissue. M1 cells express inflammatory cytokines and the cell surface marker Cd11c. Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance.
Formal Description
Interaction-ID: 45983

tissue/cell line

M1 macrophage

increases_activity of

disease

Insulin resistance

Comment Macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the 'classically activated' pro-inflammatory macrophage, to the M2 state or the 'alternatively activated' non-inflammatory cell. The M2 classification involves cells that express arginase and the anti-inflammatory cytokine Il-10 and have a high capacity to repair damaged tissue. M1 cells express inflammatory cytokines and the cell surface marker Cd11c. Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance.
Formal Description
Interaction-ID: 45984

tissue/cell line

M1 macrophage

increases_activity of

Comment Macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the 'classically activated' pro-inflammatory macrophage, to the M2 state or the 'alternatively activated' non-inflammatory cell. The M2 classification involves cells that express arginase and the anti-inflammatory cytokine Il-10 and have a high capacity to repair damaged tissue. M1 cells express inflammatory cytokines and the cell surface marker Cd11c. Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance.
Formal Description
Interaction-ID: 45985

tissue/cell line

M1 macrophage

increases_activity of