Role of Adiponectin in regulation of metabolism
Absract:
Adiponectin, an adipokine secreted by the white adipose tissue, plays an important role in regulating glucose and lipid metabolism and controlling energy homeostasis in insulin-sensitive tissues.
Details:
Adiponectin, an adipokine secreted by the white adipose tissue, plays an important role in regulating glucose and lipid metabolism and controlling energy homeostasis in insulin-sensitive tissues [1].
Adiponectin binding to AdipoR1 and AdipoR2 activates APPL [1], [2]. APPL binds to and activates LKB1 and promotes LKB1 binding to AMPK alpha subunit [3], [4]. Adiponectin-induced AMPK alpha subunit probably activates p38alpha (MAPK14) signaling [5], result in stimulation of PPARGC1 (PGC1-alpha) and PPAR-alpha [6], [7], [8]. PPARGC1 (PGC1-alpha) activation requires deacetylation by Sirtuin1 [8]. PPARGC1 (PGC1-alpha) probably promotes transcription of genes, involved in mitochondrial biogenesis, inhibition of reactive oxygen species production and fatty acid beta-oxidation: TFAM, SOD2, ACADM [8]. Adiponectin-activated PPAR-alpha forms complex PPAR-alpha/RXR-alpha [9]. PPAR-alpha/RXR-alpha promotes transcription of genes, involved in fatty acid beta-oxidation and fatty acid transport: CPT-1A and CPT-1B, ACOX1 and H-FABP [5], [7].
Adiponectin-induced AMPK alpha subunit inhibits ACACA-dependent production of Malonyl-CoA [5]. Reduction in levels of Malonyl-CoA results in attenuation of Malonyl-CoA-induced inhibition of CPT-1A and CPT-1B [7], leading to stimulation of fatty acid beta-oxidation.
Adiponectin inhibits SREBP1 precursor in a LKB1/ AMPK alpha subunit-dependent manner, results in negative regulation of lipid biosynthetic process [10].
Adiponectin stimulate activation of Insulin processed signaling cascade. Adiponectin-stimulated APPL binds to PI3K cat class IA (p110-alpha) and AKT2 [11], and thereby increases Insulin processed-induced AKT2 activation and GLUT4 translocation [1], [12]. Also, Adiponectin-induced AMPK alpha subunit phosphorylates Tuberin. Activated Tuberin together with Hamartin inhibit RHEB2/ Raptor/ mTOR signaling cascade, result in inhibition of p70 S6 kinase1. Inhibition of p70 S6 kinase1 leads to reduced phosphorylation of IRS-1 [3]. Thus Adiponectin augments Insulin processed signaling through Insulin receptor and IRS-1.
Adiponectin-induced APPL binds to and activate Rab-5A, result in increase in GLUT4 translocation [12].
Adiponectin-activated AMPK alpha subunit phosphorylates and inhibits TORC2 [13]. Suppression of TORC2 leads to reduced expression of CREB1, G6PT and PPCKC, resulting in inhibition of glucose metabolic process [14], [15], [16].
Objects list:
ACACA | Acetyl-CoA carboxylase 1 |
ACADM | Medium-chain specific acyl-CoA dehydrogenase, mitochondrial |
ACOX1 | Peroxisomal acyl-coenzyme A oxidase 1 |
AKT2 | RAC-beta serine/threonine-protein kinase |
AMPK alpha subunit | AMP-activated protein kinase alpha subunits Protein group |
APPL | DCC-interacting protein 13-alpha |
AdipoR1 | Adiponectin receptor protein 1 |
AdipoR2 | Adiponectin receptor protein 2 |
Adiponectin | Adiponectin |
CPT-1A | Carnitine O-palmitoyltransferase 1, liver isoform |
CPT-1B | Carnitine O-palmitoyltransferase 1, muscle isoform |
CREB1 | Cyclic AMP-responsive element-binding protein 1 |
G6PT | Glucose-6-phosphatase |
GLUT4 | Solute carrier family 2, facilitated glucose transporter member 4 |
H-FABP | Fatty acid-binding protein, heart |
Hamartin | Hamartin |
IRS-1 | Insulin receptor substrate 1 |
Insulin processed | Insulin processed |
Insulin receptor | Insulin receptor |
LKB1 | Serine/threonine-protein kinase 11 |
Malonyl-CoA | Chemical IUPAC name 3-[2-[3-[[4-[[[(2R,3S,4R, 5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonooxyoxolan-2-yl]methoxy- hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-2-hydroxy-3, 3-dimethylbutanoyl]amino]propanoylamino]ethylsulfanyl]-3-oxopropanoic acid |
PI3K cat class IA (p110-alpha) | Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform |
PPAR-alpha | Peroxisome proliferator-activated receptor alpha |
PPAR-alpha/RXR-alpha | PPAR-alpha/RXR-alpha Complex |
PPARGC1 (PGC1-alpha) | Peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
PPCKC | Phosphoenolpyruvate carboxykinase, cytosolic [GTP] |
RHEB2 | GTP-binding protein Rheb |
Rab-5A | Ras-related protein Rab-5A |
Raptor | Regulatory-associated protein of mTOR |
SOD2 | Superoxide dismutase [Mn], mitochondrial |
SREBP1 precursor | Sterol regulatory element-binding protein 1 |
Sirtuin1 | NAD-dependent deacetylase sirtuin-1 |
TFAM | Transcription factor A, mitochondrial |
TORC2 | CREB-regulated transcription coactivator 2 |
Tuberin | Tuberin |
mTOR | Serine/threonine-protein kinase mTOR |
p38alpha (MAPK14) | Mitogen-activated protein kinase 14 |
p70 S6 kinase1 | Ribosomal protein S6 kinase beta-1 |
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