Regulation of metabolism - Role of Adiponectin in regulation of metabolism

print

Select Species:

Click on a target from the pathway image to view related information. Zoom     View Legend

photo_map
 


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

References:

  1. Deepa SS, Dong LQ
    APPL1: role in adiponectin signaling and beyond. American journal of physiology. Endocrinology and metabolism 2009 Jan;296(1):E22-36
  2. Hosch SE, Olefsky JM, Kim JJ
    APPLied mechanics: uncovering how adiponectin modulates insulin action. Cell metabolism 2006 Jul;4(1):5-6
  3. Wang C, Mao X, Wang L, Liu M, Wetzel MD, Guan KL, Dong LQ, Liu F
    Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1. The Journal of biological chemistry 2007 Mar 16;282(11):7991-6
  4. Zhou L, Deepa SS, Etzler JC, Ryu J, Mao X, Fang Q, Liu DD, Torres JM, Jia W, Lechleiter JD, Liu F, Dong LQ
    Adiponectin activates AMP-activated protein kinase in muscle cells via APPL1/LKB1-dependent and phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinase-dependent pathways. The Journal of biological chemistry 2009 Aug 14;284(33):22426-35
  5. Yoon MJ, Lee GY, Chung JJ, Ahn YH, Hong SH, Kim JB
    Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes 2006 Sep;55(9):2562-70
  6. Barger PM, Browning AC, Garner AN, Kelly DP
    p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response. The Journal of biological chemistry 2001 Nov 30;276(48):44495-501
  7. Li L, Wu L, Wang C, Liu L, Zhao Y
    Adiponectin modulates carnitine palmitoyltransferase-1 through AMPK signaling cascade in rat cardiomyocytes. Regulatory peptides 2007 Mar 1;139(1-3):72-9
  8. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M, Ogata H, Kubota N, Takamoto I, Hayashi YK, Yamauchi N, Waki H, Fukayama M, Nishino I, Tokuyama K, Ueki K, Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K, Kadowaki T
    Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 2010 Apr 29;464(7293):1313-9
  9. Larter CZ, Farrell GC
    Insulin resistance, adiponectin, cytokines in NASH: Which is the best target to treat? Journal of hepatology 2006 Feb;44(2):253-61
  10. Awazawa M, Ueki K, Inabe K, Yamauchi T, Kaneko K, Okazaki Y, Bardeesy N, Ohnishi S, Nagai R, Kadowaki T
    Adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway. Biochemical and biophysical research communications 2009 Apr 24;382(1):51-6
  11. Mitsuuchi Y, Johnson SW, Sonoda G, Tanno S, Golemis EA, Testa JR
    Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2. Oncogene 1999 Sep 2;18(35):4891-8
  12. Mao X, Kikani CK, Riojas RA, Langlais P, Wang L, Ramos FJ, Fang Q, Christ-Roberts CY, Hong JY, Kim RY, Liu F, Dong LQ
    APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nature cell biology 2006 May;8(5):516-23
  13. Qi L, Saberi M, Zmuda E, Wang Y, Altarejos J, Zhang X, Dentin R, Hedrick S, Bandyopadhyay G, Hai T, Olefsky J, Montminy M
    Adipocyte CREB promotes insulin resistance in obesity. Cell metabolism 2009 Mar;9(3):277-86
  14. Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L
    Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. The Journal of clinical investigation 2001 Dec;108(12):1875-81
  15. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K
    Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. The Journal of clinical investigation 2006 Jul;116(7):1784-92
  16. Yano W, Kubota N, Itoh S, Kubota T, Awazawa M, Moroi M, Sugi K, Takamoto I, Ogata H, Tokuyama K, Noda T, Terauchi Y, Ueki K, Kadowaki T
    Molecular mechanism of moderate insulin resistance in adiponectin-knockout mice. Endocrine journal 2008 Jul;55(3):515-22

  1. Deepa SS, Dong LQ
    APPL1: role in adiponectin signaling and beyond. American journal of physiology. Endocrinology and metabolism 2009 Jan;296(1):E22-36
  2. Hosch SE, Olefsky JM, Kim JJ
    APPLied mechanics: uncovering how adiponectin modulates insulin action. Cell metabolism 2006 Jul;4(1):5-6
  3. Wang C, Mao X, Wang L, Liu M, Wetzel MD, Guan KL, Dong LQ, Liu F
    Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1. The Journal of biological chemistry 2007 Mar 16;282(11):7991-6
  4. Zhou L, Deepa SS, Etzler JC, Ryu J, Mao X, Fang Q, Liu DD, Torres JM, Jia W, Lechleiter JD, Liu F, Dong LQ
    Adiponectin activates AMP-activated protein kinase in muscle cells via APPL1/LKB1-dependent and phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinase-dependent pathways. The Journal of biological chemistry 2009 Aug 14;284(33):22426-35
  5. Yoon MJ, Lee GY, Chung JJ, Ahn YH, Hong SH, Kim JB
    Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes 2006 Sep;55(9):2562-70
  6. Barger PM, Browning AC, Garner AN, Kelly DP
    p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response. The Journal of biological chemistry 2001 Nov 30;276(48):44495-501
  7. Li L, Wu L, Wang C, Liu L, Zhao Y
    Adiponectin modulates carnitine palmitoyltransferase-1 through AMPK signaling cascade in rat cardiomyocytes. Regulatory peptides 2007 Mar 1;139(1-3):72-9
  8. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M, Ogata H, Kubota N, Takamoto I, Hayashi YK, Yamauchi N, Waki H, Fukayama M, Nishino I, Tokuyama K, Ueki K, Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K, Kadowaki T
    Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 2010 Apr 29;464(7293):1313-9
  9. Larter CZ, Farrell GC
    Insulin resistance, adiponectin, cytokines in NASH: Which is the best target to treat? Journal of hepatology 2006 Feb;44(2):253-61
  10. Awazawa M, Ueki K, Inabe K, Yamauchi T, Kaneko K, Okazaki Y, Bardeesy N, Ohnishi S, Nagai R, Kadowaki T
    Adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway. Biochemical and biophysical research communications 2009 Apr 24;382(1):51-6
  11. Mitsuuchi Y, Johnson SW, Sonoda G, Tanno S, Golemis EA, Testa JR
    Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2. Oncogene 1999 Sep 2;18(35):4891-8
  12. Mao X, Kikani CK, Riojas RA, Langlais P, Wang L, Ramos FJ, Fang Q, Christ-Roberts CY, Hong JY, Kim RY, Liu F, Dong LQ
    APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nature cell biology 2006 May;8(5):516-23
  13. Qi L, Saberi M, Zmuda E, Wang Y, Altarejos J, Zhang X, Dentin R, Hedrick S, Bandyopadhyay G, Hai T, Olefsky J, Montminy M
    Adipocyte CREB promotes insulin resistance in obesity. Cell metabolism 2009 Mar;9(3):277-86
  14. Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L
    Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. The Journal of clinical investigation 2001 Dec;108(12):1875-81
  15. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K
    Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. The Journal of clinical investigation 2006 Jul;116(7):1784-92
  16. Yano W, Kubota N, Itoh S, Kubota T, Awazawa M, Moroi M, Sugi K, Takamoto I, Ogata H, Tokuyama K, Noda T, Terauchi Y, Ueki K, Kadowaki T
    Molecular mechanism of moderate insulin resistance in adiponectin-knockout mice. Endocrine journal 2008 Jul;55(3):515-22

Target Details

Click on a target from the pathway image to view related information.