ENTRY ko04920 Pathway NAME Adipocytokine signaling pathway DESCRIPTION Increased adipocyte volume and number are positively correlated with leptin production, and negatively correlated with production of adiponectin. Leptin is an important regulator of energy intake and metabolic rate primarily by acting at hypothalamic nuclei. Leptin exerts its anorectic effects by modulating the levels of neuropeptides such as NPY, AGRP, and alpha-MSH. This leptin action is through the JAK kinase, STAT3 phosphorylation, and nuclear transcriptional effect. Adiponectin lowers plasma glucose and FFAs. These effects are partly accounted for by adiponectin-induced AMPK activation, which in turn stimulates skeletal muscle fatty acid oxidation and glucose uptake. Furthermore, activation of AMPK by adiponectin suppresses endogenous glucose production, concomitantly with inhibition of PEPCK and G6Pase expression. The proinflammatory cytokine TNFalpha has been implicated as a link between obesity and insulin resistance. TNFalpha interferes with early steps of insulin signaling. Several data have shown that TNFalpha inhibits IRS1 tyrosine phosphorylation by promoting its serine phosphorylation. Among the serine/threonine kinases activated by TNFalpha, JNK, mTOR and IKK have been shown to be involved in this phosphorylation. CLASS Organismal Systems; Endocrine system PATHWAY_MAP ko04920 Adipocytokine signaling pathway ORTHOLOGY K01084 G6PC; glucose-6-phosphatase [EC:3.1.3.9] K01596 E4.1.1.32, pckA, PCK; phosphoenolpyruvate carboxykinase (GTP) [EC:4.1.1.32] K01897 ACSL, fadD; long-chain-fatty-acid---CoA ligase [EC:6.2.1.3] K01946 ACACB; acetyl-CoA carboxylase / biotin carboxylase 2 [EC:6.4.1.2 6.3.4.14 2.1.3.15] K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit K02581 NFKBIB; NF-kappa-B inhibitor beta K03156 TNF, TNFA; tumor necrosis factor superfamily, member 2 K03158 TNFRSF1A, TNFR1, CD120a; tumor necrosis factor receptor superfamily member 1A K03171 TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein K03173 TRAF2; TNF receptor-associated factor 2 [EC:2.3.2.27] K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24] K04447 JAK2; Janus kinase 2 [EC:2.7.10.2] K04456 AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1] K04467 IKBKA, IKKA, CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10] K04692 STAT3; signal transducer and activator of transcription 3 K04696 SOCS3, CIS3; suppressor of cytokine signaling 3 K04734 NFKBIA; NF-kappa-B inhibitor alpha K04735 RELA; transcription factor p65 K05062 LEPR, CD295; leptin receptor K05141 TNFRSF1B, TNFR2, CD120b; tumor necrosis factor receptor superfamily member 1B K05228 POMC; proopiomelanocortin K05231 AGRP; agouti related protein K05232 NPY; neuropeptide Y K05424 LEP; leptin K05872 NFKBIE; NF-kappa-B inhibitor epsilon K06259 CD36; CD36 antigen K07187 IRS2; insulin receptor substrate 2 K07191 SLC2A4, GLUT4; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4 K07198 PRKAA, AMPK; 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31] K07199 PRKAB; 5'-AMP-activated protein kinase, regulatory beta subunit K07200 PRKAG; 5'-AMP-activated protein kinase, regulatory gamma subunit K07202 PPARGC1A, PGC1A; alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha K07203 MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1] K07209 IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10] K07210 IKBKG, IKKG, NEMO; inhibitor of nuclear factor kappa-B kinase subunit gamma K07293 PTPN11, SHP2; tyrosine-protein phosphatase non-receptor type 11 [EC:3.1.3.48] K07294 NR1C1, PPARA; peroxisome proliferator-activated receptor alpha K07296 ADIPOQ, ACDC; adiponectin K07297 ADIPOR; adiponectin receptor K07298 STK11, LKB1; serine/threonine-protein kinase 11 [EC:2.7.11.1] K07299 SLC2A1, GLUT1; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 1 K07359 CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 [EC:2.7.11.17] K08524 RXRA, NR2B1; retinoid X receptor alpha K08525 RXRB, NR2B2; retinoid X receptor beta K08526 RXRG, NR2B3; retinoid X receptor gamma K08733 APPL1, DIP13A; DCC-interacting protein 13 alpha K08765 CPT1A; carnitine O-palmitoyltransferase 1, liver isoform [EC:2.3.1.21] K15013 ACSBG; long-chain-fatty-acid---CoA ligase [EC:6.2.1.3] K16172 IRS1; insulin receptor substrate 1 K17445 IRS3; insulin receptor substrate 3 K17446 IRS4; insulin receptor substrate 4 K18052 PRKCQ; novel protein kinase C theta type [EC:2.7.11.13] K19523 CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform [EC:2.3.1.21] K19524 CPT1C; carnitine O-palmitoyltransferase 1, brain isoform [EC:2.3.1.21] COMPOUND C00040 Acyl-CoA C00076 Calcium cation C00083 Malonyl-CoA C00162 Fatty acid C00165 Diacylglycerol C00195 N-Acylsphingosine C00638 Long-chain fatty acid C15493 9-cis-Retinoic acid REFERENCE PMID:15733744 AUTHORS Gual P, Le Marchand-Brustel Y, Tanti JF. TITLE Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. JOURNAL Biochimie 87:99-109 (2005) DOI:10.1016/j.biochi.2004.10.019 REFERENCE PMID:12829246 AUTHORS Hardie DG, Scott JW, Pan DA, Hudson ER. TITLE Management of cellular energy by the AMP-activated protein kinase system. JOURNAL FEBS Lett 546:113-20 (2003) DOI:10.1016/S0014-5793(03)00560-X REFERENCE PMID:15980064 AUTHORS Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, Witters LA. TITLE The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. JOURNAL J Biol Chem 280:29060-6 (2005) DOI:10.1074/jbc.M503824200 REFERENCE PMID:10766253 AUTHORS Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. TITLE Central nervous system control of food intake. JOURNAL Nature 404:661-71 (2000) DOI:10.1038/35007534 REFERENCE PMID:15856064 AUTHORS Munzberg H, Myers MG Jr. TITLE Molecular and anatomical determinants of central leptin resistance. JOURNAL Nat Neurosci 8:566-70 (2005) DOI:10.1038/nn1454 REFERENCE PMID:12754525 AUTHORS Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, Spiegelman BM. TITLE Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. JOURNAL Nature 423:550-5 (2003) DOI:10.1038/nature01667 REFERENCE PMID:11557972 AUTHORS Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM. TITLE Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. JOURNAL Nature 413:131-8 (2001) DOI:10.1038/35093050 REFERENCE PMID:14716305 AUTHORS Inoue H, Ogawa W, Ozaki M, Haga S, Matsumoto M, Furukawa K, Hashimoto N, Kido Y, Mori T, Sakaue H, Teshigawara K, Jin S, Iguchi H, Hiramatsu R, LeRoith D, Takeda K, Akira S, Kasuga M. TITLE Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. JOURNAL Nat Med 10:168-74 (2004) DOI:10.1038/nm980 REFERENCE PMID:9671776 AUTHORS Zhou YT, Shimabukuro M, Wang MY, Lee Y, Higa M, Milburn JL, Newgard CB, Unger RH. TITLE Role of peroxisome proliferator-activated receptor alpha in disease of pancreatic beta cells. JOURNAL Proc Natl Acad Sci U S A 95:8898-903 (1998) DOI:10.1073/pnas.95.15.8898 REFERENCE PMID:10905472 AUTHORS Kelley DE, Mandarino LJ. TITLE Fuel selection in human skeletal muscle in insulin resistance: a reexamination. JOURNAL Diabetes 49:677-83 (2000) DOI:10.2337/diabetes.49.5.677 REFERENCE PMID:12368907 AUTHORS Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. TITLE Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. JOURNAL Nat Med 8:1288-95 (2002) DOI:10.1038/nm788 REFERENCE PMID:11479627 AUTHORS Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. TITLE The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. JOURNAL Nat Med 7:941-6 (2001) DOI:10.1038/90984 REFERENCE PMID:15058305 AUTHORS Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB. TITLE AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. JOURNAL Nature 428:569-74 (2004) DOI:10.1038/nature02440 REFERENCE PMID:14679176 AUTHORS Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. TITLE Obesity is associated with macrophage accumulation in adipose tissue. JOURNAL J Clin Invest 112:1796-808 (2003) DOI:10.1172/JCI19246 REL_PATHWAY ko04010 MAPK signaling pathway ko04910 Insulin signaling pathway ///