Skip to main content

Advertisement

SpringerLink
Log in

Adiponectin signaling in the liver

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

High glucose production contributes to fed and fasted hyperglycemia in Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). The breakdown of the adiponectin signaling pathway in T1D and the reduction of circulating adiponectin in T2D contribute to this abnormal increase in glucose production. Sufficient amounts of insulin could compensate for the loss of adiponectin signaling in T1D and T2D and reduce hyperglycemia. However, the combination of low adiponectin signaling and high insulin resembles an insulin resistance state associated with cardiovascular disease, fatty liver disease and decreased life expectancy. The future development of “adiponectin sensitizers”, medications that correct the deficiency in adiponectin signaling, could restore the metabolic balance in T1D and T2D and reduce the need for insulin. This article reviews the adiponectin signaling pathway in the liver through T-cadherin, AdipoR1, AdipoR2, AMPK, ceramidase activity, APPL1 and the recently discovered Suppressor Of Glucose from Autophagy (SOGA).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem. 1995;270(45):26746–9.

    Article  CAS  PubMed  Google Scholar 

  2. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem. 1996;271(18):10697–703.

    Article  CAS  PubMed  Google Scholar 

  3. Matsuzawa Y, Funahashi T, Nakamura T. Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances. Ann N Y Acad Sci. 1999;892:146–54.

    Article  CAS  PubMed  Google Scholar 

  4. Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab. 2002;13(2):84–9.

    Article  CAS  PubMed  Google Scholar 

  5. Haugen F, Drevon CA. Activation of nuclear factor kappaB by high molecular weight and globular adiponectin. Endocrinol. 2007;148(11):5478–86.

    Article  CAS  Google Scholar 

  6. Schraw T, Wang ZV, Halberg N, Hawkins M, Scherer PE. Plasma adiponectin complexes have distinct biochemical characteristics. Endocrinol. 2008;149(5):2270–82.

    Article  CAS  Google Scholar 

  7. Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A. 2001;98(4):2005–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, et al. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity. J Biol Chem. 2003;278(11):9073–85.

    Article  CAS  PubMed  Google Scholar 

  9. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7(8):947–53.

    Article  CAS  PubMed  Google Scholar 

  10. Katz EB, Stenbit AE, Hatton K, DePinho R, Cahrron MJ. Cardiac and adipose tissue abnormalilties but not diabetes in mice deficient in GLUT4. Nature. 1995;377:151–5.

    Article  CAS  PubMed  Google Scholar 

  11. Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Investig. 2001;108(12):1875–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Combs TP, Pajvani UB, Berg AH, Lin Y, Jelicks LA, Laplante M, et al. A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology. 2004;145(1):367–83.

    Article  CAS  PubMed  Google Scholar 

  13. Nawrocki AR, Rajala MW, Tomas E, Pajvani UB, Saha AK, Trumbauer ME, et al. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem. 2006;281(5):2654–60.

    Article  CAS  PubMed  Google Scholar 

  14. Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, et al. Receptor-mediated activation of ceramidase activity inititates the pleiotropic actions of adiponectin. Nat Med. 2011;17(1):55–65.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Wang Y, Xu A, Knight C, Xu LY, Cooper GJ. Hydroxylation and glycosylation of the four conserved lysine residues in the collagenous domain of adiponectin. Potential role in the modulation of its insulin-sensitizing activity. J Biol Chem. 2002;277(22):19521–9.

    Article  CAS  PubMed  Google Scholar 

  16. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257(1):79–83.

    Article  CAS  PubMed  Google Scholar 

  17. Mynarcick DC, Combs TP, McNurlan MA, Scherer PE, Komaroff E, Gelato MC. Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy. JAIDS. 2002;31(5):506–13.

    Google Scholar 

  18. Combs TP, Wagner JA, Berger J, Doebber T, Wang WJ, Zhang BB, et al. Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. Endocrinology. 2002;143(3):998–1007.

    CAS  PubMed  Google Scholar 

  19. Brooks NL, Moore KS, Clark RD, Perfetti MT, Trent CM, Combs TP. Do low levels of circulating adiponectin represent a biomarker or just another risk factor for the metabolic syndrome? Diabetes Obes Metab. 2007;9(3):246–58.

    Google Scholar 

  20. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, et al. PPARgamma signaling and metabolism: the good the bad and the future. Nat Med. 2013;99:557–66.

    Article  Google Scholar 

  21. Hoffstedt J, Arvidsson E, Sjolin E, Wahlen K, Arner P. Adipose tissue adiponectin production and adiponectin seum concentration in human obesity and insulin resistance. J Clin Endocrinol Metab. 2004;89(3):1391–6.

    Article  CAS  PubMed  Google Scholar 

  22. Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS, Lodish HF. T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. Proc Natl Acad Sci. 2004;101(28):10308–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Chan CY, Lee JM, Chan PC, Ng IO. Genetic and epigenetic inactivation of T-cadherin in human hepatocellular carcinoma cells. Cancer Cell Biol. 2008;123(5):1043–52.

    CAS  Google Scholar 

  24. Vestal DJ, Ranscht B. Glycosyl phosphatidylinositol-anchored T-cadherin mediates calcium-dependent, homophilic cell adhesion. J Cell Biol. 1992;119(2):451–61.

    Article  CAS  PubMed  Google Scholar 

  25. Denzel MS, Scimia M, Zumstein PM, Walsh K, Ruiz-Lozano P, Ranscht B. T-cadherin is critical for adiponectin-mediated cardioprotection in mice. J Clin Invest. 2010;120(12):4342–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Philippova MP, Bochkov VN, Stambolsky DV, Tkachuk VA, Resink TJ. T-cadherin and signal-transducing moleculaes co-localize in caveolin-rich membrane domains of vascular smooth muscle cells. FEBS Lett. 1998;429:207–10.

    Article  CAS  PubMed  Google Scholar 

  27. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003;423(6941):762–9.

    Article  CAS  PubMed  Google Scholar 

  28. Mao X, Kikani CK, Riojas RA, Langlais P, Wang L, Ramos FJ, et al. APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol. 2006;8(5):516–23.

    Article  CAS  PubMed  Google Scholar 

  29. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288–95.

    Article  CAS  PubMed  Google Scholar 

  30. Pagano C, Soardo G, Esposito W, Fallo F, Basan L, Donnini D, et al. Plasma adiponectin is decreased in nonalcoholic fatty liver disease. Eur J Endocrinol/Eur Fed Endocr Soc. 2005;152(1):113–8.

    Article  CAS  Google Scholar 

  31. Qiao L, Zou C, van der Westhuyzen DR, Shao J. Adiponectin reduces plasma triglyceride by increasing VLDL triglyceride catabolism. Diabetes. 2008;57(7):1824–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Brooks NL, Trent CM, Raetzsch CF, Flurkey K, Boysen G, Perfetti MT, et al. Low utilization of circulating glucose after food withdrawal in Snell dwarf mice. J Biol Chem. 2007;282(48):35069–77.

    Article  CAS  PubMed  Google Scholar 

  33. Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007;100(3):328–41.

    Article  CAS  PubMed  Google Scholar 

  34. Deepa SS, Dong LQ. APPL1: role in adiponectin signaling and beyond. Am J Physiol Endocrinol Metab. 2009;296(1):E22–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Wang C, Xin X, Xiang R, Ramos FJ, Liu M, Lee HJ, et al. Yin-Yang regulation of adiponectin signaling by APPL isoforms in muscle cells. J Biol Chem. 2009;284(46):31608–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Woods A, Azzout-Marniche D, Foretz M, Stein SC, Lemarchand P, Ferre P, et al. Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase. Mol Cell Biol. 2000;20(18):6704–11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Hattori Y, Nakano Y, Hattori S, Tomizawa A, Inukai K, Kasai K. High molecular weight adiponectin activates AMPK and suppresses cytokine-induced NF-kappaB activation in vascular endothelial cells. FEBS Lett. 2008;582(12):1719–24.

    Article  CAS  PubMed  Google Scholar 

  38. Zhou L, Deepa SS, Etzler JC, Ryu J, Mao X, Fang Q, et al. 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. J Biol Chem. 2009;284(33):22426–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, et al. Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature. 2010;464(7293):1313–9.

    Article  CAS  PubMed  Google Scholar 

  40. Buechler C, Wanninger J, Neumeier M. Adiponectin receptor binding proteins–recent advances in elucidating adiponectin signalling pathways. FEBS Lett. 2010;584(20):4280–6.

    Article  CAS  PubMed  Google Scholar 

  41. Viollet B, Andreelli F. AMP-activated protein kinase and metabolic control. Handb Exp Pharmacol. 2011;203:303–30.

    Article  CAS  PubMed  Google Scholar 

  42. Powell DJ, Hajduch E, Kular G, Hundal HS. Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Mol Cell Biol. 2003;23(21):7794–808.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Mukhopadhyay A, Saddoughi SA, Song P, Sultan I, Ponnusamy S, Senkal CE, et al. Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling. FASEB J. 2009;23(3):751–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Bourbon NA, Yun J, Berkey D, Wang Y, Kester M. Inhibitory actions of ceramide upon PKC-epsilon/ERK interactions. Am J Physiol Cell Physiol. 2001;280(6):C1403–11.

    CAS  PubMed  Google Scholar 

  45. Takabe K, Paugh SW, Milstien S, Spiegel S. “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev. 2008;60(2):181–95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Yang G, Badeanlou L, Bielawski J, Roberts AJ, Hannun YA, Samad F. Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Am J Physiol Endocrinol Metab. 2009;297(1):E211–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Yew NS, Zhao H, Hong EG, Wu IH, Przybylska M, Siegel C, et al. Increased hepatic insulin action in diet-induced obese mice following inhibition of glucosylceramide synthase. PLoS One. 2010;5(6):e11239.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Holland WL, Bikman BT, Wang LP, Yuguang G, Sargent KM, Bulchand S, et al. Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest. 2011;121(5):1858–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Lopez X, Goldfine AB, Holland WL, Gordillo R, Scherer PE. Plasma ceramides are elevated in female children and adolescents with type 2 diabetes. J Pediatr Endocrinol Metab. 2013;24.

  50. Villa NY, Kupchak BR, Garitaonandia I, Smith JL, Alonso E, Alford C, et al. Sphingolipids function as downstream effectors of a fungal PAQR. Mol Pharmacol. 2009;75(4):866–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Holland WL, Summers SA. Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev. 2008;29(4):381–402.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev. 2012;33(4):547–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Miller RA, Chu Q, Le Lay J, Scherer PE, Ahima RS, Kaestner KH, et al. Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling. J Clin Investig. 2011;121(6):2518–28.

    Google Scholar 

  54. Shklyaev S, Aslanidi G, Tennant M, Prima V, Kohlbrenner E, Kroutov V, et al. Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats. Proc Natl Acad Sci U S A. 2003;100(24):14217–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Ma Y, Liu D. Hydrodynamic delivery of adiponectin and adiponectin receptor 2 gene blocks high-fat diet-induced obesity and insulin resistance. Gene Ther. 2013.

  56. Andreelli F, Foretz M, Knauf C, Cani PD, Perrin C, Iglesias MA, et al. Liver adenosine monophosphate-activated kinase-alpha2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin. Endocrinology. 2006;147(5):2432–41.

    Article  CAS  PubMed  Google Scholar 

  57. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001;413(6852):131–8.

    Article  CAS  PubMed  Google Scholar 

  58. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310(5754):1642–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S, et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature. 2005;437(7062):1109–11.

    Article  CAS  PubMed  Google Scholar 

  60. Berasi SP, Huard C, Li D, Shih HH, Sun Y, Zhong W, et al. Inhibition of gluconeogenesis through transcriptional activation of EGR1 and DUSP4 by AMP-activated kinase. J Biol Chem. 2006;281(37):27167–77.

    Article  CAS  PubMed  Google Scholar 

  61. Jorgensen SB, Nielsen JN, Birk JB, Olsen GS, Viollet B, Andreelli F, et al. The alpha2-5′AMP-activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is responsive to glucose loading. Diabetes. 2004;53(12):3074–81.

    Article  CAS  PubMed  Google Scholar 

  62. Jakobsen SN, Hardie DG, Morrice N, Tornqvist HE. 5′-AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside. J Biol Chem. 2001;276(50):46912–6.

    Article  CAS  PubMed  Google Scholar 

  63. Awazawa M, Ueki K, Inabe K, Yamauchi T, Kubota N, Kaneko K, et al. Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6-dependent pathway. Cell Metab. 2011;13(4):401–12.

    Article  CAS  PubMed  Google Scholar 

  64. Dickens M, Svitek CA, Culbert AA, O’Brien RM, Tavare JM. Central role for phosphatidylinositide 3-kinase in the repression of glucose-6-phosphatase gene transcription by insulin. J Biol Chem. 1998;273(32):20144–9.

    Article  CAS  PubMed  Google Scholar 

  65. Nakae J, Kitamura T, Silver DL, Accili D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J Clin Invest. 2001;108(9):1359–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Du K, Herzig S, Kulkarni RN, Montminy M. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science. 2003;300(5625):1574–7.

    Article  CAS  PubMed  Google Scholar 

  67. Oberkofler H, Pfeifenberger A, Soyal S, Felder T, Hahne P, Miller K, et al. Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans. Diabetologia. 2010;53(9):1971–5.

    Article  CAS  PubMed  Google Scholar 

  68. Cheng KK, Iglesias MA, Lam KS, Wang Y, Sweeney G, Zhu W, et al. APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice. Cell Metab. 2009;9(5):417–27.

    Article  CAS  PubMed  Google Scholar 

  69. Horton RA, Ceppi ED, Knowles RG, Titheradge MA. Inhibition of hepatic gluconeogenesis by nitric oxide: a comparison with endotoxic shock. Biochem J. 1994;299(Pt 3):735–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Wang Y, Cheng KK, Lam KS, Wu D, Wang Y, Huang Y, et al. APPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in mice. Diabetes. 2011;60(11):3044–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Tsao TS, Murrey HE, Hug C, Lee DH, Lodish HF. Oligomerization state-dependent activation of NF-kappa B signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30). J Biol Chem. 2002;277(33):29359–62.

    Article  CAS  PubMed  Google Scholar 

  72. Geller DA, Nussler AK, Di Silvio M, Lowenstein CJ, Shapiro RA, Wang SC, et al. Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. Proc Natl Acad Sci U S A. 1993;90(2):522–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Waltner-Law M, Daniels MC, Sutherland C, Granner DK. NF-kappa B inhibits glucocorticoid and cAMP-mediated expression of the phosphoenolpyruvate carboxykinase gene. J Biol Chem. 2000;275(41):31847–56.

    Article  CAS  PubMed  Google Scholar 

  74. Grempler R, Kienitz A, Werner T, Meyer M, Barthel A, Ailett F, et al. Tumour necrosis factor alpha decreases glucose-6-phosphatase gene expression by activation of nuclear factor kappaB. Biochem J. 2004;382(Pt 2):471–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Raetzsch CF, Brooks NL, Alderman JM, Moore KS, Hosick PA, Klebanov S, et al. Lipopolysaccharide inhibition of glucose production through the Toll-like receptor-4, myeloid differentiation factor 88, and nuclear factor kappa b pathway. Hepatology. 2009;50(2):592–600.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Thakur V, Pritchard MT, McMullen MR, Nagy LE. Adiponectin normalizes LPS-stimulated TNF-alpha production by rat Kupffer cells after chronic ethanol feeding. Am J Physiol Gastrointest Liver Physiol. 2006;290(5):G998–G1007.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Mittelman SD, Bergman RN. Inhibition of lipolysis causes suppression of endogenous glucose production independent of changes in insulin. Am J Physiol Endocrinol Metab. 2000;279(3):E630–7.

    CAS  PubMed  Google Scholar 

  78. Felig P, Pozefsky T, Marliss E, Cahill Jr GF. Alanine: key role in gluconeogenesis. Science. 1970;167(3920):1003–4.

    Article  CAS  PubMed  Google Scholar 

  79. Felig P, Marliss E, Owen OE, Cahill Jr GF. Role of substrate in the regulation of hepatic gluconeogenesis in fasting man. Adv Enzyme Regul. 1969;7:41–6.

    Article  CAS  PubMed  Google Scholar 

  80. Molusky MM, Li S, Ma D, Yu L, Lin JD. Ubiquitin-specific protease 2 regulates hepatic gluconeogenesis and diurnal glucose metabolism through 11beta-hydroxysteroid dehydrogenase 1. Diabetes. 2012;61(5):1025–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Penn SK, Kao AH, Schott LL, Elliott JR, Toledo FG, Kuller L, et al. Hydroxychloroquine and glycemia in women with rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol. 2010;37(6):1136–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Mortimore GE, Hutson NJ, Surmacz CA. Quantitative correlation between proteolysis and macro- and microautophagy in mouse hepatocytes during starvation and refeeding. Proc Natl Acad Sci U S A. 1983;80(8):2179–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Amherdt M, Harris V, Renold AE, Orci L, Unger RH. Hepatic autography in uncontrolled experimental diabetes and its relationships to insulin and glucagon. J Clin Investig. 1974;54(1):188–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Shelburne JD, Arstila AU, Trump BF. Studies on cellular autophagocytosis. Cyclic AMP- and dibutyryl cyclic AMP-stimulated autophagy in rat liver. Am J Pathol. 1973;72(3):521–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Lenk SE, Bhat D, Blakeney W, Dunn Jr WA. Effects of streptozotocin-induced diabetes on rough endoplasmic reticulum and lysosomes of rat liver. Am J Physiol. 1992;263(5 Pt 1):E856–62.

    CAS  PubMed  Google Scholar 

  86. Forbes JM. The physiological deadlock between AMPK and gluconeogenesis: SOGA, a novel protein, may provide the key. Am J Pathol. 2010;177(4):1600–2.

    Article  PubMed Central  PubMed  Google Scholar 

  87. Zhao M, Klionsky DJ. AMPK-dependent phosphorylation of ULK1 induces autophagy. Cell Metab. 2011;13(2):119–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol. 2005;17(6):596–603.

    Article  CAS  PubMed  Google Scholar 

  89. Cowherd RB, Asmar MM, Alderman JM, Alderman EA, Garland AL, Busby WH, et al. Adiponectin lowers glucose production by increasing SOGA. Am J Pathol. 2010;177(4):1936–45.

    Article  PubMed  Google Scholar 

  90. Longnus SL, Wambolt RB, Parsons HL, Brownsey RW, Allard MF. 5-Aminoimidazole-4-carboxamide 1-beta -D-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms. Am J Physiol Regul Integr Comp Physiol. 2003;284(4):R936–44.

    CAS  PubMed  Google Scholar 

  91. Camacho RC, Pencek RR, Lacy DB, James FD, Donahue EP, Wasserman DH. Portal venous 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion overcomes hyperinsulinemic suppression of endogenous glucose output. Diabetes. 2005;54(2):373–82.

    Article  CAS  PubMed  Google Scholar 

  92. Gharbi SI, Zvelebil MJ, Shuttleworth SJ, Hancox T, Saghir N, Timms JF, et al. Exploring the specificity of the PI3K family inhibitor LY294002. Biochem J. 2007;404(1):15–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Gougeon R, Morais JA, Chevalier S, Pereira S, Lamarche M, Marliss EB. Determinants of whole-body protein metabolism in subjects with and without type 2 diabetes. Diabetes Care. 2008;31(1):128–33.

    Article  CAS  PubMed  Google Scholar 

  94. Gougeon R, Pencharz PB, Marliss EB. Effect of NIDDM on the kinetics of whole-body protein metabolism. Diabetes. 1994;43(2):318–28.

    Article  CAS  PubMed  Google Scholar 

  95. Imagawa A, Funahashi T, Nakamura T, Moriwaki M, Tanaka S, Nishizawa H, et al. Elevated serum concentration of adipose-derived factor, adiponectin, in patients with type 1 diabetes. Diabetes Care. 2002;25(9):1665–6.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Support for this article was provided from the National Institutes of Health to Dr. Combs (Grant DK075573: The Effects of Adiponectin on Liver Insulin Resistance) and the Canadian Institutes of Health Research to Dr. Marliss (Grant MOP-62889: Mechanisms of Insulin Resistance of Protein Metabolism in Human Obesity).

Conflict of interest

We certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

Author information

Authors and Affiliations

  1. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27516, USA

    Terry P. Combs

  2. Crabtree Nutrition Laboratories, Department of Medicine, McGill University, Montreal, QC H3A-1A1, Canada

    Terry P. Combs & Errol B. Marliss

Authors
  1. Terry P. Combs
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Errol B. Marliss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Terry P. Combs.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Combs, T.P., Marliss, E.B. Adiponectin signaling in the liver. Rev Endocr Metab Disord 15, 137–147 (2014). https://doi.org/10.1007/s11154-013-9280-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-013-9280-6

Keywords

Search

Navigation