Skip to main content
SpringerLink
Log in

Activation of AMPK improves inflammation and insulin resistance in adipose tissue and skeletal muscle from pregnant women

  • Original Paper
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

Gestational diabetes mellitus (GDM) is characterised by maternal peripheral insulin resistance and inflammation. Sterile inflammation and bacterial infection are key mediators of this enhanced inflammatory response. Adenosine monophosphate (AMP)-activated kinase (AMPK), which is decreased in insulin resistant states, possesses potent pro-inflammatory actions. There are, however, no studies on the role of AMPK in pregnancies complicated by GDM. Thus, the aims of this study were (i) to compare the expression of AMPK in adipose tissue and skeletal muscle from women with GDM and normal glucose-tolerant (NGT) pregnant women; and (ii) to investigate the effect of AMPK activation on inflammation and insulin resistance induced by the bacterial endotoxin lipopolysaccharide (LPS) and the pro-inflammatory cytokine IL-1β. When compared to NGT pregnant women, AMPKα activity was significantly lower in women with GDM as evidenced by a decrease in threonine phosphorylation of AMPKα. Activation of AMPK, using two pharmacologically distinct compounds, AICAR or phenformin, significantly suppressed LPS- or IL-1β-induced gene expression and secretion of pro-inflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, and COX-2 and subsequent prostaglandin release from adipose tissue and skeletal muscle. In addition, activators of AMPK decreased skeletal muscle insulin resistance induced by LPS or IL-1β as evidenced by increased insulin-stimulated phosphorylation of IRS-1, GLUT-4 expression and glucose uptake. These findings suggest that AMPK may play an important role in inflammation and insulin resistance.

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
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Boyle KE, Hwang H, Janssen RC, DeVente JM, Barbour LA, Hernandez TL, Mandarino LJ, Lappas M, Friedman JE (2014) Gestational diabetes is characterized by reduced mitochondrial protein expression and altered calcium signaling proteins in skeletal muscle. Plos One 9:e106872

    Article  PubMed Central  PubMed  Google Scholar 

  2. Canto C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, Zierath JR, Auwerx J (2010) Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 11:213–219

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Chang MY, Ho FM, Wang JS, Kang HC, Chang Y, Ye ZX, Lin WW (2010) AICAR induces cyclooxygenase-2 expression through AMP-activated protein kinase-transforming growth factor-beta-activated kinase 1-p38 mitogen-activated protein kinase signaling pathway. Biochem Pharmacol 80:1210–1220

    Article  CAS  PubMed  Google Scholar 

  4. Colomiere M, Permezel M, Lappas M (2010) Diabetes and obesity during pregnancy alter insulin signalling and glucose transporter expression in maternal skeletal muscle and subcutaneous adipose tissue. J Mol Endocrinol 44:213–223

    Article  CAS  PubMed  Google Scholar 

  5. Dabelea D, Hanson RL, Lindsay RS, Pettitt DJ, Imperatore G, Gabir MM, Roumain J, Bennett PH, Knowler WC (2000) Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 49:2208–2211

    Article  CAS  PubMed  Google Scholar 

  6. Ehrenberg HM, Mercer BM, Catalano PM (2004) The influence of obesity and diabetes on the prevalence of macrosomia. Am J Obstet Gynecol 191:964–968

    Article  CAS  PubMed  Google Scholar 

  7. Fiebich BL, Mueksch B, Boehringer M, Hull M (2000) Interleukin-1beta induces cyclooxygenase-2 and prostaglandin E(2) synthesis in human neuroblastoma cells: involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB. J Neurochem 75:2020–2028

    Article  CAS  PubMed  Google Scholar 

  8. Giri S, Nath N, Smith B, Viollet B, Singh AK, Singh I (2004) 5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. J Neurosci 24:479–487

    Article  CAS  PubMed  Google Scholar 

  9. Hayashi T, Hirshman MF, Kurth EJ, Winder WW, Goodyear LJ (1998) Evidence for 5′AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 47:1369–1373

    CAS  PubMed  Google Scholar 

  10. Henkel J, Neuschafer-Rube F, Pathe-Neuschafer-Rube A, Puschel GP (2009) Aggravation by prostaglandin E2 of interleukin-6-dependent insulin resistance in hepatocytes. Hepatology 50:781–790

    Article  CAS  PubMed  Google Scholar 

  11. Hinson RM, Williams JA, Shacter E (1996) Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2. Proc Natl Acad Sci U S A 93:4885–4890

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Hossain P, Kawar B, El Nahas M (2007) Obesity and diabetes in the developing world—a growing challenge. N Engl J Med 356:213–215

    Article  CAS  PubMed  Google Scholar 

  13. Iglesias MA, Ye JM, Frangioudakis G, Saha AK, Tomas E, Ruderman NB, Cooney GJ, Kraegen EW (2002) AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes 51:2886–2894

    Article  CAS  PubMed  Google Scholar 

  14. Jones HN, Jansson T, Powell TL (2009) IL-6 stimulates system A amino acid transporter activity in trophoblast cells through STAT3 and increased expression of SNAT2. Am J Physiol Cell Physiol 297:C1228–C1235

    Article  CAS  PubMed  Google Scholar 

  15. Katerelos M, Mudge SJ, Stapleton D, Auwardt RB, Fraser SA, Chen CG, Kemp BE, Power DA (2010) 5-Aminoimidazole-4-carboxamide ribonucleoside and AMP-activated protein kinase inhibit signalling through NF-kappaB. Immunol Cell Biol 88:754–760

    Article  CAS  PubMed  Google Scholar 

  16. Keelan JA, Blumenstein M, Helliwell RJ, Sato TA, Marvin KW, Mitchell MD (2003) Cytokines, prostaglandins and parturition—a review. Placenta Suppl A:S33–S46

    Article  Google Scholar 

  17. Lager S, Jansson N, Olsson AL, Wennergren M, Jansson T, Powell TL (2011) Effect of IL-6 and TNF-alpha on fatty acid uptake in cultured human primary trophoblast cells. Placenta 32:121–127

    Article  CAS  PubMed  Google Scholar 

  18. Lappas M, Permezel M, Rice GE (2004) Release of proinflammatory cytokines and 8-isoprostane from placenta, adipose tissue, and skeletal muscle from normal pregnant women and women with gestational diabetes mellitus. J Clin Endocrinol Metab 89:5627–5633

    Article  CAS  PubMed  Google Scholar 

  19. Lappas M (2014) Activation of inflammasomes in adipose tissue of women with gestational diabetes. Mol Cell Endocrinol 382:74–83

    Article  CAS  PubMed  Google Scholar 

  20. Lappas M (2014) GSK3beta is increased in adipose tissue and skeletal muscle from women with gestational diabetes where it regulates the inflammatory response. Plos One 9:e115854

    Article  PubMed Central  PubMed  Google Scholar 

  21. Lihn AS, Pedersen SB, Lund S, Richelsen B (2008) The anti-diabetic AMPK activator AICAR reduces IL-6 and IL-8 in human adipose tissue and skeletal muscle cells. Mol Cell Endocrinol 292:36–41

    Article  CAS  PubMed  Google Scholar 

  22. Merrill GF, Kurth EJ, Hardie DG, Winder WW (1997) AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol-Endoc M 273:E1107–E1112

    CAS  Google Scholar 

  23. Patel S, Santani D (2009) Role of NF-kappa B in the pathogenesis of diabetes and its associated complications. Pharmacol Rep 61:595–603

    Article  CAS  PubMed  Google Scholar 

  24. Persaud SJ, Burns CJ, Belin VD, Jones PM (2004) Glucose-induced regulation of COX-2 expression in human islets of Langerhans. Diabetes 53 Suppl 1:S190–S192

    Article  PubMed  Google Scholar 

  25. Pistritto G, Franzese O, Pozzoli G, Mancuso C, Tringali G, Preziosi P, Navarra P (1999) Bacterial lipopolysaccharide increases prostaglandin production by rat astrocytes via inducible cyclo-oxygenase: evidence for the involvement of nuclear factor kappaB. Biochem Biophys Res Commun 263:570–574

    Article  CAS  PubMed  Google Scholar 

  26. Radaelli T, Varastehpour A, Catalano P, Hauguel-de Mouzon S (2003) Gestational diabetes induces placental genes for chronic stress and inflammatory pathways. Diabetes 52:2951–2958

    Article  CAS  PubMed  Google Scholar 

  27. Salminen A, Hyttinen JM, Kaarniranta K (2011) AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: impact on healthspan and lifespan. J Mol Med 89:667–676

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Sriwijitkamol A, Coletta DK, Wajcberg E, Balbontin GB, Reyna SM, Barrientes J, Eagan PA, Jenkinson CP, Cersosimo E, DeFronzo RA et al (2007) Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes—a time-course and dose–response study. Diabetes 56:836–848

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Tabatabaie T, Waldon AM, Jacob JM, Floyd RA, Kotake Y (2000) COX-2 inhibition prevents insulin-dependent diabetes in low-dose streptozotocin-treated mice. Biochem Biophys Res Commun 273:699–704

    Article  CAS  PubMed  Google Scholar 

  30. Wen HT, Gris D, Lei Y, Jha S, Zhang L, Huang MTH, Brickey WJ, Ting JPY (2011) Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12:408–415

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Xu XJ, Gauthier MS, Hess DT, Apovian CM, Cacicedo JM, Gokce N, Farb M, Valentine RJ, Ruderman NB (2012) Insulin sensitive and resistant obesity in humans: AMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue. J Lipid Res 53:792–801

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Yu X, McCorkle S, Wang M, Lee Y, Li J, Saha AK, Unger RH, Ruderman NB (2004) Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition. Diabetologia 47:2012–2021

    Article  CAS  PubMed  Google Scholar 

  33. Zhang L, He H, Balschi JA (2007) Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. Am J Physiol Heart Circ Physiol 293:H457–H466

    Article  CAS  PubMed  Google Scholar 

  34. Zhao X, Zmijewski JW, Lorne E, Liu G, Park YJ, Tsuruta Y, Abraham E (2008) Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury. Am J Physiol Lung Cell Mol Physiol 295:L497–L504

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Zheng D, MacLean PS, Pohnert SC, Knight JB, Olson AL, Winder WW, Dohm GL (2001) Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase. J Appl Physiol 91:1073–1083

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The following are gratefully acknowledged: Gillian Barker (Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne) for her technical assistance; the clinical Research Midwives Genevieve Christophers, Gabrielle Fleming and Rachel Murdoch for sample collection; and the Obstetrics and Midwifery staff of the Mercy Hospital for Women for their co-operation.

Funding

Associate Professor Martha Lappas is supported by a Career Development Fellowship by the National Health and Medical Research Council (NHMRC; grant no. 1047025). Dr. Stella Liong is a recipient of the Glyn White Research Fellowship by the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) Research Foundation. This work was funded by the Medical Research Foundation for Women and Babies.

Conflict of interest

The author has nothing to declare.

Author information

Authors and Affiliations

  1. Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia

    Stella Liong & Martha Lappas

  2. Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Melbourne, Victoria, Australia

    Stella Liong & Martha Lappas

  3. Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4/163 Studley Road, Heidelberg, Melbourne, 3084, Victoria, Australia

    Martha Lappas

Authors
  1. Stella Liong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martha Lappas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martha Lappas.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liong, S., Lappas, M. Activation of AMPK improves inflammation and insulin resistance in adipose tissue and skeletal muscle from pregnant women. J Physiol Biochem 71, 703–717 (2015). https://doi.org/10.1007/s13105-015-0435-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-015-0435-7

Keywords

Search

Navigation