Human Adipose Cells in Vitro Are Either Refractory or Responsive to Insulin, Reflecting Host Metabolic State

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Mar 14

PMID 25768970

Citations 6

Authors

Vladimir A Lizunov

Karin G Stenkula

Paul S Blank

Aaron Troy

Jo-Ping Lee

Monica C Skarulis

Samuel W Cushman

Joshua Zimmerberg

Affiliations

Soon will be listed here.

Abstract

While intercellular communication processes are frequently characterized by switch-like transitions, the endocrine system, including the adipose tissue response to insulin, has been characterized by graded responses. Yet here individual cells from adipose tissue biopsies are best described by a switch-like transition between the basal and insulin-stimulated states for the trafficking of the glucose transporter GLUT4. Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells. Furthermore, subjects exhibiting high systemic insulin sensitivity indices (SI) have high fractions of responsive adipose cells in vitro, while subjects exhibiting decreasing SI have increasing fractions of refractory cells in vitro. Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI. Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI.

Citing Articles

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References

Solinas G, Naugler W, Galimi F, Lee M, Karin M . Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc Natl Acad Sci U S A. 2006; 103(44):16454-9. PMC: 1637603. DOI: 10.1073/pnas.0607626103. View

Herman M, Peroni O, Villoria J, Schon M, Abumrad N, Bluher M . A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature. 2012; 484(7394):333-8. PMC: 3341994. DOI: 10.1038/nature10986. View

Burchfield J, Lu J, Fazakerley D, Tan S, Ng Y, Mele K . Novel systems for dynamically assessing insulin action in live cells reveals heterogeneity in the insulin response. Traffic. 2012; 14(3):259-73. DOI: 10.1111/tra.12035. View

Lee Y, Cowan C . White to brite adipocyte transition and back again. Nat Cell Biol. 2013; 15(6):568-9. DOI: 10.1038/ncb2776. View

Lyssenko V, Jonsson A, Almgren P, Pulizzi N, Isomaa B, Tuomi T . Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med. 2008; 359(21):2220-32. DOI: 10.1056/NEJMoa0801869. View

Thompson D, Karpe F, Lafontan M, Frayn K . Physical activity and exercise in the regulation of human adipose tissue physiology. Physiol Rev. 2012; 92(1):157-91. DOI: 10.1152/physrev.00012.2011. View

Lizunov V, Lee J, Skarulis M, Zimmerberg J, Cushman S, Stenkula K . Impaired tethering and fusion of GLUT4 vesicles in insulin-resistant human adipose cells. Diabetes. 2013; 62(9):3114-9. PMC: 3749349. DOI: 10.2337/db12-1741. View

Crivat G, Lizunov V, Li C, Stenkula K, Zimmerberg J, Cushman S . Insulin stimulates translocation of human GLUT4 to the membrane in fat bodies of transgenic Drosophila melanogaster. PLoS One. 2013; 8(11):e77953. PMC: 3819322. DOI: 10.1371/journal.pone.0077953. View

Lizunov V, Matsumoto H, Zimmerberg J, Cushman S, Frolov V . Insulin stimulates the halting, tethering, and fusion of mobile GLUT4 vesicles in rat adipose cells. J Cell Biol. 2005; 169(3):481-9. PMC: 2171949. DOI: 10.1083/jcb.200412069. View

10.

Macotela Y, Boucher J, Tran T, Kahn C . Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism. Diabetes. 2009; 58(4):803-12. PMC: 2661589. DOI: 10.2337/db08-1054. View

11.

Muniyappa R, Lee S, Chen H, Quon M . Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab. 2007; 294(1):E15-26. DOI: 10.1152/ajpendo.00645.2007. View

12.

Lizunov V, Lisinski I, Stenkula K, Zimmerberg J, Cushman S . Insulin regulates fusion of GLUT4 vesicles independent of Exo70-mediated tethering. J Biol Chem. 2009; 284(12):7914-9. PMC: 2658084. DOI: 10.1074/jbc.M806460200. View

13.

Cantley J, Yoshimura T, Camporez J, Zhang D, Jornayvaz F, Kumashiro N . CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance. Proc Natl Acad Sci U S A. 2013; 110(5):1869-74. PMC: 3562813. DOI: 10.1073/pnas.1219456110. View

14.

Franck N, Stenkula K, Ost A, Lindstrom T, Stralfors P, Nystrom F . Insulin-induced GLUT4 translocation to the plasma membrane is blunted in large compared with small primary fat cells isolated from the same individual. Diabetologia. 2007; 50(8):1716-22. DOI: 10.1007/s00125-007-0713-1. View

15.

GLIEMANN J, Vinten J . Glucose metabolism and insulin sensitivity of single fat cells. Isr J Med Sci. 1972; 8(6):807-8. View

16.

Lizunov V, Stenkula K, Troy A, Cushman S, Zimmerberg J . Insulin regulates Glut4 confinement in plasma membrane clusters in adipose cells. PLoS One. 2013; 8(3):e57559. PMC: 3592853. DOI: 10.1371/journal.pone.0057559. View

17.

Stenkula K, Lizunov V, Cushman S, Zimmerberg J . Insulin controls the spatial distribution of GLUT4 on the cell surface through regulation of its postfusion dispersal. Cell Metab. 2010; 12(3):250-9. PMC: 3427691. DOI: 10.1016/j.cmet.2010.08.005. View

18.

Skurk T, Alberti-Huber C, Herder C, Hauner H . Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab. 2006; 92(3):1023-33. DOI: 10.1210/jc.2006-1055. View

19.

Khalifeh-Soltani A, McKleroy W, Sakuma S, Cheung Y, Tharp K, Qiu Y . Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids. Nat Med. 2014; 20(2):175-83. PMC: 4273653. DOI: 10.1038/nm.3450. View

20.

Abel E, Peroni O, Kim J, Kim Y, Boss O, Hadro E . Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature. 2001; 409(6821):729-33. DOI: 10.1038/35055575. View