Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Adipocyte and Cell Biology

Adipogenic progenitors from obese human skeletal muscle give rise to functional white adipocytes that contribute to insulin resistance

International Journal of Obesity volume 40, pages 497–506 (2016)Cite this article

Subjects

Abstract

Background/Objectives:

Recent reports indicate that inter/intramuscular adipose tissue (IMAT), composed by adipocytes underneath the deep fascia of the muscles, is positively correlated with aging, obesity and insulin resistance in humans. However, no molecular/cellular evidence is available to support these interactions. The current study aimed to better characterize human skeletal muscle-derived adipogenic progenitors obtained from obese volunteers and investigate the impact of derived adipocytes on insulin action in primary skeletal muscle cells.

Methods:

Primary cultured stroma-vascular fraction (SVF) obtained from vastus lateralis muscle biopsies of middle-aged obese subjects was immunoseparated (magnetic beads or flow cytometry). The characteristics and/or metabolic phenotype of CD56+, CD56− and CD56−CD15+ cellular fractions were investigated by complementary approaches (flow cytometry, cytology, quantitative PCR and metabolic assays). The effects of conditioned media from CD56−CD15+ cells differentiated into adipocytes on insulin action and signaling in human primary myotubes was also examined.

Results:

Our data indicate that CD56+ and CD56− cellular fractions isolated from cultured SVF of human muscle contain two distinct committed progenitors: CD56+ cells (that is, satellite cells) as myogenic progenitors and CD15+ cells as adipogenic progenitors, respectively. CD56−CD15+-derived adipocytes display the phenotype and metabolic properties of white adipocytes. Secretions of CD56−CD15+ cells differentiated into functional white adipocytes reduced insulin-mediated non-oxidative glucose disposal (P=0.0002) and insulin signaling.

Conclusions:

Using in-vitro models, we show for the first time that secretions of skeletal muscle adipocytes are able to impair insulin action and signaling of muscle fibers. This paracrine effect could explain, at least in part, the negative association between high levels of IMAT and insulin sensitivity in obesity and aging.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

References

  1. Gallagher D, Kelley DE, Yim JE, Spence N, Albu J, Boxt L et al. Adipose tissue distribution is different in type 2 diabetes. Am J Clin Nutr 2009; 89: 807–814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hilton TN, Tuttle LJ, Bohnert KL, Mueller MJ, Sinacore DR . Excessive adipose tissue infiltration in skeletal muscle in individuals with obesity, diabetes mellitus, and peripheral neuropathy: association with performance and function. Phys Ther 2008; 88: 1336–1344.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Marcus RL, Addison O, Kidde JP, Dibble LE, Lastayo PC . Skeletal muscle fat infiltration: impact of age, inactivity, and exercise. J Nutr Health Aging 2010; 14: 362–366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Boettcher M, Machann J, Stefan N, Thamer C, Haring HU, Claussen CD et al. Intermuscular adipose tissue (IMAT): association with other adipose tissue compartments and insulin sensitivity. J Magn Reson Imaging 2009; 29: 1340–1345.

    Article  PubMed  Google Scholar 

  5. Miljkovic I, Zmuda JM . Epidemiology of myosteatosis. Curr Opin Clin Nutr Metab Care 2010; 13: 260–264.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Addison O, Marcus RL, Lastayo PC, Ryan AS . Intermuscular fat: a review of the consequences and causes. Int J Endocrinol 2014; 2014: 309570.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zammit PS, Partridge TA, Yablonka-Reuveni Z . The skeletal muscle satellite cell: the stem cell that came in from the cold. J Histochem Cytochem 2006; 54: 1177–1191.

    Article  CAS  PubMed  Google Scholar 

  8. Vettor R, Milan G, Franzin C, Sanna M, De Coppi P, Rizzuto R et al. The origin of intermuscular adipose tissue and its pathophysiological implications. Am J Physiol Endocrinol Metab 2009; 297: E987–E998.

    Article  CAS  PubMed  Google Scholar 

  9. Lecourt S, Marolleau JP, Fromigue O, Vauchez K, Andriamanalijaona R, Ternaux B et al. Characterization of distinct mesenchymal-like cell populations from human skeletal muscle in situ and in vitro. Exp Cell Res 2010; 316: 2513–2526.

    Article  CAS  PubMed  Google Scholar 

  10. Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K . Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol 2010; 12: 143–152.

    Article  CAS  PubMed  Google Scholar 

  11. Blau HM, Webster C . Isolation and characterization of human muscle cells. Proc Natl Acad Sci USA 1981; 78: 5623–5627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pisani DF, Clement N, Loubat A, Plaisant M, Sacconi S, Kurzenne JY et al. Hierarchization of myogenic and adipogenic progenitors within human skeletal muscle. Stem Cells 2010; 28: 2182–2194.

    Article  PubMed  Google Scholar 

  13. Vauchez K, Marolleau JP, Schmid M, Khattar P, Chapel A, Catelain C et al. Aldehyde dehydrogenase activity identifies a population of human skeletal muscle cells with high myogenic capacities. Mol Ther 2009; 17: 1948–1958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Agley CC, Rowlerson AM, Velloso CP, Lazarus NR, Harridge SD . Human skeletal muscle fibroblasts, but not myogenic cells, readily undergo adipogenic differentiation. J Cell Sci 2013; 126: 5610–5625.

    Article  CAS  PubMed  Google Scholar 

  15. Badin PM, Loubiere C, Coonen M, Louche K, Tavernier G, Bourlier V et al. Regulation of skeletal muscle lipolysis and oxidative metabolism by the co-lipase CGI-58. J Lipid Res 2012; 53: 839–848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Badin PM, Louche K, Mairal A, Liebisch G, Schmitz G, Rustan AC et al. Altered skeletal muscle lipase expression and activity contribute to insulin resistance in humans. Diabetes 2011; 60: 1734–1742.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bourlier V, Saint-Laurent C, Louche K, Badin PM, Thalamas C, de Glisezinski I et al. Enhanced glucose metabolism is preserved in cultured primary myotubes from obese donors in response to exercise training. J Clin Endocrinol Metab 2013; 98: 3739–3747.

    Article  CAS  PubMed  Google Scholar 

  18. Hulver MW, Berggren JR, Carper MJ, Miyazaki M, Ntambi JM, Hoffman EP et al. Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans. Cell Metab 2005; 2: 251–261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Boldrin L, Muntoni F, Morgan JE . Are human and mouse satellite cells really the same? J Histochem Cytochem 2010; 58: 941–955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Crisan M, Casteilla L, Lehr L, Carmona M, Paoloni-Giacobino A, Yap S et al. A reservoir of brown adipocyte progenitors in human skeletal muscle. Stem Cells 2008; 26: 2425–2433.

    Article  CAS  PubMed  Google Scholar 

  21. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012; 150: 366–376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Langin D, Dicker A, Tavernier G, Hoffstedt J, Mairal A, Ryden M et al. Adipocyte lipases and defect of lipolysis in human obesity. Diabetes 2005; 54: 3190–3197.

    Article  CAS  PubMed  Google Scholar 

  23. Bezaire V, Mairal A, Ribet C, Lefort C, Girousse A, Jocken J et al. Contribution of adipose triglyceride lipase and hormone-sensitive lipase to lipolysis in hMADS adipocytes. J Biol Chem 2009; 284: 18282–18291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Aas V, Bakke SS, Feng YZ, Kase ET, Jensen J, Bajpeyi S et al. Are cultured human myotubes far from home? Cell Tissue Res 2013; 354: 671–682.

    Article  CAS  PubMed  Google Scholar 

  25. Goodpaster BH, Thaete FL, Kelley DE . Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr 2000; 71: 885–892.

    Article  CAS  PubMed  Google Scholar 

  26. Rossi CA, Pozzobon M, Ditadi A, Archacka K, Gastaldello A, Sanna M et al. Clonal characterization of rat muscle satellite cells: proliferation, metabolism and differentiation define an intrinsic heterogeneity. PLoS One 2010; 5: e8523.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Shefer G, Wleklinski-Lee M, Yablonka-Reuveni Z . Skeletal muscle satellite cells can spontaneously enter an alternative mesenchymal pathway. J Cell Sci 2004; 117: 5393–5404.

    Article  CAS  PubMed  Google Scholar 

  28. Akimoto T, Ushida T, Miyaki S, Akaogi H, Tsuchiya K, Yan Z et al. Mechanical stretch inhibits myoblast-to-adipocyte differentiation through Wnt signaling. Biochem Biophys Res Commun 2005; 329: 381–385.

    Article  CAS  PubMed  Google Scholar 

  29. Yeow K, Phillips B, Dani C, Cabane C, Amri EZ, Derijard B . Inhibition of myogenesis enables adipogenic trans-differentiation in the C2C12 myogenic cell line. FEBS Lett 2001; 506: 157–162.

    Article  CAS  PubMed  Google Scholar 

  30. Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 2007; 317: 807–810.

    Article  CAS  PubMed  Google Scholar 

  31. Taylor-Jones JM, McGehee RE, Rando TA, Lecka-Czernik B, Lipschitz DA, Peterson CA . Activation of an adipogenic program in adult myoblasts with age. Mech Ageing Dev 2002; 123: 649–661.

    Article  CAS  PubMed  Google Scholar 

  32. De Coppi P, Milan G, Scarda A, Boldrin L, Centobene C, Piccoli M et al. Rosiglitazone modifies the adipogenic potential of human muscle satellite cells. Diabetologia 2006; 49: 1962–1973.

    Article  CAS  PubMed  Google Scholar 

  33. Joe AW, Yi L, Natarajan A, Le Grand F, So L, Wang J et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol 2010; 12: 153–163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu W, Liu Y, Lai X, Kuang S . Intramuscular adipose is derived from a non-Pax3 lineage and required for efficient regeneration of skeletal muscles. Dev Biol 2012; 361: 27–38.

    Article  CAS  PubMed  Google Scholar 

  35. Starkey JD, Yamamoto M, Yamamoto S, Goldhamer DJ . Skeletal muscle satellite cells are committed to myogenesis and do not spontaneously adopt nonmyogenic fates. J Histochem Cytochem 2011; 59: 33–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hall PA, D'Ardenne AJ . Value of CD15 immunostaining in diagnosing Hodgkin's disease: a review of published literature. J Clin Pathol 1987; 40: 1298–1304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ukropcova B, McNeil M, Sereda O, de Jonge L, Xie H, Bray GA et al. Dynamic changes in fat oxidation in human primary myocytes mirror metabolic characteristics of the donor. J Clin Invest 2005; 115: 1934–1941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gardan D, Gondret F, Louveau I . Lipid metabolism and secretory function of porcine intramuscular adipocytes compared with subcutaneous and perirenal adipocytes. Am J Physiol Endocrinol Metab 2006; 291: E372–E380.

    Article  CAS  PubMed  Google Scholar 

  39. Gondret F, Guitton N, Guillerm-Regost C, Louveau I . Regional differences in porcine adipocytes isolated from skeletal muscle and adipose tissues as identified by a proteomic approach. J Anim Sci 2008; 86: 2115–2125.

    Article  CAS  PubMed  Google Scholar 

  40. Arrighi N, Moratal C, Clement N, Giorgetti-Peraldi S, Peraldi P, Loubat A et al. Characterization of adipocytes derived from fibro/adipogenic progenitors resident in human skeletal muscle. Cell Death Dis 2015; 6: e1733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Beasley LE, Koster A, Newman AB, Javaid MK, Ferrucci L, Kritchevsky SB et al. Inflammation and race and gender differences in computerized tomography-measured adipose depots. Obesity (Silver Spring) 2009; 17: 1062–1069.

    Article  Google Scholar 

  42. Eckardt K, Sell H, Eckel J . Novel aspects of adipocyte-induced skeletal muscle insulin resistance. Arch Physiol Biochem 2008; 114: 287–298.

    Article  CAS  PubMed  Google Scholar 

  43. Dietze D, Koenen M, Rohrig K, Horikoshi H, Hauner H, Eckel J . Impairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes. Diabetes 2002; 51: 2369–2376.

    Article  CAS  PubMed  Google Scholar 

  44. Lee DE, Kehlenbrink S, Lee H, Hawkins M, Yudkin JS . Getting the message across: mechanisms of physiological cross talk by adipose tissue. Am J Physiol Endocrinol Metab 2009; 296: E1210–E1229.

    Article  CAS  PubMed  Google Scholar 

  45. Sell H, Dietze-Schroeder D, Eckel J . The adipocyte-myocyte axis in insulin resistance. Trends Endocrinol Metab 2006; 17: 416–422.

    Article  CAS  PubMed  Google Scholar 

  46. Samuel VT, Shulman GI . Mechanisms for insulin resistance: common threads and missing links. Cell 2012; 148: 852–871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kovalik JP, Slentz D, Stevens RD, Kraus WE, Houmard JA, Nicoll JB et al. Metabolic remodeling of human skeletal myocytes by cocultured adipocytes depends on the lipolytic state of the system. Diabetes 2011; 60: 1882–1893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 1999; 42: 113–116.

    Article  CAS  PubMed  Google Scholar 

  49. Moro C, Galgani JE, Luu L, Pasarica M, Mairal A, Bajpeyi S et al. Influence of gender, obesity, and muscle lipase activity on intramyocellular lipids in sedentary individuals. J Clin Endocrinol Metab 2009; 94: 3440–3447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogardus C et al. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 1997; 46: 983–988.

    Article  CAS  PubMed  Google Scholar 

  51. Abdul-Ghani MA, DeFronzo RA . Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol 2010; 2010: 476279.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 2008; 7: 45–56.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A Zakaroff-Girard and C Pêcher (Cytometry Core Facility Inserm 1048 part of Toulouse Genotoul Platform) for cytometry analysis, advice and technical assistance. We are grateful to D Garandeau and E Melet (Inserm 1048) for their technical assistance. This study was supported by grants from the National Research Agency ANR-12-JSV1-0010-01 (CM) and ANR LIPOB, Fondation pour la Recherche Médicale, GlaxoSmithKline, Inserm DHOS Recherche Translationnelle and AOL Hôpitaux de Toulouse (DL).

Author information

Authors and Affiliations

  1. INSERM UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France

    C Laurens, K Louche, M Coué, D Langin, C Moro & V Bourlier

  2. University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France

    C Laurens, K Louche, M Coué, D Langin, C Moro & V Bourlier

  3. UMR5273 UPS/CNRS/EFS/INSERM U1031, STROMALab, University de Toulouse, Toulouse, France

    C Sengenes

  4. Department of Clinical Biochemistry, Toulouse University Hospitals, Toulouse, France

    D Langin

Authors
  1. C Laurens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Louche
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Sengenes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Coué
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Langin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Moro
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V Bourlier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V Bourlier.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Laurens, C., Louche, K., Sengenes, C. et al. Adipogenic progenitors from obese human skeletal muscle give rise to functional white adipocytes that contribute to insulin resistance. Int J Obes 40, 497–506 (2016). https://doi.org/10.1038/ijo.2015.193

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2015.193

This article is cited by

Search

Advanced search

Quick links