Skip to main content

Advertisement

SpringerLink
Log in

Fibroblast growth factor-21 restores insulin sensitivity but induces aberrant bone microstructure in obese insulin-resistant rats

  • Original Article
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Fibroblast growth factor (FGF)-21 is a potent endocrine factor that improves insulin resistance and obesity-associated metabolic disorders. However, concomitant activation of peroxisome proliferator-activated receptor-γ by FGF-21 makes bone susceptible to osteopenia and fragility fracture. Since an increase in body weight often induced adaptive change in bone by making it resistant to fracture, it was unclear whether FGF-21 would still induce bone defects in overweight rats. Therefore, the present study aimed to investigate bone microstructure and its mechanical properties in high fat diet (HF)-fed rats treated with 0.1 mg/kg/day FGF-21. Eighteen male rats were divided into two groups to receive either a normal diet or HF for 12 weeks. HF rats were then divided into two subgroups to receive either vehicle or FGF-21 for 4 weeks. The results showed that HF led to obesity, dyslipidemia and insulin resistance, as indicated by hyperinsulinemia with euglycemia. In HF rats, there was an increase in tibial yield displacement (an indicator of ability to be deformed without losing toughness, as determined by 3-point bending) without changes in tibial trabecular volumetric bone mineral density (vBMD) or cortical bone parameters, e.g., cortical thickness and bone area. FGF-21 treatment strongly improved the metabolic parameters and increased insulin sensitivity in HF rats. However, FGF-21-treated HF rats showed lower yield displacement, trabecular vBMD, trabecular bone volume, trabecular thickness, and osteoblast surface compared with vehicle-treated HF rats. These findings suggest that, despite being a potent antagonist of insulin resistance and visceral fat accumulation, FGF-21 is associated with bone defects in HF rats.

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

Similar content being viewed by others

References

  1. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB (2005) FGF-21 as a novel metabolic regulator. J Clin Invest 115:1627–1635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, Hansen BC, Shanafelt AB, Etgen GJ (2007) The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148:774–781

    Article  CAS  PubMed  Google Scholar 

  3. Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK et al (2007) Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 27:3417–3428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM (2006) Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 281:15694–15700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nishimura T, Nakatake Y, Konishi M, Itoh N (2000) Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta 1492:203–206

    Article  CAS  PubMed  Google Scholar 

  6. Wente W, Efanov AM, Brenner M, Kharitonenkov A, Koster A, Sandusky GE, Sewing S, Treinies I, Zitzer H, Gromada J (2006) Fibroblast growth factor-21 improves pancreatic β-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 55:2470–2478

    Article  CAS  PubMed  Google Scholar 

  7. Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X, Mu J, Thompson JR, Berger JP, Wong KK (2008) Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor γ and altered metabolic states. Mol Pharmacol 74:403–412

    Article  CAS  PubMed  Google Scholar 

  8. Cantó C, Auwerx J (2012) Cell biology. FGF21 takes a fat bite. Science 336:675–676

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wei W, Dutchak PA, Wang X, Ding X, Wang X, Bookout AL, Goetz R, Mohammadi M, Gerard RD, Dechow PC, Mangelsdorf DJ, Kliewer SA, Wan Y (2012) Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor gamma. Proc Natl Acad Sci USA 109:3143–3148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ali AA, Weinstein RS, Stewart SA, Parfitt AM, Manolagas SC, Jilka RL (2005) Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology 146:1226–1235

    Article  CAS  PubMed  Google Scholar 

  11. Apaijai N, Pintana H, Chattipakorn SC, Chattipakorn N (2012) Cardioprotective effects of metformin and vildagliptin in adult rats with insulin resistance induced by a high-fat diet. Endocrinology 153:3878–3885

    Article  CAS  PubMed  Google Scholar 

  12. Pintana H, Apaijai N, Pratchayasakul W, Chattipakorn N, Chattipakorn SC (2012) Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats. Life Sci 91:409–414

    Article  CAS  PubMed  Google Scholar 

  13. Suntornsaratoon P, Krishnamra N, Charoenphandhu N (2015) Positive long-term outcomes from presuckling calcium supplementation in lactating rats and the offspring. Am J Physiol Endocrinol Metab 308:E1010–E1022

    Article  CAS  PubMed  Google Scholar 

  14. Appleton DJ, Rand JS, Sunvold GD (2005) Basal plasma insulin and homeostasis model assessment (HOMA) are indicators of insulin sensitivity in cats. J Feline Med Surg 7:183–193

    Article  CAS  PubMed  Google Scholar 

  15. Haffner SM, Miettinen H, Stern MP (1997) The homeostasis model in the San Antonio Heart Study. Diabetes Care 20:1087–1092

    Article  CAS  PubMed  Google Scholar 

  16. Pipatpiboon N, Pintana H, Pratchayasakul W, Chattipakorn N, Chattipakorn SC (2013) DPP4-inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption. Eur J Neurosci 37:839–849

    Article  PubMed  Google Scholar 

  17. Pipatpiboon N, Pratchayasakul W, Chattipakorn N, Chattipakorn SC (2012) PPARγ agonist improves neuronal insulin receptor function in hippocampus and brain mitochondria function in rats with insulin resistance induced by long term high-fat diets. Endocrinology 153:329–338

    Article  CAS  PubMed  Google Scholar 

  18. Huang J, Ishino T, Chen G, Rolzin P, Osothprarop TF, Retting K, Li L, Jin P, Matin MJ, Huyghe B, Talukdar S, Bradshaw CW, Palanki M, Violand BN, Woodnutt G, Lappe RW, Ogilvie K, Levin N (2013) Development of a novel long-acting antidiabetic FGF21 mimetic by targeted conjugation to a scaffold antibody. J Pharmacol Exp Ther 346:270–280

    Article  CAS  PubMed  Google Scholar 

  19. Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht S, Hecht R, Li YS, Lindberg RA, Chen JL, Jung DY, Zhang Z, Ko HJ, Kim JK, Veniant MM (2009) Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58:250–259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Berglund ED, Li CY, Bina HA, Lynes SE, Michael MD, Shanafelt AB, Kharitonenkov A, Wasserman DH (2009) Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity. Endocrinology 150:4084–4093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lecka-Czernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka RL (2002) Divergent effects of selective peroxisome proliferator-activated receptor-γ 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology 143:2376–2384

    CAS  Google Scholar 

  22. Rzonca SO, Suva LJ, Gaddy D, Montague DC, Lecka-Czernik B (2004) Bone is a target for the antidiabetic compound rosiglitazone. Endocrinology 145:401–406

    Article  CAS  PubMed  Google Scholar 

  23. Caverzasio J, Thouverey C (2011) Activation of FGF receptors is a new mechanism by which strontium ranelate induces osteoblastic cell growth. Cell Physiol Biochem 27:243–250

    Article  CAS  PubMed  Google Scholar 

  24. Wan Y, Chong LW, Evans RM (2007) PPAR-γ regulates osteoclastogenesis in mice. Nat Med 13:1496–1503

    Article  CAS  PubMed  Google Scholar 

  25. Wan Y (2013) Bone marrow mesenchymal stem cells: fat on and blast off by FGF21. Int J Biochem Cell Biol 45:546–549

    Article  CAS  PubMed  Google Scholar 

  26. Chen XX, Yang T (2015) Roles of leptin in bone metabolism and bone diseases. J Bone Miner Metab 33:474–485

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Cluster and Program Management Office (CPMO), National Science and Technology Development Agency (P-13-00100 to N. Charoenphandhu), the Thailand Research Fund (TRF)–Mahidol University through the TRF Senior Research Scholar Grant (RTA5780001 to N. Charoenphandhu), Government Budget, Mahidol University (N. Charoenphandhu), Thailand Research Fund Grants: TRF-BRG 5780016 (S. Chattipakorn), a NSTDA Research Chair Grant from the National Science and Technology Development Agency (N. Chattipakorn), and a Chiang Mai University Center of Excellence Award (N. Chattipakorn).

Author information

Authors and Affiliations

  1. Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand

    Narattaphol Charoenphandhu & Nateetip Krishnamra

  2. Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand

    Narattaphol Charoenphandhu, Panan Suntornsaratoon & Nateetip Krishnamra

  3. Neurophysiology Unit, Faculty of Medicine, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai, Thailand

    Piangkwan Sa-nguanmoo, Pongpun Tanajak, Nipon Chattipakorn & Siriporn Chattipakorn

  4. Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

    Piangkwan Sa-nguanmoo, Pongpun Tanajak & Nipon Chattipakorn

  5. School of Pharmaceutical Sciences, Wenzhou Medical University, University-town, Wenzhou, Zhejiang, China

    Xiaojie Wang, Guang Liang, Xiaokun Li & Chao Jiang

  6. Department of Oral Biology and Diagnostic Science, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand

    Siriporn Chattipakorn

Authors
  1. Narattaphol Charoenphandhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Panan Suntornsaratoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nateetip Krishnamra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Piangkwan Sa-nguanmoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pongpun Tanajak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaojie Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guang Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaokun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nipon Chattipakorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Siriporn Chattipakorn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Siriporn Chattipakorn.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 81 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Charoenphandhu, N., Suntornsaratoon, P., Krishnamra, N. et al. Fibroblast growth factor-21 restores insulin sensitivity but induces aberrant bone microstructure in obese insulin-resistant rats. J Bone Miner Metab 35, 142–149 (2017). https://doi.org/10.1007/s00774-016-0745-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-016-0745-z

Keywords

Search

Navigation