Inflammation Research

, Volume 68, Issue 5, pp 351–358 | Cite as

Fibroblast growth factor 21 deficiency aggravates obesity-induced hypothalamic inflammation and impairs thermogenic response

  • Luthfiyyah Mutsnaini
  • Chu-Sook Kim
  • Jiye Kim
  • Yeonsoo Joe
  • Hun Taeg Chung
  • Hye-Seon Choi
  • Eun Roh
  • Min-Seon Kim
  • Rina YuEmail author
Original Research Paper


Objective and design

Hypothalamic inflammation is closely associated with metabolic dysregulation. Fibroblast growth factor 21 (FGF21) is known to be an important metabolic regulator with anti-inflammatory properties. In this study, we investigated the effects of FGF21 deficiency on obesity-induced hypothalamic inflammation and thermogenic responses.

Materials and methods

FGF21-deficient mice and/or wild-type (WT) mice were fed a high-fat diet (HFD) for 12 weeks.


FGF21-deficient mice fed an HFD showed increased levels of inflammatory cytokines compared with WT obese control, and this was accompanied by upregulation of gliosis markers in the hypothalamus. Expression of heat-shock protein 72, a marker of neuronal damage, was increased in the FGF21-deficient obese mice, and the expression of hypothalamic neuronal markers involved in anti-thermogenic or thermogenic responses was altered. Moreover, the protein level of uncoupling protein 1 and other thermogenic genes were markedly reduced in the brown adipose tissue of the FGF21-deficient obese mice.


These findings suggest that FGF21 deficiency aggravates obesity-induced hypothalamic inflammation and neuronal injury, leading to alterations in hypothalamic neural circuits accompanied by a reduction of the thermogenic response.


FGF21 Hypothalamic inflammation Metabolism Obesity 



This research was supported by the SRC program (Center for Food & Nutritional Genomics Research: Grant no. 2015R1A5A6001906). MSK was supported by the National Research Foundation (NRF) of Korea funded by the Ministry of Education, Science and Technology, Korean government (no. 2017R1A2B3007123).

Compliance with ethical standards

Conflict of interest

Authors declare that there is no conflict of interest associated with this publication that could have influenced its outcome.


  1. 1.
    Le Thuc O, Stobbe K, Cansell C, Nahon J-L, Blondeau N, Rovère C. Hypothalamic inflammation and energy balance disruptions: spotlight on chemokines. Front Endocrinol. 2017;8:197.CrossRefGoogle Scholar
  2. 2.
    Guillemot-Legris O, Muccioli GG. Obesity-induced neuroinflammation: beyond the hypothalamus. Trends Neurosci. 2017;40(4):237–53.CrossRefGoogle Scholar
  3. 3.
    Yang J, Kim C-S, Tu TH, Kim M-S, Goto T, Kawada T, et al. Quercetin protects obesity-induced hypothalamic inflammation by reducing microglia-mediated inflammatory responses via HO-1 induction. Nutrients. 2017;9(7):650.CrossRefGoogle Scholar
  4. 4.
    Lee CH, Kim HJ, Lee Y-S, Kang GM, Lim HS, Lee S-h, et al. Hypothalamic macrophage inducible nitric oxide synthase mediates obesity-associated hypothalamic inflammation. Cell Rep. 2018;25(4):934–46.e5.CrossRefGoogle Scholar
  5. 5.
    Arruda AP, Milanski M, Coope A, Torsoni AS, Ropelle E, Carvalho DP, et al. Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion. Endocrinology. 2011;152(4):1314–26.CrossRefGoogle Scholar
  6. 6.
    Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKβ/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell. 2008;135(1):61–73.CrossRefGoogle Scholar
  7. 7.
    Kim KH, Lee M-S. FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs. J Endocrinol. 2015;226(1):R1–16.CrossRefGoogle Scholar
  8. 8.
    Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. J Clin Investig. 2005;115(6):1627.CrossRefGoogle Scholar
  9. 9.
    Sonoda J, Chen MZ, Baruch A. FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases. Horm Mol Biol Clin Investig. 2017. Scholar
  10. 10.
    Markan KR, Naber MC, Ameka MK, Anderegg MD, Mangelsdorf DJ, Kliewer SA, et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes. 2014;63(12):4057–63.CrossRefGoogle Scholar
  11. 11.
    Staiger H, Keuper M, Berti L, Hrabě de Angelis M, Häring H-U. Fibroblast growth factor 21-metabolic role in mice and men. Endocr Rev. 2017;38(5):468–88.CrossRefGoogle Scholar
  12. 12.
    Jimenez V, Jambrina C, Casana E, Sacristan V, Muñoz S, Darriba S, et al. FGF21 gene therapy as treatment for obesity and insulin resistance. EMBO Mol Med. 2018;10(8):e8791.CrossRefGoogle Scholar
  13. 13.
    Tan BK, Hallschmid M, Adya R, Kern W, Lehnert H, Randeva HS. Fibroblast growth factor 21 (FGF21) in human cerebrospinal fluid. Diabetes. 2011;60(11):2758–62.CrossRefGoogle Scholar
  14. 14.
    Hsuchou H, Pan W, Kastin AJ. The fasting polypeptide FGF21 can enter brain from blood. Peptides. 2007;28(12):2382–6.CrossRefGoogle Scholar
  15. 15.
    Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol. 2010;24(10):2050–64.CrossRefGoogle Scholar
  16. 16.
    Bookout AL, De Groot MH, Owen BM, Lee S, Gautron L, Lawrence HL, et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med. 2013;19(9):1147–52.CrossRefGoogle Scholar
  17. 17.
    Kharitonenkov A, Dunbar JD, Bina HA, Bright S, Moyers JS, Zhang C, et al. FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho. J Cell Physiol. 2008;215(1):1–7.CrossRefGoogle Scholar
  18. 18.
    Wang Q, Yuan J, Yu Z, Lin L, Jiang Y, Cao Z, et al. FGF21 attenuates high-fat diet-induced cognitive impairment via metabolic regulation and anti-inflammation of obese mice. Mol Neurobiol. 2017;55(6):4702–17.CrossRefGoogle Scholar
  19. 19.
    Fotuhi M, Lubinski B. The effects of obesity on brain structure and size. Practical Neurol. 2013. Accessed Jul/Aug 2013.
  20. 20.
    Shi Y-C, Lau J, Lin Z, Zhang H, Zhai L, Sperk G, et al. Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab. 2013;17(2):236–48.CrossRefGoogle Scholar
  21. 21.
    Morton G, Cummings D, Baskin D, Barsh G, Schwartz M. Central nervous system control of food intake and body weight. Nature. 2006;443(7109):289–95.CrossRefGoogle Scholar
  22. 22.
    Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008;454(7203):455–62.CrossRefGoogle Scholar
  23. 23.
    Dorfman MD, Thaler JP. Hypothalamic inflammation and gliosis in obesity. Curr Opin Endocrinol Diabetes Obes. 2015;22(5):325.CrossRefGoogle Scholar
  24. 24.
    Xanthos DN, Sandkühler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014;15(1):43.CrossRefGoogle Scholar
  25. 25.
    Block ML, Zecca L, Hong J-S. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8(1):57.CrossRefGoogle Scholar
  26. 26.
    Turturici G, Sconzo G, Geraci F. Hsp70 and its molecular role in nervous system diseases. Biochem Res Int. 2011. Scholar
  27. 27.
    Kwon YH, Kim J, Kim CS, Tu TH, Kim MS, Suk K, et al. Hypothalamic lipid-laden astrocytes induce microglia migration and activation. FEBS Lett. 2017;591(12):1742–51.CrossRefGoogle Scholar
  28. 28.
    Leng Y, Wang Z, Tsai L-K, Leeds P, Fessler EB, Wang J, et al. FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers. Mol Psychiatry. 2015;20(2):215.CrossRefGoogle Scholar
  29. 29.
    Raji CA, Ho AJ, Parikshak NN, Becker JT, Lopez OL, Kuller LH, et al. Brain structure and obesity. Hum Brain Mapp. 2010;31(3):353–64.Google Scholar
  30. 30.
    Wang H, Wen B, Cheng J, Li H. Brain structural differences between normal and obese adults and their links with lack of perseverance, negative urgency, and sensation seeking. Sci Rep. 2017;7:40595.CrossRefGoogle Scholar
  31. 31.
    Butler AB, Hodos W. Evolution and adaptation of the brain, behavior, and intelligence. In: Butler AB, editor. Comparative vertebrate neuroanatomy: evolution and adaptation. 2nd ed. New Jersey: Wiley; 2005. p. 93–111.CrossRefGoogle Scholar
  32. 32.
    Chechi K, Carpentier AC, Richard D. Understanding the brown adipocyte as a contributor to energy homeostasis. Trends Endoctinol Metab. 2013;24(8):408–20.CrossRefGoogle Scholar
  33. 33.
    Contreras C, Gonzalez F, Fernø J, Diéguez C, Rahmouni K, Nogueiras R, et al. The brain and brown fat. Ann Med. 2015;47(2):150–68.CrossRefGoogle Scholar
  34. 34.
    Yang X, Ruan H-B. Neuronal control of adaptive thermogenesis. Front Endocrinol. 2015;6:149.CrossRefGoogle Scholar
  35. 35.
    Zhang X, van den Pol AN. Thyrotropin-releasing hormone (TRH) inhibits melanin-concentrating hormone neurons: implications for TRH-mediated anorexic and arousal actions. J Neurosci. 2012;32(9):3032–43.CrossRefGoogle Scholar
  36. 36.
    Diniz GB, Bittencourt JC. The melanin-concentrating hormone as an integrative peptide driving motivated behaviors. Front Syst Neurosci. 2017;11:32.CrossRefGoogle Scholar
  37. 37.
    Dalvi P, Chalmers J, Luo V, Han D-Y, Wellhauser L, Liu Y, et al. High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-α on appetite-regulating NPY neurons. Int J Obes. 2017;41(1):149–58.CrossRefGoogle Scholar
  38. 38.
    Sarruf DA, Thaler JP, Morton GJ, German J, Fischer JD, Ogimoto K, et al. Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes. 2010;59(7):1817–24.CrossRefGoogle Scholar
  39. 39.
    Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012;26(3):271–81.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Luthfiyyah Mutsnaini
    • 1
  • Chu-Sook Kim
    • 1
  • Jiye Kim
    • 1
    • 2
  • Yeonsoo Joe
    • 3
  • Hun Taeg Chung
    • 3
  • Hye-Seon Choi
    • 3
  • Eun Roh
    • 2
    • 4
  • Min-Seon Kim
    • 2
  • Rina Yu
    • 1
    Email author
  1. 1.Department of Food Science and NutritionUniversity of UlsanUlsanSouth Korea
  2. 2.Division of Endocrinology and MetabolismUniversity of Ulsan College of MedicineSeoulSouth Korea
  3. 3.Department of Biological ScienceUniversity of UlsanUlsanSouth Korea
  4. 4.Appetite Regulation Laboratory, Asan Institute for Life SciencesUniversity of Ulsan College of MedicineSeoulSouth Korea

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