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Inflammation Research
Published in: Inflammation Research 5/2019

01-05-2019 | Obesity | Original Research Paper

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

Authors: Luthfiyyah Mutsnaini, Chu-Sook Kim, Jiye Kim, Yeonsoo Joe, Hun Taeg Chung, Hye-Seon Choi, Eun Roh, Min-Seon Kim, Rina Yu

Published in: Inflammation Research | Issue 5/2019

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Abstract

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.

Results

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.

Conclusions

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.
Literature
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.CrossRef
2.
Guillemot-Legris O, Muccioli GG. Obesity-induced neuroinflammation: beyond the hypothalamus. Trends Neurosci. 2017;40(4):237–53.CrossRefPubMed
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.CrossRefPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
9.
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
14.
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
19.
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.CrossRefPubMed
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.CrossRefPubMed
22.
23.
24.
Xanthos DN, Sandkühler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014;15(1):43.CrossRefPubMed
25.
Block ML, Zecca L, Hong J-S. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8(1):57.CrossRefPubMed
26.
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.CrossRefPubMed
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.CrossRefPubMed
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.PubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRef
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.CrossRef
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.CrossRefPubMed
34.
Yang X, Ruan H-B. Neuronal control of adaptive thermogenesis. Front Endocrinol. 2015;6:149.CrossRef
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.CrossRefPubMedPubMedCentral
36.
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.CrossRef
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
Metadata
Title
Fibroblast growth factor 21 deficiency aggravates obesity-induced hypothalamic inflammation and impairs thermogenic response
Authors
Luthfiyyah Mutsnaini
Chu-Sook Kim
Jiye Kim
Yeonsoo Joe
Hun Taeg Chung
Hye-Seon Choi
Eun Roh
Min-Seon Kim
Rina Yu
Publication date
01-05-2019
Publisher
Springer International Publishing
Keywords
Obesity
Obesity
Published in
Inflammation Research / Issue 5/2019
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-019-01222-2

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