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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Polyunsaturated fatty acid receptors, GPR40 and GPR120, are expressed in the hypothalamus and control energy homeostasis and inflammation

Authors: Nathalia R. V. Dragano, Carina Solon, Albina F. Ramalho, Rodrigo F. de Moura, Daniela S. Razolli, Elisabeth Christiansen, Carlos Azevedo, Trond Ulven, Licio A. Velloso

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

The consumption of large amounts of dietary fats is one of the most important environmental factors contributing to the development of obesity and metabolic disorders. GPR120 and GPR40 are polyunsaturated fatty acid receptors that exert a number of systemic effects that are beneficial for metabolic and inflammatory diseases. Here, we evaluate the expression and potential role of hypothalamic GPR120 and GPR40 as targets for the treatment of obesity.

Methods

Male Swiss (6-weeks old), were fed with a high fat diet (HFD, 60% of kcal from fat) for 4 weeks. Next, mice underwent stereotaxic surgery to place an indwelling cannula into the right lateral ventricle. intracerebroventricular (icv)-cannulated mice were treated twice a day for 6 days with 2.0 μL saline or GPR40 and GPR120 agonists: GW9508, TUG1197, or TUG905 (2.0 μL, 1.0 mM). Food intake and body mass were measured during the treatment period. At the end of the experiment, the hypothalamus was collected for real-time PCR analysis.

Results

We show that both receptors are expressed in the hypothalamus; GPR120 is primarily present in microglia, whereas GPR40 is expressed in neurons. Upon intracerebroventricular treatment, GW9508, a non-specific agonist for both receptors, reduced energy efficiency and the expression of inflammatory genes in the hypothalamus. Reducing GPR120 hypothalamic expression using a lentivirus-based approach resulted in the loss of the anti-inflammatory effect of GW9508 and increased energy efficiency. Intracerebroventricular treatment with the GPR120- and GPR40-specific agonists TUG1197 and TUG905, respectively, resulted in milder effects than those produced by GW9508.

Conclusions

GPR120 and GPR40 act in concert in the hypothalamus to reduce energy efficiency and regulate the inflammation associated with obesity. The combined activation of both receptors in the hypothalamus results in better metabolic outcomes than the isolated activation of either receptor alone.
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Literature
1.
Hotamisligil GS. Inflammation and endoplasmic reticulum stress in obesity and diabetes. Int J Obes (Lond). 2008;32 Suppl 7:S52–54.CrossRef
2.
Hill JO, Peters JC. Environmental contributions to the obesity epidemic. Science. 1998;280:1371–4.CrossRefPubMed
3.
Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell. 2004;116:337–50.CrossRefPubMed
4.
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116:3015–25.CrossRefPubMedPubMedCentral
5.
Velloso LA, Eizirik DL, Cnop M. Type 2 diabetes mellitus—an autoimmune disease? Nat Rev Endocrinol. 2013;9:750–5.CrossRefPubMed
6.
Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18:363–74.CrossRefPubMed
7.
Velloso LA, Schwartz MW. Altered hypothalamic function in diet-induced obesity. Int J Obes (Lond). 2011;35:1455–65.CrossRef
8.
Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev. 2008;29:42–61.CrossRefPubMed
9.
Cnop M, Foufelle F, Velloso LA. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med. 2012;18:59–68.CrossRefPubMed
10.
11.
Purkayastha S, Zhang G, Cai D. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-beta and NF-kappaB. Nat Med. 2011;17:883–7.CrossRefPubMedPubMedCentral
12.
Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D. Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH. Nature. 2013;497:211–6.CrossRefPubMedPubMedCentral
13.
Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11:98–107.CrossRefPubMed
14.
Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415–45.CrossRefPubMed
15.
16.
Goldfine AB, Fonseca V, Jablonski KA, Chen YD, Tipton L, Staten MA, Shoelson SE. Targeting inflammation using salsalate in type 2 diabetes study t: salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann Intern Med. 2013;159:1–12.CrossRefPubMedPubMedCentral
17.
Nagasumi K, Esaki R, Iwachidow K, Yasuhara Y, Ogi K, Tanaka H, Nakata M, Yano T, Shimakawa K, Taketomi S, et al. Overexpression of GPR40 in pancreatic beta-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes. 2009;58:1067–76.CrossRefPubMedPubMedCentral
18.
Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, Olefsky JM. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010;142:687–98.CrossRefPubMedPubMedCentral
19.
Cintra DE, Ropelle ER, Moraes JC, Pauli JR, Morari J, Souza CT, Grimaldi R, Stahl M, Carvalheira JB, Saad MJ, Velloso LA. Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity. PLoS One. 2012;7:e30571.CrossRefPubMedPubMedCentral
20.
Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H, et al. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature. 2003;422:173–6.CrossRefPubMed
21.
22.
da Oh Y, Walenta E, Akiyama TE, Lagakos WS, Lackey D, Pessentheiner AR, Sasik R, Hah N, Chi TJ, Cox JM, et al. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nat Med. 2014;20:942–7.CrossRefPubMedPubMedCentral
23.
Ichimura A, Hasegawa S, Kasubuchi M, Kimura I. Free fatty acid receptors as therapeutic targets for the treatment of diabetes. Front Pharmacol. 2014;5:236.CrossRefPubMedPubMedCentral
24.
25.
Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS, Minnick DT, et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem. 2003;278:11303–11.CrossRefPubMed
26.
Briscoe CP, Peat AJ, McKeown SC, Corbett DF, Goetz AS, Littleton TR, McCoy DC, Kenakin TP, Andrews JL, Ammala C, et al. Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules. Br J Pharmacol. 2006;148:619–28.CrossRefPubMedPubMedCentral
27.
Edfalk S, Steneberg P, Edlund H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes. 2008;57:2280–7.CrossRefPubMedPubMedCentral
28.
Boneva NB, Yamashima T. New insights into “GPR40-CREB interaction in adult neurogenesis” specific for primates. Hippocampus. 2012;22:896–905.CrossRefPubMed
29.
Christiansen E, Due-Hansen ME, Urban C, Grundmann M, Schroder R, Hudson BD, Milligan G, Cawthorne MA, Kostenis E, Kassack MU, Ulven T. Free fatty acid receptor 1 (FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophilicity and improves ADME properties. J Med Chem. 2012;55:6624–8.CrossRefPubMed
30.
Azevedo CM, Watterson KR, Wargent ET, Hansen SV, Hudson BD, Kepczynska MA, Dunlop J, Shimpukade B, Christiansen E, Milligan G, et al. Non-acidic free fatty acid receptor 4 agonists with antidiabetic Activity. J Med Chem. 2016;59:8868–78.CrossRefPubMed
31.
Dragano NR, Marques A, Cintra DE, Solon C, Morari J, Leite-Legatti AV, Velloso LA, Marostica-Junior MR. Freeze-dried jaboticaba peel powder improves insulin sensitivity in high-fat-fed mice. Br J Nutr. 2013;110:447–55.CrossRefPubMed
32.
Morari J, Anhe GF, Nascimento LF, de Moura RF, Razolli D, Solon C, Guadagnini D, Souza G, Mattos AH, Tobar N, et al. Fractalkine (CX3CL1) is involved in the early activation of hypothalamic inflammation in experimental obesity. Diabetes. 2014;63:3770–84.CrossRefPubMed
33.
Razolli DS, Moraes JC, Morari J, Moura RF, Vinolo MA, Velloso LA. TLR4 expression in bone marrow-derived cells is both necessary and sufficient to produce the insulin resistance phenotype in diet-induced obesity. Endocrinology. 2015;156:103–13.CrossRefPubMed
34.
Goodman T, Hajihosseini MK. Hypothalamic tanycytes-masters and servants of metabolic, neuroendocrine, and neurogenic functions. Front Neurosci. 2015;9:387.CrossRefPubMedPubMedCentral
35.
Balland E, Dam J, Langlet F, Caron E, Steculorum S, Messina A, Rasika S, Falluel-Morel A, Anouar Y, Dehouck B, et al. Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metab. 2014;19:293–301.CrossRefPubMedPubMedCentral
36.
Chalmers JA, Jang JJ, Belsham DD. Glucose sensing mechanisms in hypothalamic cell models: glucose inhibition of AgRP synthesis and secretion. Mol Cell Endocrinol. 2014;382:262–70.CrossRefPubMed
37.
Henn A, Lund S, Hedtjarn M, Schrattenholz A, Porzgen P, Leist M. The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. ALTEX. 2009;26:83–94.CrossRefPubMed
38.
Hudson BD, Shimpukade B, Mackenzie AE, Butcher AJ, Pediani JD, Christiansen E, Heathcote H, Tobin AB, Ulven T, Milligan G. The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism. Mol Pharmacol. 2013;84:710–25.CrossRefPubMedPubMedCentral
39.
Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, Elwood PC, Deadman NM. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;2:757–61.CrossRefPubMed
40.
Bjerregaard P, Mulvad G, Pedersen HS. Cardiovascular risk factors in Inuit of Greenland. Int J Epidemiol. 1997;26:1182–90.CrossRefPubMed
41.
Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, Gomez-Gracia E, Ruiz-Gutierrez V, Fiol M, Lapetra J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279–90.CrossRefPubMed
42.
Fischer S, Weber PC. Prostaglandin I3 is formed in vivo in man after dietary eicosapentaenoic acid. Nature. 1984;307:165–8.CrossRefPubMed
43.
Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med. 2000;192:1197–204.CrossRefPubMedPubMedCentral
44.
Schmitz G, Ecker J. The opposing effects of n-3 and n-6 fatty acids. Prog Lipid Res. 2008;47:147–55.CrossRefPubMed
45.
46.
47.
Sampath H, Ntambi JM. Polyunsaturated fatty acid regulation of gene expression. Nutr Rev. 2004;62:333–9.CrossRefPubMed
48.
Wolfrum C, Borchers T, Sacchettini JC, Spener F. Binding of fatty acids and peroxisome proliferators to orthologous fatty acid binding proteins from human, murine, and bovine liver. Biochemistry. 2000;39:1469–74.CrossRefPubMed
49.
Delerive P, Gervois P, Fruchart JC, Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem. 2000;275:36703–7.CrossRefPubMed
50.
De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology. 2005;146:4192–9.CrossRefPubMed
51.
Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, Tsukumo DM, Anhe G, Amaral ME, Takahashi HK, et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci. 2009;29:359–70.CrossRefPubMed
52.
Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, Myers Jr MG, Ozcan U. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009;9:35–51.CrossRefPubMed
53.
Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest. 2012;122:153–62.CrossRefPubMed
54.
Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell. 2008;135:61–73.CrossRefPubMedPubMedCentral
55.
Benoit SC, Kemp CJ, Elias CF, Abplanalp W, Herman JP, Migrenne S, Lefevre AL, Cruciani-Guglielmacci C, Magnan C, Yu F, et al. Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents. J Clin Invest. 2009;119:2577–89.CrossRefPubMedPubMedCentral
56.
Nascimento LF, Souza GF, Morari J, Barbosa GO, Solon C, Moura RF, Victorio SC, Ignacio-Souza LM, Razolli DS, Carvalho HF, Velloso LA. n-3 fatty acids induce neurogenesis of predominantly POMC-expressing cells in the hypothalamus. Diabetes. 2016;65:673–86.CrossRefPubMed
57.
Ma D, Lu L, Boneva NB, Warashina S, Kaplamadzhiev DB, Mori Y, Nakaya MA, Kikuchi M, Tonchev AB, Okano H, Yamashima T. Expression of free fatty acid receptor GPR40 in the neurogenic niche of adult monkey hippocampus. Hippocampus. 2008;18:326–33.CrossRefPubMed
58.
Nakamoto K, Nishinaka T, Sato N, Mankura M, Koyama Y, Kasuya F, Tokuyama S. Hypothalamic GPR40 signaling activated by free long chain fatty acids suppresses CFA-induced inflammatory chronic pain. PLoS One. 2013;8:e81563.CrossRefPubMedPubMedCentral
59.
Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med. 2005;11:90–4.CrossRefPubMed
60.
Wellhauser L, Belsham DD. Activation of the omega-3 fatty acid receptor GPR120 mediates anti-inflammatory actions in immortalized hypothalamic neurons. J Neuroinflammation. 2014;11:60.CrossRefPubMedPubMedCentral
61.
Horvath TL, Sarman B, Garcia-Caceres C, Enriori PJ, Sotonyi P, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, et al. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci U S A. 2010;107:14875–80.CrossRefPubMedPubMedCentral
62.
Bell ME, Bhatnagar S, Akana SF, Choi S, Dallman MF. Disruption of arcuate/paraventricular nucleus connections changes body energy balance and response to acute stress. J Neurosci. 2000;20:6707–13.PubMed
63.
Dietrich MO, Antunes C, Geliang G, Liu ZW, Borok E, Nie Y, Xu AW, Souza DO, Gao Q, Diano S, et al. Agrp neurons mediate Sirt1’s action on the melanocortin system and energy balance: roles for Sirt1 in neuronal firing and synaptic plasticity. J Neurosci. 2010;30:11815–25.CrossRefPubMedPubMedCentral
Metadata
Title
Polyunsaturated fatty acid receptors, GPR40 and GPR120, are expressed in the hypothalamus and control energy homeostasis and inflammation
Authors
Nathalia R. V. Dragano
Carina Solon
Albina F. Ramalho
Rodrigo F. de Moura
Daniela S. Razolli
Elisabeth Christiansen
Carlos Azevedo
Trond Ulven
Licio A. Velloso
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-0869-7

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