nach oben

Erschienen in:

01.11.2015 | Article

Fatty acids from fat cell lipolysis do not activate an inflammatory response but are stored as triacylglycerols in adipose tissue macrophages

verfasst von: Sylvie Caspar-Bauguil, Catherine-Ines Kolditz, Corinne Lefort, Isabelle Vila, Etienne Mouisel, Diane Beuzelin, Geneviève Tavernier, Marie-Adeline Marques, Alexia Zakaroff-Girard, Christiane Pecher, Marianne Houssier, Lucile Mir, Sarah Nicolas, Cédric Moro, Dominique Langin

Erschienen in: Diabetologia | Ausgabe 11/2015

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

Activation of macrophages by fatty acids (FAs) is a potential mechanism linking obesity to adipose tissue (AT) inflammation and insulin resistance. Here, we investigated the effects of FAs released during adipocyte lipolysis on AT macrophages (ATMs).

Methods

Human THP-1 macrophages were treated with media from human multipotent adipose-derived stem (hMADS) adipocytes stimulated with lipolytic drugs. Macrophages were also treated with mixtures of FAs and an inhibitor of Toll-like receptor 4, since this receptor is activated by saturated FAs. Levels of mRNA and the secretion of inflammation-related molecules were measured in macrophages. FA composition was determined in adipocytes, conditioned media and macrophages. The effect of chronic inhibition or acute activation of fat cell lipolysis on ATM response was investigated in vivo in mice.

Results

Whereas palmitic acid alone activates THP-1, conditioned media from hMADS adipocyte lipolysis had no effect on IL, chemokine and cytokine gene expression, and secretion by macrophages. Mixtures of FAs representing de novo lipogenesis or habitual dietary conditions also had no effect. FAs derived from adipocyte lipolysis were taken up by macrophages and stored as triacylglycerol droplets. In vivo, chronic treatment with an antilipolytic drug did not modify gene expression and number of ATMs in mice with intact or defective Tlr4. Stimulation of adipocyte lipolysis increased storage of neutral lipids by macrophages without change in number and phenotype.

Conclusions/interpretation

Our data suggest that adipocyte lipolysis does not activate inflammatory pathways in ATMs, which instead may act as scavengers of FAs.

Nur mit Berechtigung zugänglich

Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111–2117PubMedCentralCrossRefPubMed

Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246CrossRefPubMed

Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808PubMedCentralCrossRefPubMed

Xu H, Barnes GT, Yang Q et al (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830PubMedCentralCrossRefPubMed

Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271:665–668CrossRefPubMed

Kanda H, Tateya S, Tamori Y et al (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116:1494–1505PubMedCentralCrossRefPubMed

Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS (2007) Regulation of lipolysis in adipocytes. Annu Rev Nutr 27:79–101PubMedCentralCrossRefPubMed

Langin D, Arner P (2006) Importance of TNFalpha and neutral lipases in human adipose tissue lipolysis. Trends Endocrinol Metab 17:314–320CrossRefPubMed

Samuel VT, Petersen KF, Shulman GI (2010) Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375:2267–2277PubMedCentralCrossRefPubMed

10.

Suganami T, Nishida J, Ogawa Y (2005) A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 25:2062–2068CrossRefPubMed

11.

Lee JY, Sohn KH, Rhee SH, Hwang D (2001) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 276:16683–16689CrossRefPubMed

12.

Nguyen MT, Favelyukis S, Nguyen AK et al (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 282:35279–35292CrossRefPubMed

13.

Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–3025PubMedCentralCrossRefPubMed

14.

Suganami T, Tanimoto-Koyama K, Nishida J et al (2007) Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler Thromb Vasc Biol 27:84–91CrossRefPubMed

15.

Tsukumo DM, Carvalho-Filho MA, Carvalheira JB et al (2007) Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56:1986–1998CrossRefPubMed

16.

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

17.

Tavernier G, Galitzky J, Valet P et al (1995) Molecular mechanisms underlying regional variations of catecholamine-induced lipolysis in rat adipocytes. Am J Physiol 268:E1135–E1142PubMed

18.

Langin D, Dicker A, Tavernier G et al (2005) Adipocyte lipases and defect of lipolysis in human obesity. Diabetes 54:3190–3197CrossRefPubMed

19.

Raclot T, Langin D, Lafontan M, Groscolas R (1997) Selective release of human adipocyte fatty acids according to molecular structure. Biochem J 324:911–915PubMedCentralCrossRefPubMed

20.

Caspar-Bauguil S, Fioroni A, Galinier A et al (2012) Pro-inflammatory phospholipid arachidonic acid/eicosapentaenoic acid ratio of dysmetabolic severely obese women. Obes Surg 22:935–944CrossRefPubMed

21.

Girousse A, Tavernier G, Valle C et al (2013) Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass. PLoS Biol 11:e1001485PubMedCentralCrossRefPubMed

22.

Viguerie N, Montastier E, Maoret JJ et al (2012) Determinants of human adipose tissue gene expression: impact of diet, sex, metabolic status, and cis genetic regulation. PLoS Genet 8:e1002959PubMedCentralCrossRefPubMed

23.

Ii M, Matsunaga N, Hazeki K et al (2006) A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol Pharmacol 69:1288–1295CrossRefPubMed

24.

Vila IK, Badin PM, Marques MA et al (2014) Immune cell Toll-like receptor 4 mediates the development of obesity- and endotoxemia-associated adipose tissue fibrosis. Cell Rep 7:1116–1129CrossRefPubMed

25.

Lee JY, Plakidas A, Lee WH et al (2003) Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res 44:479–486CrossRefPubMed

26.

Erridge C, Samani NJ (2009) Saturated fatty acids do not directly stimulate Toll-like receptor signaling. Arterioscler Thromb Vasc Biol 29:1944–1949CrossRefPubMed

27.

Schaeffler A, Gross P, Buettner R et al (2009) Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity. Immunology 126:233–245PubMedCentralCrossRefPubMed

28.

Heinrichsdorff J, Olefsky JM (2012) Fetuin-A: the missing link in lipid-induced inflammation. Nat Med 18:1182–1183CrossRefPubMed

29.

Pal D, Dasgupta S, Kundu R et al (2012) Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 18:1279–1285CrossRefPubMed

30.

Collins JM, Neville MJ, Pinnick KE et al (2011) De novo lipogenesis in the differentiating human adipocyte can provide all fatty acids necessary for maturation. J Lipid Res 52:1683–1692PubMedCentralCrossRefPubMed

31.

Hodson L, Skeaff CM, Fielding BA (2008) Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake. Prog Lipid Res 47:348–380CrossRefPubMed

32.

Huang S, Rutkowsky JM, Snodgrass RG et al (2012) Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J Lipid Res 53:2002–2013PubMedCentralCrossRefPubMed

33.

Dasu MR, Jialal I (2011) Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors. Am J Physiol Endocrinol Metab 300:E145–E154PubMedCentralCrossRefPubMed

34.

Chang CF, Chau YP, Kung HN, Lu KS (2012) The lipopolysaccharide-induced pro-inflammatory response in RAW264.7 cells is attenuated by an unsaturated fatty acid-bovine serum albumin complex and enhanced by a saturated fatty acid-bovine serum albumin complex. Inflamm Res 61:151–160CrossRefPubMed

35.

Collins JM, Neville MJ, Hoppa MB, Frayn KN (2010) De novo lipogenesis and stearoyl-CoA desaturase are coordinately regulated in the human adipocyte and protect against palmitate-induced cell injury. J Biol Chem 285:6044–6052PubMedCentralCrossRefPubMed

36.

Ishiyama J, Taguchi R, Akasaka Y et al (2011) Unsaturated FAs prevent palmitate-induced LOX-1 induction via inhibition of ER stress in macrophages. J Lipid Res 52:299–307PubMedCentralCrossRefPubMed

37.

Kadotani A, Tsuchiya Y, Hatakeyama H, Katagiri H, Kanzaki M (2009) Different impacts of saturated and unsaturated free fatty acids on COX-2 expression in C(2)C(12) myotubes. Am J Physiol Endocrinol Metab 297:E1291–E1303CrossRefPubMed

38.

L'Homme L, Esser N, Riva L et al (2013) Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages. J Lipid Res 54:2998–3008PubMedCentralCrossRefPubMed

39.

Staiger K, Staiger H, Weigert C, Haas C, Haring HU, Kellerer M (2006) Saturated, but not unsaturated, fatty acids induce apoptosis of human coronary artery endothelial cells via nuclear factor-kappaB activation. Diabetes 55:3121–3126CrossRefPubMed

40.

Cinti S, Mitchell G, Barbatelli G et al (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46:2347–2355CrossRefPubMed

41.

Saberi M, Woods NB, de Luca C et al (2009) Hematopoietic cell-specific deletion of Toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab 10:419–429PubMedCentralCrossRefPubMed

42.

Kosteli A, Sugaru E, Haemmerle G et al (2010) Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest 120:3466–3479PubMedCentralCrossRefPubMed

43.

Huang SC, Everts B, Ivanova Y et al (2014) Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol 15:846–855PubMedCentralCrossRefPubMed

44.

Klein-Wieringa IR, Andersen SN, Kwekkeboom JC et al (2013) Adipocytes modulate the phenotyped of human macrophages through secreted lipids. J Immunol 191:1356–1363CrossRefPubMed

45.

Xu X, Grijalva A, Skowronski A, van Eijk M, Serlie MJ, Ferrante AW Jr (2013) Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab 18:816–830PubMedCentralCrossRefPubMed

46.

Prieur X, Mok CY, Velagapudi VR et al (2011) Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes 60:797–809PubMedCentralCrossRefPubMed

Titel: Fatty acids from fat cell lipolysis do not activate an inflammatory response but are stored as triacylglycerols in adipose tissue macrophages
verfasst von: Sylvie Caspar-Bauguil
Catherine-Ines Kolditz
Corinne Lefort
Isabelle Vila
Etienne Mouisel
Diane Beuzelin
Geneviève Tavernier
Marie-Adeline Marques
Alexia Zakaroff-Girard
Christiane Pecher
Marianne Houssier
Lucile Mir
Sarah Nicolas
Cédric Moro
Dominique Langin
Publikationsdatum: 01.11.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 11/2015
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-015-3719-0

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Bei Herzinsuffizienz muss „Eisenmangel“ neu definiert werden!

16.05.2024 Herzinsuffizienz Nachrichten

Bei chronischer Herzinsuffizienz macht es einem internationalen Expertenteam zufolge wenig Sinn, die Diagnose „Eisenmangel“ am Serumferritin festzumachen. Das Team schlägt vor, sich lieber an die Transferrinsättigung zu halten.

Herzinfarkt mit 85 – trotzdem noch intensive Lipidsenkung?

16.05.2024 Hypercholesterinämie Nachrichten

Profitieren nach einem akuten Myokardinfarkt auch Betroffene über 80 Jahre noch von einer intensiven Lipidsenkung zur Sekundärprävention? Um diese Frage zu beantworten, wurden jetzt Registerdaten aus Frankreich ausgewertet.

ADHS-Medikation erhöht das kardiovaskuläre Risiko

16.05.2024 Herzinsuffizienz Nachrichten

Erwachsene, die Medikamente gegen das Aufmerksamkeitsdefizit-Hyperaktivitätssyndrom einnehmen, laufen offenbar erhöhte Gefahr, an Herzschwäche zu erkranken oder einen Schlaganfall zu erleiden. Es scheint eine Dosis-Wirkungs-Beziehung zu bestehen.

Erstmanifestation eines Diabetes-Typ-1 bei Kindern: Ein Notfall!

16.05.2024 DDG-Jahrestagung 2024 Kongressbericht

Manifestiert sich ein Typ-1-Diabetes bei Kindern, ist das ein Notfall – ebenso wie eine diabetische Ketoazidose. Die Grundsäulen der Therapie bestehen aus Rehydratation, Insulin und Kaliumgabe. Insulin ist das Medikament der Wahl zur Behandlung der Ketoazidose.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 11/2015

Mechanisms through which a small protein and lipid preload improves glucose tolerance

Activation of GLP-1 and gastrin signalling induces in vivo reprogramming of pancreatic exocrine cells into beta cells in mice

Sensory neuropathy hampers nociception-mediated bone marrow stem cell release in mice and patients with diabetes

Sex of the baby and risk of gestational diabetes mellitus in the mother: a systematic review and meta-analysis

Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial