Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes
Tóm tắt
Obesity and insulin resistance are associated with low-grade chronic inflammation. Glucagon-like peptide-1 (GLP-1) is known to reduce insulin resistance. We investigated whether GLP-1 has anti-inflammatory effects on adipose tissue, including adipocytes and adipose tissue macrophages (ATM). We administered a recombinant adenovirus (rAd) producing GLP-1 (rAd-GLP-1) to an ob/ob mouse model of diabetes. We examined insulin sensitivity, body fat mass, the infiltration of ATM and metabolic profiles. We analysed the mRNA expression of inflammatory cytokines, lipogenic genes, and M1 and M2 macrophage-specific genes in adipose tissue by real-time quantitative PCR. We also examined the activation of nuclear factor κB (NF-κB), extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase (JNK) in vivo and in vitro. Fat mass, adipocyte size and mRNA expression of lipogenic genes were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Macrophage populations (F4/80+ and F4/80+CD11b+CD11c+ cells), as well as the expression and production of IL-6, TNF-α and monocyte chemoattractant protein-1, were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Expression of M1-specific mRNAs was significantly reduced, but that of M2-specific mRNAs was unchanged in rAd-GLP-1-treated ob/ob mice. NF-κB and JNK activation was significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Lipopolysaccharide-induced inflammation was reduced by the GLP-1 receptor agonist, exendin-4, in 3T3-L1 adipocytes and ATM. We suggest that GLP-1 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and ATM, possibly contributing to the improvement of insulin sensitivity.
Tài liệu tham khảo
Bastard JP, Maachi M, Lagathu C et al (2006) Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 17:4–12
Aldhahi W, Hamdy O (2003) Adipokines, inflammation, and the endothelium in diabetes. Curr Diab Rep 3:293–298
Lumeng CN, Deyoung SM, Saltiel AR (2007) Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins. Am J Physiol Endocrinol Metab 292:E166–E174
Arkan MC, Hevener AL, Greten FR et al (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198
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 116:1494–1505
Weisberg SP, Hunter D, Huber R et al (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116:115–124
Winer S, Chan Y, Paltser G et al (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929
Kieffer TJ, Habener JF (1999) The glucagon-like peptides. Endocr Rev 20:876–913
Drucker DJ (2006) The biology of incretin hormones. Cell Metab 3:153–165
Lee YS, Shin S, Shigihara T et al (2007) Glucagon-like peptide-1 gene therapy in obese diabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. Diabetes 56:1671–1679
Zander M, Madsbad S, Madsen JL, Holst JJ (2002) Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 359:824–830
Parlevliet ET, de Leeuw van Weenen JE, Romijn JA, Pijl H (2010) GLP-1 treatment reduces endogenous insulin resistance via activation of central GLP-1 receptors in mice fed a high-fat diet. Am J Physiol Endocrinol Metab 299:E318–E324
Idris I, Patiag D, Gray S, Donnelly R (2002) Exendin-4 increases insulin sensitivity via a PI-3-kinase-dependent mechanism: contrasting effects of GLP-1. Biochem Pharmacol 63:993–996
Gao H, Wang X, Zhang Z et al (2007) GLP-1 amplifies insulin signaling by up-regulation of IRbeta, IRS-1 and Glut4 in 3T3-L1 adipocytes. Endocrine 32:90–95
le Kim Chung T, Hosaka T, Yoshida M et al (2009) Exendin-4, a GLP-1 receptor agonist, directly induces adiponectin expression through protein kinase A pathway and prevents inflammatory adipokine expression. Biochem Biophys Res Commun 390:613–618
Rotter V, Nagaev I, Smith U (2003) Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 278:45777–45784
Ajuwon KM, Spurlock ME (2005) Palmitate activates the NF-kappaB transcription factor and induces IL-6 and TNFalpha expression in 3T3-L1 adipocytes. J Nutr 135:1841–1846
Wadman IA, Osada H, Grutz GG et al (1997) The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. EMBO J 16:3145–3157
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 282:35279–35292
Filipov NM, Seegal RF, Lawrence DA (2005) Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism. Toxicol Sci 84:139–148
Edelman DA, Jiang Y, Tyburski JG, Wilson RF, Steffes CP (2007) Cytokine production in lipopolysaccharide-exposed rat lung pericytes. J Trauma 62:89–93
Rodriguez-Calvo R, Serrano L, Coll T et al (2008) Activation of peroxisome proliferator-activated receptor beta/delta inhibits lipopolysaccharide-induced cytokine production in adipocytes by lowering nuclear factor-kappaB activity via extracellular signal-related kinase 1/2. Diabetes 57:2149–2157
Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85
Nam KN, Son MS, Park JH, Lee EH (2008) Shikonins attenuate microglial inflammatory responses by inhibition of ERK, Akt, and NF-kappaB: neuroprotective implications. Neuropharmacology 55:819–825
Cai D, Yuan M, Frantz DF et al (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11:183–190
Kim JK, Kim YJ, Fillmore JJ et al (2001) Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 108:437–446
Kiefer FW, Zeyda M, Gollinger K et al (2010) Neutralization of osteopontin inhibits obesity-induced inflammation and insulin resistance. Diabetes 59:935–946
Sandeep S, Gokulakrishnan K, Velmurugan K, Deepa M, Mohan V (2010) Visceral & subcutaneous abdominal fat in relation to insulin resistance & metabolic syndrome in non-diabetic south Indians. Indian J Med Res 131:629–635
Usui C, Asaka M, Kawano H et al (2010) Visceral fat is a strong predictor of insulin resistance regardless of cardiorespiratory fitness in non-diabetic people. J Nutr Sci Vitaminol (Tokyo) 56:109–116
Valverde I, Merida E, Delgado E, Trapote MA, Villanueva-Penacarrillo ML (1993) Presence and characterization of glucagon-like peptide-1(7-36) amide receptors in solubilized membranes of rat adipose tissue. Endocrinology 132:75–79
Sancho V, Trigo MV, Gonzalez N, Valverde I, Malaisse WJ, Villanueva-Penacarrillo ML (2005) Effects of glucagon-like peptide-1 and exendins on kinase activity, glucose transport and lipid metabolism in adipocytes from normal and type-2 diabetic rats. J Mol Endocrinol 35:27–38
Pandey AK, Munjal N, Datta M (2010) Gene expression profiling and network analysis reveals lipid and steroid metabolism to be the most favored by TNFalpha in HepG2 cells. PLoS One 5:e9063
Girard J, Perdereau D, Foufelle F, Prip-Buus C, Ferre P (1994) Regulation of lipogenic enzyme gene expression by nutrients and hormones. FASEB J 8:36–42
Foufelle F, Girard J, Ferre P (1996) Regulation of lipogenic enzyme expression by glucose in liver and adipose tissue: a review of the potential cellular and molecular mechanisms. Adv Enzyme Regul 36:199–226
Samuvel DJ, Sundararaj KP, Li Y, Lopes-Virella MF, Huang Y (2010) Adipocyte-mononuclear cell interaction, Toll-like receptor 4 activation, and high glucose synergistically up-regulate osteopontin expression via an interleukin 6-mediated mechanism. J Biol Chem 285:3916–3927
Xie L, Ortega MT, Mora S, Chapes SK (2010) Interactive changes between macrophages and adipocytes. Clin Vaccine Immunol 17:651–659
Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG (2008) Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 8:301–309
Fuentes L, Roszer T, Ricote M (2010) Inflammatory mediators and insulin resistance in obesity: role of nuclear receptor signaling in macrophages. Mediators Inflamm 2010:219583
Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ (2009) Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology 49:87–96
Wunderlich FT, Luedde T, Singer S et al (2008) Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc Natl Acad Sci U S A 105:1297–1302
Schmidt C, Hocherl K, Kurt B, Bucher M (2008) Role of nuclear factor-kappaB-dependent induction of cytokines in the regulation of vasopressin V1A-receptors during cecal ligation and puncture-induced circulatory failure. Crit Care Med 36:2363–2372
De Souza CT, Araujo EP, Bordin S et al (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146:4192–4199
Kodera R, Shikata K, Kataoka HU et al (2011) Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia 54:965–978
Shiraki A, Oyama J, Komoda H et al (2012) The glucagon-like peptide 1 analog liraglutide reduces TNF-alpha-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis 221:375–382
Redinger RN (2009) Fat storage and the biology of energy expenditure. Transl Res 154:52–60
MacDonald IA, Webber J (1995) Feeding, fasting and starvation: factors affecting fuel utilization. Proc Nutr Soc 54:267–274