GLP-1 secretion by microglial cells and decreased CNS expression in obesity

Journal of Neuroinflammation

Åke Sjöholm¹  Kerstin Iverfeldt²  Cesare Patrone¹  Linda M Tracy²  Camilla Kappe¹ 

[1] Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Stockholm, 11883, Sweden;Department of Neurochemistry, Stockholm University, Stockholm, 10691, Sweden

关键词: Proglucagon;    Neuroprotection;    Neuroinflammation;    Microglia;    Glucagon-like peptide-1;   

Others  :  1160097
DOI  :  10.1186/1742-2094-9-276

 received in 2012-10-24, accepted in 2012-11-29,  发布年份 2012

【 摘 要 】

Background

Type 2 diabetes (T2D) is a strong risk factor for developing neurodegenerative pathologies. T2D patients have a deficiency in the intestinal incretin hormone GLP-1, which has been shown to exert neuroprotective and anti-inflammatory properties in the brain.

Methods

Here we investigate potential sources of GLP-1 in the CNS and the effect of diabetic conditions on the proglucagon mRNA expression in the CNS. The obese mouse model ob/ob, characterized by its high levels of free fatty acids, and the microglia cell line BV-2 were used as models. mRNA expression and protein secretion were analyzed by qPCR, immunofluorescence and ELISA.

Results

We show evidence for microglia as a central source of GLP-1 secretion. Furthermore, we observed that expression and secretion are stimulated by cAMP and dependent on microglial activation state. We also show that insulin-resistant conditions reduce the central mRNA expression of proglucagon.

Conclusion

The findings that microglial mRNA expression of proglucagon and GLP-1 protein expression are affected by high levels of free fatty acids and that both mRNA expression levels of proglucagon and secretion levels of GLP-1 are affected by inflammatory stimuli could be of pathogenic importance for the premature neurodegeneration and cognitive decline commonly seen in T2D patients, and they may also be harnessed to advantage in therapeutic efforts to prevent or treat such disorders.

【 授权许可】

   
2012 Kappe et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Giorda CB, Avogaro A, Maggini M, Lombardo F, Mannucci E, Turco S, Alegiani SS, Raschetti R, Velussi M, Ferrannini E: Incidence and risk factors for stroke in type 2 diabetic patients: the DAI study. Stroke 2007, 38:1154-1160.
• [2]Isacson R, Nielsen E, Dannaeus K, Bertilsson G, Patrone C, Zachrisson O, Wikstrom L: The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test. Eur J Pharmacol 2011, 650:249-255.
• [3]Kroner Z: The relationship between Alzheimer’s disease and diabetes: Type 3 diabetes? Altern Med Rev 2009, 14:373-379.
• [4]Karmi A, Iozzo P, Viljanen A, Hirvonen J, Fielding BA, Virtanen K, Oikonen V, Kemppainen J, Viljanen T, Guiducci L, et al.: Increased brain fatty acid uptake in metabolic syndrome. Diabetes 2010, 59:2171-2177.
• [5]Drucker DJ: The role of gut hormones in glucose homeostasis. J Clin Invest 2007, 117:24-32.
• [6]Laakso M, Zilinskaite J, Hansen T, Boesgaard TW, Vanttinen M, Stancakova A, Jansson PA, Pellme F, Holst JJ, Kuulasmaa T, et al.: Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study. Diabetologia 2008, 51:502-511.
• [7]Williams DL: Minireview: finding the sweet spot: peripheral versus central glucagon-like peptide 1 action in feeding and glucose homeostasis. Endocrinology 2009, 150:2997-3001.
• [8]Perry T, Holloway HW, Weerasuriya A, Mouton PR, Duffy K, Mattison JA, Greig NH: Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy. Exp Neurol 2007, 203:293-301.
• [9]Darsalia V, Mansouri S, Ortsater H, Olverling A, Nozadze N, Kappe C, Iverfeldt K, Tracy LM, Grankvist N, Sjoholm A, Patrone C: Glucagon-like peptide-1 receptor activation reduces ischemic brain damage following stroke in type 2 diabetic rats. Clin Sci (Lond) 2012, 122:473-483.
• [10]During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN: Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 2003, 9:1173-1179.
• [11]Li Y, Tweedie D, Mattson MP, Holloway HW, Greig NH: Enhancing the GLP-1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells. J Neurochem 2010, 113:1621-1631.
• [12]Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, Kortesmaa J, Mercer A, Nielsen E, Ronnholm H, Wikstrom L: Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J Neurosci Res 2008, 86:326-338.
• [13]Li Y, Duffy KB, Ottinger MA, Ray B, Bailey JA, Holloway HW, Tweedie D, Perry T, Mattson MP, Kapogiannis D, et al.: GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer’s disease. J Alzheimers Dis 2010, 19:1205-1219.
• [14]Vrang N, Hansen M, Larsen PJ, Tang-Christensen M: Characterization of brainstem preproglucagon projections to the paraventricular and dorsomedial hypothalamic nuclei. Brain Res 2007, 1149:118-126.
• [15]Iwai T, Ito S, Tanimitsu K, Udagawa S, Oka J: Glucagon-like peptide-1 inhibits LPS-induced IL-1beta production in cultured rat astrocytes. Neurosci Res 2006, 55:352-360.
• [16]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.
• [17]Ramberg V, Tracy LM, Samuelsson M, Nilsson LN, Iverfeldt K: The CCAAT/enhancer binding protein (C/EBP) delta is differently regulated by fibrillar and oligomeric forms of the Alzheimer amyloid-beta peptide. J Neuroinflammation 2011, 8:34. BioMed Central Full Text
• [18]Sjoholm A, Nystrom T: Endothelial inflammation in insulin resistance. Lancet 2005, 365:610-612.
• [19]Merchenthaler I, Lane M, Shughrue P: Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J Comp Neurol 1999, 403:261-280.
• [20]Brubaker PL, Schloos J, Drucker DJ: Regulation of glucagon-like peptide-1 synthesis and secretion in the GLUTag enteroendocrine cell line. Endocrinology 1998, 139:4108-4114.
• [21]Persson M, Brantefjord M, Hansson E, Ronnback L: Lipopolysaccharide increases microglial GLT-1 expression and glutamate uptake capacity in vitro by a mechanism dependent on TNF-alpha. Glia 2005, 51:111-120.
• [22]Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP: Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 2006, 3:27. BioMed Central Full Text
• [23]Coleman DL: Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 1978, 14:141-148.
• [24]Macia L, Delacre M, Abboud G, Ouk TS, Delanoye A, Verwaerde C, Saule P, Wolowczuk I: Impairment of dendritic cell functionality and steady-state number in obese mice. J Immunol 2006, 177:5997-6006.
• [25]Nishina PM, Lowe S, Wang J, Paigen B: Characterization of plasma lipids in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow. Metabolism 1994, 43:549-553.
• [26]Kleinfeld AM, Prothro D, Brown DL, Davis RC, Richieri GV, DeMaria A: Increases in serum unbound free fatty acid levels following coronary angioplasty. Am J Cardiol 1996, 78:1350-1354.
• [27]Shafrir E: Partition of unesterified fatty acids in normal and nephrotic syndrome serum and its effect on serum electrophoretic pattern. J Clin Invest 1958, 37:1775-1782.
• [28]Samokhvalov V, Bilan PJ, Schertzer JD, Antonescu CN, Klip A: Palmitate- and lipopolysaccharide-activated macrophages evoke contrasting insulin responses in muscle cells. Am J Physiol Endocrinol Metab 2009, 296:E37-E46.
• [29]Bunn RC, Cockrell GE, Ou Y, Thrailkill KM, Lumpkin CK Jr, Fowlkes JL: Palmitate and insulin synergistically induce IL-6 expression in human monocytes. Cardiovasc Diabetol 2010, 9:73. BioMed Central Full Text
• [30]Little JP, Madeira JM, Klegeris A: The saturated fatty acid palmitate induces human monocytic cell toxicity toward neuronal cells: exploring a possible link between obesity-related metabolic impairments and neuroinflammation. J Alzheimers Dis 2012, 30(Suppl 2):S179-S183.
• [31]David S, Kroner A: Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 2011, 12:388-399.
• [32]Krogh-Madsen R, Plomgaard P, Akerstrom T, Moller K, Schmitz O, Pedersen BK: Effect of short-term intralipid infusion on the immune response during low-dose endotoxemia in humans. Am J Physiol Endocrinol Metab 2008, 294:E371-E379.