Enhanced β-adrenergic signalling underlies an age-dependent beneficial metabolic effect of PI3K p110α inactivation in adipose tissue.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 04 2019
04 04 2019
Historique:
received:
06
02
2018
accepted:
12
03
2019
entrez:
6
4
2019
pubmed:
6
4
2019
medline:
2
5
2019
Statut:
epublish
Résumé
The insulin/IGF-1 signalling pathway is a key regulator of metabolism and the rate of ageing. We previously documented that systemic inactivation of phosphoinositide 3-kinase (PI3K) p110α, the principal PI3K isoform that positively regulates insulin signalling, results in a beneficial metabolic effect in aged mice. Here we demonstrate that deletion of p110α specifically in the adipose tissue leads to less fat accumulation over a significant part of adult life and allows the maintenance of normal glucose tolerance despite insulin resistance. This effect of p110α inactivation is due to a potentiating effect on β-adrenergic signalling, which leads to increased catecholamine-induced energy expenditure in the adipose tissue. Our findings provide a paradigm of how partial inactivation of an essential component of the insulin signalling pathway can have an overall beneficial metabolic effect and suggest that PI3K inhibition could potentiate the effect of β-adrenergic agonists in the treatment of obesity and its associated comorbidities.
Identifiants
pubmed: 30948720
doi: 10.1038/s41467-019-09514-1
pii: 10.1038/s41467-019-09514-1
pmc: PMC6449391
doi:
Substances chimiques
1-phosphatidylinositol 3-kinase p110 subunit, mouse
EC 2.7.1.137
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1546Subventions
Organisme : British Heart Foundation
ID : RG/12/13/29853
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0802051
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400192
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0600717
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/2
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Références
Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).
pubmed: 20336132
doi: 10.1038/nature08980
Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005).
pubmed: 15734678
doi: 10.1016/j.cell.2005.02.002
Bartke, A. Insulin and aging. Cell Cycle 7, 3338–3343 (2008).
pubmed: 18948730
doi: 10.4161/cc.7.21.7012
Blagosklonny, M. V. Revisiting the antagonistic pleiotropy theory of aging: TOR-driven program and quasi-program. Cell Cycle 9, 3151–3156 (2010).
pubmed: 20724817
doi: 10.4161/cc.9.16.12814
Barzilai, N., Huffman, D. M., Muzumdar, R. H. & Bartke, A. The critical role of metabolic pathways in aging. Diabetes 61, 1315–1322 (2012).
pubmed: 22618766
pmcid: 3357299
doi: 10.2337/db11-1300
Bartke, A. & Westbrook, R. Metabolic characteristics of long-lived mice. Front. Genet. 3, 288 (2012).
pubmed: 23248643
pmcid: 3521393
doi: 10.3389/fgene.2012.00288
Lamming, D.W. & Anderson, R. M. Metabolic effects of caloric restriction. In: eLS (John Wiley & Sons, Ltd. Chichester) https://doi.org/10.1002/9780470015902.a0021316.pub2 (2014).
Rutkowski, J. M., Stern, J. H. & Scherer, P. E. The cell biology of fat expansion. J. Cell Biol. 208, 501–512 (2015).
pubmed: 25733711
pmcid: 4347644
doi: 10.1083/jcb.201409063
Bluher, M., Kahn, B. B. & Kahn, C. R. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574 (2003).
pubmed: 12543978
doi: 10.1126/science.1078223
Foukas, L. C. et al. Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441, 366–370 (2006).
pubmed: 16625210
doi: 10.1038/nature04694
Knight, Z. A. et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125, 733–747 (2006).
pubmed: 16647110
pmcid: 2946820
doi: 10.1016/j.cell.2006.03.035
Foukas, L. C. et al. Long-term p110alpha PI3K inactivation exerts a beneficial effect on metabolism. EMBO Mol. Med. 5, 563–571 (2013).
pubmed: 23483710
pmcid: 3628103
doi: 10.1002/emmm.201201953
Graupera, M. et al. Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 453, 662–666 (2008).
pubmed: 18449193
doi: 10.1038/nature06892
Eguchi, J. et al. Transcriptional control of adipose lipid handling by IRF4. Cell Metab. 13, 249–259 (2011).
pubmed: 21356515
pmcid: 3063358
doi: 10.1016/j.cmet.2011.02.005
Lee, K. Y. et al. Lessons on conditional gene targeting in mouse adipose tissue. Diabetes 62, 864–874 (2013).
pubmed: 23321074
pmcid: 3581196
doi: 10.2337/db12-1089
Delporte, M. L., Funahashi, T., Takahashi, M., Matsuzawa, Y. & Brichard, S. M. Pre- and post-translational negative effect of beta-adrenoceptor agonists on adiponectin secretion: in vitro and in vivo studies. Biochem. J. 367, 677–685 (2002).
pubmed: 12139486
pmcid: 1222924
doi: 10.1042/bj20020610
Fuente-Martin, E., Argente-Arizon, P., Ros, P., Argente, J. & Chowen, J. A. Sex differences in adipose tissue: it is not only a question of quantity and distribution. Adipocyte 2, 128–134 (2013).
pubmed: 23991358
pmcid: 3756100
doi: 10.4161/adip.24075
Luque-Ramirez, M. et al. Sexual dimorphism in adipose tissue function as evidenced by circulating adipokine concentrations in the fasting state and after an oral glucose challenge. Hum. Reprod. 28, 1908–1918 (2013).
pubmed: 23559188
doi: 10.1093/humrep/det097
Feldmann, H. M., Golozoubova, V., Cannon, B. & Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell. Metab. 9, 203–209 (2009).
pubmed: 19187776
doi: 10.1016/j.cmet.2008.12.014
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
pubmed: 14715917
doi: 10.1152/physrev.00015.2003
Kolditz, C. I. & Langin, D. Adipose tissue lipolysis. Curr. Opin. Clin. Nutr. Metab. Care. 13, 377–381 (2010).
pubmed: 20531174
doi: 10.1097/MCO.0b013e32833bed6a
Jamieson, S. et al. A drug targeting only p110alpha can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. Biochem. J. 438, 53–62 (2011).
pubmed: 21668414
doi: 10.1042/BJ20110502
Boucher, J. et al. Human alpha 2A-adrenergic receptor gene expressed in transgenic mouse adipose tissue under the control of its regulatory elements. J. Mol. Endocrinol. 29, 251–264 (2002).
pubmed: 12370125
doi: 10.1677/jme.0.0290251
Rodriguez, A. M. et al. Transplantation of a multipotent cell population from human adipose tissue induces dystrophin expression in the immunocompetent mdx mouse. J. Exp. Med. 201, 1397–1405 (2005).
pubmed: 15867092
pmcid: 2213197
doi: 10.1084/jem.20042224
Duncan, R. E., Ahmadian, M., Jaworski, K., Sarkadi-Nagy, E. & Sul, H. S. Regulation of lipolysis in adipocytes. Annu. Rev. Nutr. 27, 79–101 (2007).
pubmed: 17313320
pmcid: 2885771
doi: 10.1146/annurev.nutr.27.061406.093734
Choi, S. M. et al. Insulin regulates adipocyte lipolysis via an Akt-independent signaling pathway. Mol. Cell. Biol. 30, 5009–5020 (2010).
pubmed: 20733001
pmcid: 2953052
doi: 10.1128/MCB.00797-10
Cao, W. et al. p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol. Cell. Biol. 24, 3057–3067 (2004).
pubmed: 15024092
pmcid: 371122
doi: 10.1128/MCB.24.7.3057-3067.2004
Zmuda-Trzebiatowska, E., Manganiello, V. & Degerman, E. Novel mechanisms of the regulation of protein kinase B in adipocytes; implications for protein kinase A, Epac, phosphodiesterases 3 and 4. Cell Signal. 19, 81–86 (2007).
pubmed: 16839743
doi: 10.1016/j.cellsig.2006.05.024
Oknianska, A., Zmuda-Trzebiatowska, E., Manganiello, V. & Degerman, E. Long-term regulation of cyclic nucleotide phosphodiesterase type 3B and 4 in 3T3-L1 adipocytes. Biochem. Biophys. Res. Commun. 353, 1080–1085 (2007).
pubmed: 17198676
doi: 10.1016/j.bbrc.2006.12.141
Mei, F. C. et al. Differential signaling of cyclic AMP: opposing effects of exchange protein directly activated by cyclic AMP and cAMP-dependent protein kinase on protein kinase B activation. J. Biol. Chem. 277, 11497–11504 (2002).
pubmed: 11801596
doi: 10.1074/jbc.M110856200
Wu, J., Cohen, P. & Spiegelman, B. M. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev. 27, 234–250 (2013).
pubmed: 23388824
pmcid: 3576510
doi: 10.1101/gad.211649.112
Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
pubmed: 23746838
pmcid: 3836174
doi: 10.1016/j.cell.2013.05.039
Chung, Y. W. et al. White to beige conversion in PDE3B KO adipose tissue through activation of AMPK signaling and mitochondrial function. Sci. Rep. 7, 40445 (2017).
pubmed: 28084425
pmcid: 5234021
doi: 10.1038/srep40445
Kerckhoffs, D. A., Blaak, E. E., Van Baak, M. A. & Saris, W. H. Effect of aging on beta-adrenergically mediated thermogenesis in men. Am. J. Physiol. 274, E1075–E1079 (1998).
pubmed: 9611158
doi: 10.1152/ajpcell.1998.274.4.C1075
Seals, D. R. & Bell, C. Chronic sympathetic activation: consequence and cause of age-associated obesity? Diabetes 53, 276–284 (2004).
pubmed: 14747276
doi: 10.2337/diabetes.53.2.276
Gregerman, R. I. Aging and hormone-sensitive lipolysis: reconciling the literature. J. Gerontol. 49, B135–B139 (1994).
pubmed: 8014384
doi: 10.1093/geronj/49.4.B135
Nelson, V. L., Jiang, Y. P., Dickman, K. G., Ballou, L. M. & Lin, R. Z. Adipose tissue insulin resistance due to loss of PI3K p110alpha leads to decreased energy expenditure and obesity. Am. J. Physiol. Endocrinol. Metab. 306, E1205–E1216 (2014).
pubmed: 24691033
pmcid: 4025064
doi: 10.1152/ajpendo.00625.2013
Ortega-Molina, A. et al. Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys. Cell Metab. 21, 558–570 (2015).
pubmed: 25817535
pmcid: 5867518
doi: 10.1016/j.cmet.2015.02.017
Lopez-Guadamillas, E. et al. PI3Kalpha inhibition reduces obesity in mice. Aging 8, 2747–2753 (2016).
pubmed: 27816049
pmcid: 5191867
doi: 10.18632/aging.101075
Katic, M. et al. Mitochondrial gene expression and increased oxidative metabolism: role in increased lifespan of fat-specific insulin receptor knock-out mice. Aging Cell 6, 827–839 (2007).
pubmed: 18001293
doi: 10.1111/j.1474-9726.2007.00346.x
Ortega-Molina, A. et al. Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell Metab. 15, 382–394 (2012).
pubmed: 22405073
doi: 10.1016/j.cmet.2012.02.001
Pirzgalska, R. M. et al. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat. Med. 23, 1309–1318 (2017).
pubmed: 29035364
pmcid: 7104364
doi: 10.1038/nm.4422
Camell, C. D. et al. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550, 119–123 (2017).
pubmed: 28953873
pmcid: 5718149
doi: 10.1038/nature24022
Tseng, Y. H., Cypess, A. M. & Kahn, C. R. Cellular bioenergetics as a target for obesity therapy. Nat. Rev. Drug Discov. 9, 465–482 (2010).
pubmed: 20514071
pmcid: 2880836
doi: 10.1038/nrd3138
Whittle, A., Relat-Pardo, J. & Vidal-Puig, A. Pharmacological strategies for targeting BAT thermogenesis. Trends Pharmacol. Sci. 34, 347–355 (2013).
pubmed: 23648356
doi: 10.1016/j.tips.2013.04.004
Peng, X. R., Gennemark, P., O’Mahony, G. & Bartesaghi, S. Unlock the thermogenic potential of adipose tissue: pharmacological modulation and implications for treatment of diabetes and obesity. Front. Endocrinol. 6, 174 (2015).
doi: 10.3389/fendo.2015.00174
Cypess, A. M. et al. Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist. Cell Metab. 21, 33–38 (2015).
pubmed: 25565203
pmcid: 4298351
doi: 10.1016/j.cmet.2014.12.009
Zaragosi, L. E., Ailhaud, G. & Dani, C. Autocrine fibroblast growth factor 2 signaling is critical for self-renewal of human multipotent adipose-derived stem cells. Stem Cells 24, 2412–2419 (2006).
pubmed: 16840552
doi: 10.1634/stemcells.2006-0006
Fueger, P. T., Bracy, D. P., Malabanan, C. M., Pencek, R. R. & Wasserman, D. H. Distributed control of glucose uptake by working muscles of conscious mice: roles of transport and phosphorylation. Am. J. Physiol. Endocrinol. Metab. 286, E77–E84 (2004).
pubmed: 13129858
doi: 10.1152/ajpendo.00309.2003
Tan, C. Y. et al. Brown adipose tissue thermogenic capacity is regulated by Elovl6. Cell Rep. 13, 2039–2047 (2015).
pubmed: 26628376
pmcid: 4688035
doi: 10.1016/j.celrep.2015.11.004