Myelin-laden macrophages (mye-MΦ), resulting primarily from internalization of myelin debris by infiltrating bone marrow–derived macrophages in spinal cord injury (SCI), trigger inflammatory responses that largely contribute to secondary injury. Adiponectin, which is secreted from adipose tissue, is an important hormone that modulates macrophage inflammation. In the present study, we examined the role of adiponectin on macrophage-mediated neuroinflammation after SCI. We found that in vitro activation of adiponectin receptors (AdipoRs) by their agonist AdipoRon suppressed myelin lipid accumulation in mye-MΦ through APPL1/PPARγ/LXRα/ABCA1-mediated lipid efflux, subsequently inhibiting inflammation and restoring normal function to mye-MΦ. In vivo data further confirmed that intravenous administration of AdipoRon after SCI dampened recruitment of macrophages and reduced myelin lipid accumulation. Accordingly, AdipoRon treatment ameliorated post-SCI tissue damage and astrogliosis, resulting in improved motor function. Although there was no significant pathological exacerbation in adiponectin-null mice subjected to SCI, our work reveals a functional link between adiponectin and hematogenous macrophages in the context of SCI, suggesting that activation of adiponectin signaling is a promising therapeutic approach to mitigate mye-MΦ-mediated neuroinflammation in neurological disorders involving demyelination.
Get full access to this article
View all access options for this article.
References
1.
YoungW. (1993). Secondary injury mechanisms in acute spinal cord injury. J. Emerg. Med. 11 Suppl, 1, 13–22.
2.
RenY. and YoungW. (2013). Managing inflammation after spinal cord injury through manipulation of macrophage function. Neural Plast. 2013, 945034.
3.
SkaperS.D., FacciL., and GiustiP. (2014). Neuroinflammation, microglia and mast cells in the pathophysiology of neurocognitive disorders: a review. CNS Neurol. Disord. Drug Targets, 13, 1654–1666.
4.
ZhouX., HeX., and RenY. (2014). Function of microglia and macrophages in secondary damage after spinal cord injury. Neural Regen. Res. 9, 1787–1795.
5.
SunX., WangX., ChenT., LiT., CaoK., LuA., ChenY., SunD., LuoJ., FanJ., YoungW., and RenY. (2010). Myelin activates FAK/Akt/NF-kappaB pathways and provokes CR3-dependent inflammatory response in murine system. PLoS One, 5, e9380.
6.
GenselJ.C. and ZhangB. (2015). Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res. 1619, 1–11.
7.
WangX., CaoK., SunX., ChenY., DuanZ., SunL., GuoL., BaiP., SunD., FanJ., HeX., YoungW., and RenY. (2015). Macrophages in spinal cord injury: phenotypic and functional change from exposure to myelin debris. Glia, 63, 635–651.
8.
BovenL.A., Van MeursM., Van ZwamM., Wierenga-WolfA., HintzenR.Q., BootR.G., AertsJ.M., AmorS., NieuwenhuisE.E., and LamanJ.D. (2006). Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis. Brain, 129, 517–526.
9.
van RossumD., HilbertS., StrassenburgS., HanischU.K., and BruckW. (2008). Myelin-phagocytosing macrophages in isolated sciatic and optic nerves reveal a unique reactive phenotype. Glia, 56, 271–283.
10.
VogelD.Y., VereykenE.J., GlimJ.E., HeijnenP.D., MoetonM., van der ValkP., AmorS., TeunissenC.E., van HorssenJ., and DijkstraC.D. (2013). Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. J. Neuroinflammation, 10, 35.
11.
ZhuY., LyapichevK., LeeD.H., MottiD., FerraroN.M., ZhangY., YahnS., SoderblomC., ZhaJ., BetheaJ.R., SpillerK.L., LemmonV.P., and LeeJ.K. (2017). Macrophage transcriptional profile identifies lipid catabolic pathways that can be therapeutically targeted after spinal cord injury. J. Neurosci. 37, 2362–2376.
12.
GuoL., RolfeA.J., WangX., TaiW., ChengZ., CaoK., ChenX., XuY., SunD., LiJ., HeX., YoungW., FanJ., and RenY. (2016). Rescuing macrophage normal function in spinal cord injury with embryonic stem cell conditioned media. Mol. Brain, 9, 48.
13.
LiuY., HaoW., LetiembreM., WalterS., KulangaM., NeumannH., and FassbenderK. (2006). Suppression of microglial inflammatory activity by myelin phagocytosis: role of p47-PHOX-mediated generation of reactive oxygen species. J. Neurosci. 26, 12904–12913.
14.
GlimJ.E., VereykenE.J., HeijnenD.A., Garcia VallejoJ.J., and DijkstraC.D. (2010). The release of cytokines by macrophages is not affected by myelin ingestion. Glia, 58, 1928–1936.
15.
KronerA., GreenhalghA.D., ZarrukJ.G., Passos Dos SantosR., GaestelM., and DavidS. (2014). TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron, 83, 1098–1116.
16.
JeonS.B., YoonH.J., ParkS.H., KimI.H., and ParkE.J. (2008). Sulfatide, a major lipid component of myelin sheath, activates inflammatory responses as an endogenous stimulator in brain-resident immune cells. J. Immunol. 181, 8077–8087.
17.
van der LaanL.J., RuulsS.R., WeberK.S., LodderI.J., DoppE.A., and DijkstraC.D. (1996). Macrophage phagocytosis of myelin in vitro determined by flow cytometry: phagocytosis is mediated by CR3 and induces production of tumor necrosis factor-alpha and nitric oxide. J. Neuroimmunol. 70, 145–152.
18.
LeeS. and KwakH.B. (2014). Role of adiponectin in metabolic and cardiovascular disease. J. Exerc. Rehabil. 10, 54–59.
19.
HuE., LiangP., and SpiegelmanB.M. (1996). AdipoQ is a novel adipose-specific gene dysregulated in obesity. J. Biol. Chem. 271, 10697–10703.
20.
PajvaniU.B., HawkinsM., CombsT.P., RajalaM.W., DoebberT., BergerJ.P., WagnerJ.A., WuM., KnoppsA., XiangA.H., UtzschneiderK.M., KahnS.E., OlefskyJ.M., BuchananT.A., and SchererP.E. (2004). Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J. Biol. Chem. 279, 12152–12162.
21.
PajvaniU.B., DuX., CombsT.P., BergA.H., RajalaM.W., SchulthessT., EngelJ., BrownleeM., and SchererP.E. (2003). Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity. J. Biol. Chem. 278, 9073–9085.
22.
StefanN., VozarovaB., FunahashiT., MatsuzawaY., WeyerC., LindsayR.S., YoungrenJ.F., HavelP.J., PratleyR.E., BogardusC., and TataranniP.A. (2002). Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes, 51, 1884–1888.
23.
NigroE., ScudieroO., MonacoM.L., PalmieriA., MazzarellaG., CostagliolaC., BiancoA., and DanieleA. (2014). New insight into adiponectin role in obesity and obesity-related diseases. Biomed. Res. Int. 2014, 658913.
24.
GhoshalK. and BhattacharyyaM. (2015). Adiponectin: probe of the molecular paradigm associating diabetes and obesity. World J. Diabetes, 6, 151–166.
25.
QiaoL., KinneyB., YooH.S., LeeB., SchaackJ., and ShaoJ. (2012). Adiponectin increases skeletal muscle mitochondrial biogenesis by suppressing mitogen-activated protein kinase phosphatase-1. Diabetes, 61, 1463–1470.
26.
YoonM.J., LeeG.Y., ChungJ.J., AhnY.H., HongS.H., and KimJ.B. (2006). Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes, 55, 2562–2570.
27.
YamauchiT., KamonJ., MinokoshiY., ItoY., WakiH., UchidaS., YamashitaS., NodaM., KitaS., UekiK., EtoK., AkanumaY., FroguelP., FoufelleF., FerreP., CarlingD., KimuraS., NagaiR., KahnB.B., and KadowakiT. (2002). Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8, 1288–1295.
28.
IwabuM., YamauchiT., Okada-IwabuM., SatoK., NakagawaT., FunataM., YamaguchiM., NamikiS., NakayamaR., TabataM., OgataH., KubotaN., TakamotoI., HayashiY.K., YamauchiN., WakiH., FukayamaM., NishinoI., TokuyamaK., UekiK., OikeY., IshiiS., HiroseK., ShimizuT., TouharaK., and KadowakiT. (2010). Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature, 464, 1313–1319.
29.
ChanK.H., LamK.S., ChengO.Y., KwanJ.S., HoP.W., ChengK.K., ChungS.K., HoJ.W., GuoV.Y., and XuA. (2012). Adiponectin is protective against oxidative stress induced cytotoxicity in amyloid-beta neurotoxicity. PloS One, 7, e52354.
30.
ChabryJ., NicolasS., CazarethJ., MurrisE., GuyonA., GlaichenhausN., HeurteauxC., and Petit-PaitelA. (2015). Enriched environment decreases microglia and brain macrophages inflammatory phenotypes through adiponectin-dependent mechanisms: Relevance to depressive-like behavior. Brain, Behav. Immun. 50, 275–287.
31.
van StijnC.M., KimJ., BarishG.D., TietgeU.J., and TangiralaR.K. (2014). Adiponectin expression protects against angiotensin II-mediated inflammation and accelerated atherosclerosis. PLoS One, 9, e86404.
32.
SongJ., KangS.M., KimE., KimC.H., SongH.T., and LeeJ.E. (2015). Adiponectin receptor-mediated signaling ameliorates cerebral cell damage and regulates the neurogenesis of neural stem cells at high glucose concentrations: an in vivo and in vitro study. Cell Death Dis. 6, e1844.
33.
NicolasS., VeyssiereJ., GandinC., ZsurgerN., PietriM., HeurteauxC., GlaichenhausN., Petit-PaitelA., and ChabryJ. (2015). Neurogenesis-independent antidepressant-like effects of enriched environment is dependent on adiponectin. Psychoneuroendocrinology, 57, 72–83.
34.
YauS.Y., LiA., HooR.L., ChingY.P., ChristieB.R., LeeT.M., XuA., and SoK.F. (2014). Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin. Proc. Natl. Acad. Sci. U. S. A. 111, 15810–15815.
35.
AjuwonK.M. and SpurlockM.E. (2005). Adiponectin inhibits LPS-induced NF-kappaB activation and IL-6 production and increases PPARgamma2 expression in adipocytes. Am. J. Physiol. 288, R1220–R1225.
36.
PiccioL., CantoniC., HendersonJ.G., HawigerD., RamsbottomM., MikesellR., RyuJ., HsiehC.S., CremascoV., HaynesW., DongL.Q., ChanL., GalimbertiD., and CrossA.H. (2013). Lack of adiponectin leads to increased lymphocyte activation and increased disease severity in a mouse model of multiple sclerosis. Eur. J. Immunol. 43, 2089–2100.
37.
PunN.T., SubediA., KimM.J., and ParkP.H. (2015). Globular adiponectin causes tolerance to LPS-induced TNF-alpha expression via autophagy induction in RAW 264.7 macrophages: involvement of SIRT1/FoxO3A axis. PloS One, 10, e0124636.
38.
ZhangD., WangX., WangB., GarzaJ.C., FangX., WangJ., SchererP.E., BrennerR., ZhangW., and LuX.Y. (2016). Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors. Mol. psychiatry. 22, 1044–1055
39.
TianL., LuoN., ZhuX., ChungB.H., GarveyW.T., and FuY. (2012). Adiponectin-AdipoR1/2-APPL1 signaling axis suppresses human foam cell formation: differential ability of AdipoR1 and AdipoR2 to regulate inflammatory cytokine responses. Atherosclerosis, 221, 66–75.
40.
LuoN., ChungB.H., WangX., KleinR.L., TangC.K., GarveyW.T., and FuY. (2013). Enhanced adiponectin actions by overexpression of adiponectin receptor 1 in macrophages. Atherosclerosis, 228, 124–135.
41.
TianL., LuoN., KleinR.L., ChungB.H., GarveyW.T., and FuY. (2009). Adiponectin reduces lipid accumulation in macrophage foam cells. Atherosclerosis, 202, 152–161.
42.
LiangB., WangX., GuoX., YangZ., BaiR., LiuM., XiaoC., and BianY. (2015). Adiponectin upregulates ABCA1 expression through liver X receptor alpha signaling pathway in RAW 264.7 macrophages. Int. J. Clin. Exp. Pathol. 8, 450–457.
43.
HegyiL., SkepperJ.N., CaryN.R., and MitchinsonM.J. (1996). Foam cell apoptosis and the development of the lipid core of human atherosclerosis. J. Pathol. 180, 423–429.
44.
TabasI., SeimonT., TimminsJ., LiG., and LimW. (2009). Macrophage apoptosis in advanced atherosclerosis. Annals of the New York Academy of Sciences 1173 Suppl, 1, E40–E45.
45.
Okada-IwabuM., YamauchiT., IwabuM., HonmaT., HamagamiK., MatsudaK., YamaguchiM., TanabeH., Kimura-SomeyaT., ShirouzuM., OgataH., TokuyamaK., UekiK., NaganoT., TanakaA., YokoyamaS., and KadowakiT. (2013). A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature, 503, 493–499.
46.
ZhangY., ZhaoJ., LiR., LauW.B., YuanY.X., LiangB., GaoE.H., KochW.J., MaX.L., and WangY.J. (2015). AdipoRon, the first orally active adiponectin receptor activator, attenuates postischemic myocardial apoptosis through both AMPK-mediated and AMPK-independent signalings. Am. J. Physiol. Endocrinol. Metab. 309, E275–282.
47.
HongK., LeeS., LiR., YangY., TannerM.A., WuJ., and HillM.A. (2016). Adiponectin receptor agonist, AdipoRon, causes vasorelaxation predominantly via a direct smooth muscle action. Microcirculation, 23, 207–220.
48.
NortonW.T. and PodusloS.E. (1973). Myelination in rat brain: method of myelin isolation. J. Neurochem. 21, 749–757.
49.
ZhangY.P., BurkeD.A., ShieldsL.B., ChekmenevS.Y., DincmanT., ZhangY., ZhengY., SmithR.R., BentonR.L., DeVriesW.H., HuX., MagnusonD.S., WhittemoreS.R., and ShieldsC.B. (2008). Spinal cord contusion based on precise vertebral stabilization and tissue displacement measured by combined assessment to discriminate small functional differences. J. Neurotrauma, 25, 1227–1240.
50.
BassoD.M., FisherL.C., AndersonA.J., JakemanL.B., McTigueD.M., and PopovichP.G. (2006). Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J. Neurotrauma, 23, 635–659.
51.
ChinettiG., ZawadskiC., FruchartJ.C., and StaelsB. (2004). Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARalpha, PPARgamma, and LXR. Biochem. Biophys. Res. Commun. 314, 151–158.
52.
MaoX., KikaniC.K., RiojasR.A., LanglaisP., WangL., RamosF.J., FangQ., Christ-RobertsC.Y., HongJ.Y., KimR.Y., LiuF., and DongL.Q. (2006). APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat. Cell Biol. 8, 516–523.
53.
ChawlaA., BoisvertW.A., LeeC.H., LaffitteB.A., BarakY., JosephS.B., LiaoD., NagyL., EdwardsP.A., CurtissL.K., EvansR.M., and TontonozP. (2001). A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol. Cell, 7, 161–171.
54.
McWhorterF.Y., WangT., NguyenP., ChungT., and LiuW.F. (2013). Modulation of macrophage phenotype by cell shape. Proc. Natl. Acad. Sci. U. S. A. 110, 17253–17258.
55.
WangX., ChenT., LengL., FanJ., CaoK., DuanZ., ZhangX., ShaoC., WuM., TadmoriI., LiT., LiangL., SunD., ZhengS., MeinhardtA., YoungW., BucalaR., and RenY. (2012). MIF produced by bone marrow-derived macrophages contributes to teratoma progression after embryonic stem cell transplantation. Cancer Res. 72, 2867–2878.
56.
BoatoF., HendrixS., HuelsenbeckS.C., HofmannF., GrosseG., DjalaliS., KlimaschewskiL., AuerM., JustI., Ahnert-HilgerG., and HoltjeM. (2010). C3 peptide enhances recovery from spinal cord injury by improved regenerative growth of descending fiber tracts. J. Cell Sci. 123, 1652–1662.
57.
HendrikxT., WalenberghS.M., HofkerM.H., and Shiri-SverdlovR. (2014). Lysosomal cholesterol accumulation: driver on the road to inflammation during atherosclerosis and non-alcoholic steatohepatitis. Obesity Rev. 15, 424–433.
58.
EtoY., MeierC., and HerschkowitzN.N. (1976). Chemical compositions of brain and myelin in two patients with multiple sulphatase deficiency (a variant form of metachromatic leukodystrophy). J. Neurochem. 27, 1071–1076.
59.
BerghoffS.A., GerndtN., WinchenbachJ., StumpfS.K., HosangL., OdoardiF., RuhwedelT., BohlerC., BarretteB., StassartR., LiebetanzD., DibajP., MobiusW., EdgarJ.M., and SaherG. (2017). Dietary cholesterol promotes repair of demyelinated lesions in the adult brain. Nat. Commun. 8, 14241.
NeirinckxV., CosteC., FranzenR., GothotA., RogisterB., and WisletS. (2014). Neutrophil contribution to spinal cord injury and repair. J. Neuroinflammation, 11, 150.
62.
SilvaM.T., do ValeA., and dos SantosN.M. (2008). Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications. Apoptosis, 13, 463–482.
63.
TrivediA., OlivasA.D., and Noble-HaeussleinL.J. (2006). Inflammation and spinal cord injury: infiltrating leukocytes as determinants of injury and repair processes. Clin. Neurosci. Res. 6, 283–292.
64.
ShechterR., LondonA., VarolC., RaposoC., CusimanoM., YovelG., RollsA., MackM., PluchinoS., MartinoG., JungS., and SchwartzM. (2009). Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 6, e1000113.
65.
GhirnikarR.S., LeeY.L., and EngL.F. (2000). Chemokine antagonist infusion attenuates cellular infiltration following spinal cord contusion injury in rat. J. Neurosci. Res. 59, 63–73.
66.
GhirnikarR.S., LeeY.L., and EngL.F. (2001). Chemokine antagonist infusion promotes axonal sparing after spinal cord contusion injury in rat. J. Neurosci. Res. 64, 582–589.
MaM., WeiT., BoringL., CharoI.F., RansohoffR.M., and JakemanL.B. (2002). Monocyte recruitment and myelin removal are delayed following spinal cord injury in mice with CCR2 chemokine receptor deletion. J. Neurosci. Res. 68, 691–702.
69.
LiF., ChengB., ChengJ., WangD., LiH., and HeX. (2015). CCR5 blockade promotes M2 macrophage activation and improves locomotor recovery after spinal cord injury in mice. Inflammation, 38, 126–133.
SongJ., ChoiS.M., and KimB.C. (2017). Adiponectin fegulates the polarization and function of microglia via PPAR-gamma signaling under amyloid beta toxicity. Front. Cell. Neurosci. 11, 64.
72.
WanZ., MahD., SimtchoukS., KlegerisA., and LittleJ.P. (2014). Globular adiponectin induces a pro-inflammatory response in human astrocytic cells. Biochem. Biophys. Res. Commun. 446, 37–42.
73.
KosK., HarteA.L., da SilvaN.F., TonchevA., ChaldakovG., JamesS., SneadD.R., HoggartB., O'HareJ.P., McTernanP.G., and KumarS. (2007). Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin receptors in the human hypothalamus. J. Clin. Endocrinol. Metab. 92, 1129–1136.
74.
KusminskiC.M., McTernanP.G., SchrawT., KosK., O'HareJ.P., AhimaR., KumarS., and SchererP.E. (2007). Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum. Diabetologia, 50, 634–642.
75.
NeumeierM., WeigertJ., BuettnerR., WanningerJ., SchafflerA., MullerA.M., KillianS., SauerbruchS., SchlachetzkiF., SteinbrecherA., AslanidisC., ScholmerichJ., and BuechlerC. (2007). Detection of adiponectin in cerebrospinal fluid in humans. Am. J. Physiol. Endocrinol. Metab. 293, E965–E969.
76.
SaundersT.J., PalombellaA., McGuireK.A., JaniszewskiP.M., DespresJ.P., and RossR. (2012). Acute exercise increases adiponectin levels in abdominally obese men. J. Nutr. Metab. 2012, 148729.
77.
KriketosA.D., GanS.K., PoyntenA.M., FurlerS.M., ChisholmD.J., and CampbellL.V. (2004). Exercise increases adiponectin levels and insulin sensitivity in humans. Diabetes Care, 27, 629–630.
78.
SimpsonK.A. and SinghM.A. (2008). Effects of exercise on adiponectin: a systematic review. Obesity (Silver Spring) 16, 241–256.
79.
ChenJ.H., OuyangC., DingQ., SongJ., CaoW., and MaoL. (2015). A moderate low-carbohydrate low-calorie diet improves lipid profile, insulin sensitivity and adiponectin expression in rats. Nutrients, 7, 4724–4738.
80.
CombsT.P., BergA.H., RajalaM.W., KlebanovS., IyengarP., Jimenez-ChillaronJ.C., PattiM.E., KleinS.L., WeinsteinR.S., and SchererP.E. (2003). Sexual differentiation, pregnancy, calorie restriction, and aging affect the adipocyte-specific secretory protein adiponectin. Diabetes, 52, 268–276.
81.
VaradyK.A., AllisterC.A., RoohkD.J., and HellersteinM.K. (2010). Improvements in body fat distribution and circulating adiponectin by alternate-day fasting versus calorie restriction. J. Nutr. Biochem. 21, 188–195.
82.
RogozinaO.P., BonordenM.J., SeppanenC.N., GrandeJ.P., and ClearyM.P. (2011). Effect of chronic and intermittent calorie restriction on serum adiponectin and leptin and mammary tumorigenesis. Cancer Prev. Res. (Phila) 4, 568–581.
83.
HalbergN., HenriksenM., SoderhamnN., StallknechtB., PlougT., SchjerlingP., and DelaF. (2005). Effect of intermittent fasting and refeeding on insulin action in healthy men. J. Appl. Physiol. (1985) 99, 2128–2136.
84.
WanR., AhmetI., BrownM., ChengA., KamimuraN., TalanM., and MattsonM.P. (2010). Cardioprotective effect of intermittent fasting is associated with an elevation of adiponectin levels in rats. J. Nutr. Biochem. 21, 413–417.
85.
OtvosL.Jr., HaspingerE., La RussaF., MasperoF., GrazianoP., KovalszkyI., LovasS., NamaK., HoffmannR., KnappeD., CassoneM., WadeJ., and SurmaczE. (2011). Design and development of a peptide-based adiponectin receptor agonist for cancer treatment. BMC Biotechnol. 11, 90.
86.
OtvosL.Jr., KnappeD., HoffmannR., KovalszkyI., OlahJ., HewitsonT.D., StawikowskaR., StawikowskiM., CudicP., LinF., WadeJ.D., SurmaczE., and LovasS. (2014). Development of second generation peptides modulating cellular adiponectin receptor responses. Front. Chem. 2, 93.
87.
KumarP., SmithT., RahmanK., ThornN.E., and AnaniaF.A. (2014). Adiponectin agonist ADP355 attenuates CCl4-induced liver fibrosis in mice. PLoS One, 9, e110405.
88.
WangH., ZhangH., ZhangZ., HuangB., ChengX., WangD., la GahuZ., XueZ., DaY., LiD., YaoZ., GaoF., XuA., and ZhangR. (2016). Adiponectin-derived active peptide ADP355 exerts anti-inflammatory and anti-fibrotic activities in thioacetamide-induced liver injury. Sci. Rep. 6, 19445.
89.
PeppingJ.K., OtvosL.Jr., SurmaczE., GuptaS., KellerJ.N., and Bruce-KellerA.J. (2014). Designer adiponectin receptor agonist stabilizes metabolic function and prevents brain injury caused by HIV protease inhibitors. J. Neuroimmune Pharmacol. 9, 388–398.
90.
YamauchiT., NioY., MakiT., KobayashiM., TakazawaT., IwabuM., Okada-IwabuM., KawamotoS., KubotaN., KubotaT., ItoY., KamonJ., TsuchidaA., KumagaiK., KozonoH., HadaY., OgataH., TokuyamaK., TsunodaM., IdeT., MurakamiK., AwazawaM., TakamotoI., FroguelP., HaraK., TobeK., NagaiR., UekiK., and KadowakiT. (2007). Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 13, 332–339.
91.
WilkS., ScheibenbogenC., BauerS., JenkeA., RotherM., GuerreiroM., KudernatschR., GoernerN., PollerW., Elligsen-MerkelD., UtkuN., MagraneJ., VolkH.D., and SkurkC. (2011). Adiponectin is a negative regulator of antigen-activated T cells. Eur. J. Immunol. 41, 2323–2332.
92.
ChengX., FolcoE.J., ShimizuK., and LibbyP. (2012). Adiponectin induces pro-inflammatory programs in human macrophages and CD4+ T cells. J. Biol. Chem. 287, 36896–36904.
93.
TanP.H., TyrrellH.E., GaoL., XuD., QuanJ., GillD., RaiL., DingY., PlantG., ChenY., XueJ.Z., HandaA.I., GreenallM.J., WalshK., and XueS.A. (2014). Adiponectin receptor signaling on dendritic cells blunts antitumor immunity. Cancer Res. 74, 5711–5722.
94.
WangY., WanY., YeG., WangP., XueX., WuG., and YeB. (2016). Hepatoprotective effects of AdipoRon against d-galactosamine-induced liver injury in mice. Eur. J. Pharm. Sci. 93, 123–131.
95.
WangY., QiuY., YinS., ZhangL., ShiK., GaoH., ZhangZ., and HeQ. (2017). A functional nanocarrier that copenetrates extracellular matrix and multiple layers of tumor cells for sequential and deep tumor autophagy inhibitor and chemotherapeutic delivery. Autophagy, 13, 359–370.
96.
MessaggioF., MendonsaA.M., CastellanosJ., NagathihalliN.S., GordenL., MerchantN.B., and VanSaunM.N. (2017). Adiponectin receptor agonists inhibit leptin induced pSTAT3 and in vivo pancreatic tumor growth. Oncotarget, 8, 85378–85391.
97.
AkimotoM., MaruyamaR., KawabataY., TajimaY., and TakenagaK. (2018). Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERK-dependent necroptosis. Cell Death Dis. 9, 804.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
