Adipose tissue-derived stem cells from affected and unaffected areas in patients with multiple symmetric lipomatosis show differential regulation of mTOR pathway genes
Restricted accessResearch articleFirst published online May 5, 2018
Adipose tissue-derived stem cells from affected and unaffected areas in patients with multiple symmetric lipomatosis show differential regulation of mTOR pathway genes
Multiple symmetric lipomatosis is a rare disease characterized by the excessive growth of uncapsulated masses of adipose tissue. Although the etiology has yet to be elucidated, a connection to brown adipose tissue has been proposed recently. The mTOR pathway which is found to be regulated in lipomatous tissue as well as associated with brown adipose tissue can be inhibited by a compound called rapamycin.
METHODS:
We isolated adipose tissue derived stem cells from both affected and unaffected tissue and treated these cells with different concentrations of rapamycin.
RESULTS:
The differences in both proliferation and differentiation between adipose tissue derived stem cells (ASCs) from lipomatous and normal tissue decreased after mTOR pathway inhibition. In some patients regulation of mTOR genes was opposed in the ASCs from the two different tissues.
CONCLUSIONS:
Treatment with rapamycin might be a novel therapeutical approach for patients suffering from multiple symmetric lipomatosis.
GdyniaHJ, SperfeldAD, KnirschU, HombergV, RosenbohmA, Müller-HöckerJ, LudolphAC, HanemannCO. Benign symmetric lipomatosis with axonal neuropathy and abnormalities in specific mitochondrial tRNA regions. Eur J Med Res. 2006;11(12):545–6.
6.
SawyerSL, Cheuk-HimNg A, InnesAM, WagnerJD, DymentDA, TetreaultM, MajewskiJ, BoycottKM, ScreatonRA, NicholsonG. Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy. Hum Mol Genet. 2015;24(18):5109–14.
7.
HolmeE, LarssonNG, OldforsA, TuliniusM, SahlinP, StenmanG. Multiple symmetric lipomas with high levels of mtDNA with the tRNA(Lys) A–>Gmutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome. Am J Hum Genet. 1993;52(3):551–6.
8.
GámezJ, PlayánA, AndreuAL, BrunoC, NavarroC, CerveraC, ArbósMA, SchwartzS, EnriquezJA, MontoyaJ. Familialmultiple symmetric lipomatosis associated with the AG mutationof mitochondrial DNA. Neurology. 1998;51(1):258–60.
9.
EnziG, DigitoM, MarinR, CarraroR, BaritussioA, ManzatoE. Mediastino-abdominal lipomatosis: Deep accumulation of fatmimicking a respiratory disease and ascites. Clinical aspects andmetabolic studies in vitro. Q J Med. 1984;53, 453–63.
10.
SenturkT, AkarH, KadikoiluG. Multiple symmetric lipomatosis with mediastinal involvement and subclinical hypothyroidism in a female patient. T Klin Med Sci. 2002;22, 413e6.
11.
RamosS, PinheiroS, DiogoC, CabralL, CruzeiroC. Madelung disease: A not-so-rare disorder. Ann Plast Surg. 2010;64, 122–4.
12.
MilisavljevicD, ZivicM, StankovicP. Severe dyspnea as atypical presenting symptom of madelung’s disease. Hippokratia. 2010;14, 133e5.
13.
FonsecaVA, AlvesC, MarquesH, CamachoE, SaraivaAP. Madelung’s disease as a rare cause of obstructive sleep apnea. J Bras Pneumol. 2009;35(10):1053–6.
14.
EnziG, BusettoL, CeschinE, CoinA, DigitoM, PigozzoS. Multiple symmetric lipomatosis: Clinical aspects and outcome in a long-term longitudinal study. Int J Obes Relat Metab Disord. 2002;26(2):253–61.
15.
FonsecaVR, FreitasC, PalmeiraM, FerreiraC, VictorinoR. Cardiac noradrenergic denervation in a patient with multiple symmetric lipomatosis. Cardiology. 2012;121(3):160–3.
16.
EnziG, BusettoL, SergiG, CoinA, InelmenEM, VindigniV, BassettoF, CintiS. Multiple symmetric lipomatosis: A raredisease and its possible links to brown adipose tissue. Nutr Metab Cardiovasc Dis. 2015;25(4):347–53.
17.
NaumannM, SchalkeB, KlopstockT, ReichmannH, LangeKW, WiesbeckG, ToykaKV, ReinersK. Neurological multisystem manifestation in multiple symmetric lipomatosis: A clinical and electrophysiological study. Muscle Nerve. 1995;18(7):693–8.
18.
KlopstockT, NaumannM, SchalkeB, BischofF, SeibelP, KottlorsM, EckertP, ReinersK, ToykaKV, ReichmannH. Multiple symmetric lipomatosis: Abnormalities in complex IV and multiple deletions in mitochondrial DNA. Neurology. 1994;44(5):862–6.
19.
MeningaudJP1, Pitak-ArnnopP, BertrandJC. Multiple symmetric lipomatosis: Case report and review of the literature. J Oral Maxillofac Surg. 2007;65(7):1365–9.
20.
ArdeleanuV, ChicosS, GeorgescuC, TutunaruD. Multiple benign symmetric lipomatosis – a differential diagnosis of obesity. Chirurgia (Bucur). 2013;108(4):580–3.
PlummerC1, SpringPJ, MarottaR, ChinJ, TaylorG, SharpeD, AthanasouNA, ThyagarajanD, BerkovicSF. Multiple symmetrical Lipomatosis–a mitochondrial disorder of brown fat. Mitochondrion. 2013;13(4):269–76.
23.
SchulzTJ, TsengY. Brown adipose tissue: Development, metabolism and beyond. Biochem J.. 2013;453(2):10.1042/BJ20130457
24.
CedikovaM, KripnerováM, DvorakovaJ, PituleP, GrundmanovaM, BabuskaV, MullerovaD, Jitka KuncovaJ. Mitochondria in white,brown, and beige adipocytes. Stem Cells Int. 2016;6067349.
25.
KodishME, AlseverRN, BlockMB. Benign symmetric lipomatosis: Functional sympathetic denervation of adipose tissue and possible hypertrophy of brown fat. Metabolism. 1974;23(10):937–45.
26.
PrantlL, SchremlJ, GehmertS, KleinS, BaiX, ZeitlerK, SchremlS, AltE, GehmertS, FelthausO. Transcription profile in sporadic multiple symmetric lipomatosis reveals differential expression at the level of adipose tissue-derived stem cells. Plast Reconstr Surg. 2016;137(4):1181–90.
27.
LammingDW, SabatiniDM. A Central role for mTOR in lipid homeostasis. Cell Metab. 2013;18(4):465–9.
28.
MannaaM, KrämerS, BoschmannM, GollaschM. mTOR and regulation of energy homeostasis in humans. J Mol Med (Berl). 2013;91(10):1167–75.
29.
AlbertV, HallMN2. mTOR signaling in cellular and organismal energetics. Curr Opin Cell Biol. 2015;33, 55–66.
30.
YangA, XiaoX, ZhaoM, LaRueAC, SchulteBA, WangGY. Differential reponses of hematopoietic stem and progenitor cells to mTOR inhibition. Stem Cells Int. 2015;2015:561404.
31.
DannSG, SelvarajA, ThomasG. mTOR Complex1-S6K1 signaling: At the crossroads of obesity, diabetes and cancer. Trends Mol Med. 2007;13(6):252–9.
32.
MałgorzewiczS, DardzińskaJA, GnacińskaM, JankunJ, BrylE, SworczakK. Complex interaction between the immune systemand adipose tissue (Review). Int J Mol Med. 2014;33(1):3–7.
33.
HarschIA, SchahinSP, FuchsFS, HahnEG, LohmannT, KonturekPC, FickerJH. Insulin resistance, hyperleptinemia, and obstructive sleep apnea in Launois-Bensaude syndrome. Obes Res. 2002;10(7):625–32.
34.
CojocaruDC, CozmaCD, PostolacheP. Markers of insulin resistance in a case of Launois-Bensaude syndrome. Rev Med Chir Soc Med Nat Iasi. 2013;117(2):404–8.
35.
D’EttorreM, GniuliD, GuidoneC, BracagliaR, TambascoD, MingroneG. Insulin sensitivity in familial multiple lipomatosis. Eur Rev Med Pharmacol Sci. 2013;17(16):2254–6.
36.
CarnevalliLS, MasudaK, FrigerioF, Le BacquerO, UmSH, GandinV, TopisirovicI, SonenbergN, ThomasG, KozmaSC. S6K1 plays a critical role in early adipocyte differentiation. Dev Cell. 2010;18(5):763–74.
37.
WuX, SchneiderN, PlatenA, MitraI, BlazekM, ZengerleR, SchüleR, MeierM. In situ characterization of the mTORC1during adipogenesis of human adult stem cells on chiProc NatlAcad Sci U S A. E. 2016;113(29):4143–50.
38.
VézinaC, KudelskiA, SehgalSN. Rapamycin (AY-22,989), a newantifungal antibiotic. I. Taxonomy of the producing streptomyceteand isolation of the active principle. J Antibiot (Tokyo). 1975;28(10):721–6.
39.
AbizaidA. Sirolimus-eluting coronary stents: A review. Vasc Health Risk Manag. 2007;3(2):191–201.
40.
AnadolR, GoriT. The mechanisms of late scaffold thrombosis. Clin Hemorheol Microcirc. 2017. DOI: 10.3233/CH-
179214 [Epub ahead of print].
41.
Krüger-GengeA, HieblB, FrankeRP, LendleinA, JungF. Effects of Tacrolimus or Sirolimus on the adhesion of vascular wall cells: Controlled in-vitro comparison study. Clin Hemorheol Microcirc. 2017. DOI: 10.3233/CH-179211
[Epub ahead of print].
42.
WankhadeUD, ShenM, KolheR, Sadanand FulzeleS. Advances in adipose-derived stem cells isolation, characterization, and application in regenerative tissue engineering. Stem Cells Int. 2016;2016:3206807.
43.
HadjievB, StefanovaP, ShipkovC, UchikovA, MojallalA. Madelung disease: On the morphologic criteria for diagnosis and treatment. Ann Plast Surg. 2010;64(6):807–8.
44.
Brea-GarcíaB, Cameselle-TeijeiroJ, Couto-GonzálezI, Taboada-SuárezA, González-ÁlvarezE. Madelung’sdisease: Comorbidities, fatty mass distribution, and response totreatment of 22 patients. Aesthetic Plast Surg. 2013;37(2):409–16.
45.
HeckmannJG, KrausB, StefanH, NeundörferB. Progressive muscle pain, weight gain, fatique and unusual body shape change. Eur J Neurol. 2000;7(2):243–4.
46.
KlopstockT, NaumannM, SeibelP, ShalkeB, ReinersK, ReichmannH. Mitochondrial DNA mutations in multiple symmetric lipomatosis. Mol Cell Biochem. 1997;174(1-2):271–5.
47.
BlanchardPG, FestucciaWT, HoudeVP, St-PierreP, BrûléS, TurcotteV, CôtéM, BellmannK, MaretteA, DeshaiesY. Major involvement of mTOR in the PPARγ-inducedstimulation of adipose tissue lipid uptake and fat accretion. J Lipid Res. 2012;53(6):1117–25.
48.
ShanT, XiongY, ZhangP, LiZ, JiangQ, BiP, YueF, YangG, WangY, LiuX, KuangS. Lkb1 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3. Nat Commun. 2016;7, 12205.
49.
ShanT, ZhangP, JiangQ, XiongY, WangY, KuangS. Adipocyte-specific deletion of mTOR inhibits adipose tissue development and causes insulin resistance in mice. Diabetologia. 2016;59(9):1995–2004.
RoSH, SempleI, HoA, ParkHW, LeeJH. Sestrin2, a regulator of thermogenesis and mitohormesis in brown adipose tissue. Front Endocrinol (Lausanne). 2015;6, 114.
52.
Muñoz-MálagaA, BautistaJ, SalazarJA, AguileraI, GarciaR, ChinchonI, SeguraMD, CamposY, ArenasJ. Lipomatosis,proximal myopathy, and the mitochondrial mutation. A lipidstorage myopathy?Muscle Nerve. 2000;23, 538–42.
53.
BerkovicSF, AndermannF, ShoubridgeEA, CarpenterS, RobitailleY, AndermannE, MelmedC, KarpatiG. Mitochondrial dysfunction in multiple symmetrical lipomatosis. Ann Neurol. 1991;29, 566–9.
54.
KratzC, LenardHG, RuzickaT, GärtnerJ. Multiple symmetric lipomatosis: An unusual cause of childhood obesity and mental retardation. Eur J Paediatr Neurol. 2000;4, 63–7.
55.
LiaoCY, RikkeBA, JohnsonTE, GelfondJA, DiazV, NelsonJF. Fat maintenance is a predictor of the murine lifespan response to dietary restriction. Aging Cell. 2011;10(4):629–39.
56.
HarrisonDE, StrongR, SharpZD, NelsonJF, AstleCM, FlurkeyK, NadonNL, WilkinsonJE, FrenkelK, CarterCS, PahorM, JavorsMA, FernandezE, MillerRA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 460. 2009;460(7253):392–5.
57.
ZhaoG, GuoS, SomelM, KhaitovichP. Evolution of human longevity uncoupled from caloric restriction mechanisms. PLoS One. 2014;9(1):e84117.
58.
DeyoJC, NicolsenN, LachiewiczA, KozlowskiT. Salvage treatment of mucormycosis post-liver transplant with posaconazole during sirolimus maintenance immunosuppression. J Pharm Pract. 2016. pii: 0897190016628702.
59.
KarakasNM, ErdoganI, OzdemirB, SezginA. Pain syndrome and ventricular arrhythmia induced by sirolimus and resolved by dosage adjustment in a child after heart transplant: A case report. Exp Clin Transplant. 2016. doi: 10.6002/ect.2015.0320.
60.
HaasovaM, SnowsillT, Jones-HughesT, CrathorneL, CooperC, Varley-CampbellJ, Mujica-MotaR, CoelhoH, HuxleyN, LoweJ, DudleyJ, MarksS, HydeC, BondM, AndersonR. Immunosuppressive therapy for kidney transplantation in children and adolescents: Systematic review and economic evaluation. Health Technol Assess. 2016;20(61):1–324.
61.
NguyenQD, MerrillPT, ClarkWL, BankerAS, FardeauC, FrancoP, LeHoangP, OhnoS, RathinamSR, ThurauS, AbrahamA, WilsonL, YangY, ShamsN. Intravitreal sirolimus for noninfectious Uveitis: A phase III sirolimus study assessing double-masKed Uveitis TReAtment (SAKURA). Ophthalmology. 2016;123(11):2413–23.
62.
TaMH, SchwensenKG, FosterS, KorgaonkarM, Ozimek-KulikJE, PhillipsJK, PedutoA, RanganGK. Effects of TORC1 inhibition during the early and established phases of polycystic kidney disease. PLoS One. 2016;11(10):e0164193.
