Circulating factors present in the sera of naturally skinny people may influence cell commitment and adipocyte differentiation of mesenchymal stromal cells
|
摘要
BACKGROUND Research on physiopathology of obesity may receive new hints from studies on skinny people(SP). These are individuals who show a poor or null gaining of body weight, in spite of high-calorie intake, by far exceeding the body requirements.AIM To evaluate how circulating factors present in the SP sera may affect adipogenesis of mesenchymal stromal cells(MSCs).METHODS We isolated MSCs from bone marrow of healthy donors with both normal body mass index(BMI) and caloric consumption. MSC cultures were primed with sera collected from SP or normal people(NP). Then biomolecular assays were performed to evaluate effect on proliferation, apoptosis, senescence, cell commitment, and differentiation.RESULTS SP priming affected adipocyte cell commitment and reduced spontaneous adipogenesis. Moreover, an in-depth analysis of exogenous-induced adipocyte differentiation showed striking differences between differentiation in SP-primed samples compared with NP ones. In adipocytes from SP cultures we observed a reduced size of lipid droplets, an increased expression of adipose triglyceride lipase, along with high mitochondria content and ability to produce ATP in starvation condition. These data and the expression of UCP1 protein, indicated that SP pretreatment produced a bias toward brown adipocyte differentiation.CONCLUSION Our data suggest that sera from SP may promote brown adipogenesis rather that white adipocyte differentiation. This finding could explain why SP present normal body composition in spite of an excess of caloric intake. We hypothesize that some circulating components present in the blood of these individuals may favor brown adipogenesis at expense of white adipocyte production.
BACKGROUND Research on physiopathology of obesity may receive new hints from studies on skinny people(SP). These are individuals who show a poor or null gaining of body weight, in spite of high-calorie intake, by far exceeding the body requirements.AIM To evaluate how circulating factors present in the SP sera may affect adipogenesis of mesenchymal stromal cells(MSCs).METHODS We isolated MSCs from bone marrow of healthy donors with both normal body mass index(BMI) and caloric consumption. MSC cultures were primed with sera collected from SP or normal people(NP). Then biomolecular assays were performed to evaluate effect on proliferation, apoptosis, senescence, cell commitment, and differentiation.RESULTS SP priming affected adipocyte cell commitment and reduced spontaneous adipogenesis. Moreover, an in-depth analysis of exogenous-induced adipocyte differentiation showed striking differences between differentiation in SP-primed samples compared with NP ones. In adipocytes from SP cultures we observed a reduced size of lipid droplets, an increased expression of adipose triglyceride lipase, along with high mitochondria content and ability to produce ATP in starvation condition. These data and the expression of UCP1 protein, indicated that SP pretreatment produced a bias toward brown adipocyte differentiation.CONCLUSION Our data suggest that sera from SP may promote brown adipogenesis rather that white adipocyte differentiation. This finding could explain why SP present normal body composition in spite of an excess of caloric intake. We hypothesize that some circulating components present in the blood of these individuals may favor brown adipogenesis at expense of white adipocyte production.
BACKGROUND Research on physiopathology of obesity may receive new hints from studies on skinny people(SP). These are individuals who show a poor or null gaining of body weight, in spite of high-calorie intake, by far exceeding the body requirements.AIM To evaluate how circulating factors present in the SP sera may affect adipogenesis of mesenchymal stromal cells(MSCs).METHODS We isolated MSCs from bone marrow of healthy donors with both normal body mass index(BMI) and caloric consumption. MSC cultures were primed with sera collected from SP or normal people(NP). Then biomolecular assays were performed to evaluate effect on proliferation, apoptosis, senescence, cell commitment, and differentiation.RESULTS SP priming affected adipocyte cell commitment and reduced spontaneous adipogenesis. Moreover, an in-depth analysis of exogenous-induced adipocyte differentiation showed striking differences between differentiation in SP-primed samples compared with NP ones. In adipocytes from SP cultures we observed a reduced size of lipid droplets, an increased expression of adipose triglyceride lipase, along with high mitochondria content and ability to produce ATP in starvation condition. These data and the expression of UCP1 protein, indicated that SP pretreatment produced a bias toward brown adipocyte differentiation.CONCLUSION Our data suggest that sera from SP may promote brown adipogenesis rather that white adipocyte differentiation. This finding could explain why SP present normal body composition in spite of an excess of caloric intake. We hypothesize that some circulating components present in the blood of these individuals may favor brown adipogenesis at expense of white adipocyte production.
引文
1 Roberto CA,Swinburn B,Hawkes C,Huang TT,Costa SA,Ashe M,Zwicker L,Cawley JH,Brownell KD.Patchy progress on obesity prevention:emerging examples,entrenched barriers,and new thinking.Lancet 2015;385:2400-2409[PMID:25703111 DOI:10.1016/S0140-6736(14)61744-X]
2 Nuttall FQ.Body Mass Index:Obesity,BMI,and Health:A Critical Review.Nutr Today 2015;50:117-128[PMID:27340299 DOI:10.1097/NT.0000000000000092]
3 Lamberto M,Mantovan M,Novi RF.Essential obesity:an unresolved clinical problem.Considerations on central appetite stimulants and inhibitors.Minerva Endocrinol 1993;18:27-35[PMID:7901745]
4 GBD 2015 Obesity Collaborators;Afshin A,Forouzanfar MH,Reitsma MB,Sur P,Estep K,Lee A,Marczak L,Mokdad AH,Moradi-Lakeh M,Naghavi M,Salama JS,Vos T,Abate KH,Abbafati C,Ahmed MB,Al-Aly Z,Alkerwi A,Al-Raddadi R,Amare AT,Amberbir A,Amegah AK,Amini E,Amrock SM,Anjana RM,?rnl?v J,Asayesh H,Banerjee A,Barac A,Baye E,Bennett DA,Beyene AS,Biadgilign S,Biryukov S,Bjertness E,Boneya DJ,Campos-Nonato I,Carrero JJ,Cecilio P,Cercy K,Ciobanu LG,Cornaby L,Damtew SA,Dandona L,Dandona R,Dharmaratne SD,Duncan BB,Eshrati B,Esteghamati A,Feigin VL,Fernandes JC,Fürst T,Gebrehiwot TT,Gold A,Gona PN,Goto A,Habtewold TD,Hadush KT,Hafezi-Nejad N,Hay SI,Horino M,Islami F,Kamal R,Kasaeian A,Katikireddi SV,Kengne AP,Kesavachandran CN,Khader YS,Khang YH,Khubchandani J,Kim D,Kim YJ,Kinfu Y,Kosen S,Ku T,Defo BK,Kumar GA,Larson HJ,Leinsalu M,Liang X,Lim SS,Liu P,Lopez AD,Lozano R,Majeed A,Malekzadeh R,Malta DC,Mazidi M,McAlinden C,McGarvey ST,Mengistu DT,Mensah GA,Mensink GBM,Mezgebe HB,Mirrakhimov EM,Mueller UO,Noubiap JJ,Obermeyer CM,Ogbo FA,Owolabi MO,Patton GC,Pourmalek F,Qorbani M,Rafay A,Rai RK,Ranabhat CL,Reinig N,Safiri S,Salomon JA,Sanabria JR,Santos IS,Sartorius B,Sawhney M,Schmidhuber J,Schutte AE,Schmidt MI,Sepanlou SG,Shamsizadeh M,Sheikhbahaei S,Shin MJ,Shiri R,Shiue I,Roba HS,Silva DAS,Silverberg JI,Singh JA,Stranges S,Swaminathan S,Tabarés-Seisdedos R,Tadese F,Tedla BA,Tegegne BS,Terkawi AS,Thakur JS,Tonelli M,Topor-Madry R,Tyrovolas S,Ukwaja KN,Uthman OA,Vaezghasemi M,Vasankari T,Vlassov VV,Vollset SE,Weiderpass E,Werdecker A,Wesana J,Westerman R,Yano Y,Yonemoto N,Yonga G,Zaidi Z,Zenebe ZM,Zipkin B,Murray CJL.Health Effects of Overweight and Obesity in 195 Countries over 25 Years.N Engl J Med 2017;377:13-27[PMID:28604169 DOI:10.1056/NEJMoa1614362]
5 Guglielmi V,Sbraccia P.Obesity phenotypes:depot-differences in adipose tissue and their clinical implications.Eat Weight Disord 2018;23:3-14[PMID:29230714 DOI:10.1007/s40519-017-0467-9]
6 Wiklund P,Toss F,Weinehall L,Hallmans G,Franks PW,Nordstr?m A,Nordstr?m P.Abdominal and gynoid fat mass are associated with cardiovascular risk factors in men and women.J Clin Endocrinol Metab 2008;93:4360-4366[PMID:18728169 DOI:10.1210/jc.2008-0804]
7 Xia Q,Grant SF.The genetics of human obesity.Ann N Y Acad Sci 2013;1281:178-190[PMID:23360386 DOI:10.1111/nyas.12020]
8 Garrow JS,Blaza SE,Warwick PM,Ashwell MA.Predisposition to obesity.Lancet 1980;1:1103-1104[PMID:6103439 DOI:10.1016/S0140-6736(80)91552-4]
9 Falchi M,El-Sayed Moustafa JS,Takousis P,Pesce F,Bonnefond A,Andersson-Assarsson JC,Sudmant PH,Dorajoo R,Al-Shafai MN,Bottolo L,Ozdemir E,So HC,Davies RW,Patrice A,Dent R,Mangino M,Hysi PG,Dechaume A,Huyvaert M,Skinner J,Pigeyre M,Caiazzo R,Raverdy V,Vaillant E,Field S,Balkau B,Marre M,Visvikis-Siest S,Weill J,Poulain-Godefroy O,Jacobson P,Sjostrom L,Hammond CJ,Deloukas P,Sham PC,McPherson R,Lee J,Tai ES,Sladek R,Carlsson LM,Walley A,Eichler EE,Pattou F,Spector TD,Froguel P.Low copy number of the salivary amylase gene predisposes to obesity.Nat Genet 2014;46:492-497[PMID:24686848 DOI:10.1038/ng.2939]
10 Gavini CK,Jones WC 2nd,Novak CM.Ventromedial hypothalamic melanocortin receptor activation:regulation of activity energy expenditure and skeletal muscle thermogenesis.J Physiol 2016;594:5285-5301[PMID:27126579 DOI:10.1113/JP272352]
11 Scheja L,Heeren J.Metabolic interplay between white,beige,brown adipocytes and the liver.J Hepatol2016;64:1176-1186[PMID:26829204 DOI:10.1016/j.jhep.2016.01.025]
12 Broeders EP,Nascimento EB,Havekes B,Brans B,Roumans KH,Tailleux A,Schaart G,Kouach M,Charton J,Deprez B,Bouvy ND,Mottaghy F,Staels B,van Marken Lichtenbelt WD,Schrauwen P.The Bile Acid Chenodeoxycholic Acid Increases Human Brown Adipose Tissue Activity.Cell Metab 2015;22:418-426[PMID:26235421 DOI:10.1016/j.cmet.2015.07.002]
13 Vargovic P,Ukropec J,Laukova M,Cleary S,Manz B,Pacak K,Kvetnansky R.Adipocytes as a new source of catecholamine production.FEBS Lett 2011;585:2279-2284[PMID:21689652 DOI:10.1016/j.febslet.2011.06.001]
14 Sakellariou P,Valente A,Carrillo AE,Metsios GS,Nadolnik L,Jamurtas AZ,Koutedakis Y,Boguszewski C,Andrade CM,Svensson PA,Kawashita NH,Flouris AD.Chronic l-menthol-induced browning of white adipose tissue hypothesis:A putative therapeutic regime for combating obesity and improving metabolic health.Med Hypotheses 2016;93:21-26[PMID:27372851 DOI:10.1016/j.mehy.2016.05.006]
15 Bartelt A,Heeren J.Adipose tissue browning and metabolic health.Nat Rev Endocrinol 2014;10:24-36[PMID:24146030 DOI:10.1038/nrendo.2013.204]
16 Squillaro T,Peluso G,Galderisi U.Clinical Trials With Mesenchymal Stem Cells:An Update.Cell Transplant 2016;25:829-848[PMID:26423725 DOI:10.3727/096368915X689622]
17 Park A,Kim WK,Bae KH.Distinction of white,beige and brown adipocytes derived from mesenchymal stem cells.World J Stem Cells 2014;6:33-42[PMID:24567786 DOI:10.4252/wjsc.v6.i1.33]
18 Timmons JA,Wennmalm K,Larsson O,Walden TB,Lassmann T,Petrovic N,Hamilton DL,Gimeno RE,Wahlestedt C,Baar K,Nedergaard J,Cannon B.Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages.Proc Natl Acad Sci USA 2007;104:4401-4406[PMID:17360536 DOI:10.1073/pnas.0610615104]
19 Di Bernardo G,Messina G,Capasso S,Del Gaudio S,Cipollaro M,Peluso G,Casale F,Monda M,Galderisi U.Sera of overweight people promote in vitro adipocyte differentiation of bone marrow stromal cells.Stem Cell Res Ther 2014;5:4[PMID:24405848 DOI:10.1186/scrt393]
20 Dominici M,Le Blanc K,Mueller I,Slaper-Cortenbach I,Marini F,Krause D,Deans R,Keating A,Prockop Dj,Horwitz E.Minimal criteria for defining multipotent mesenchymal stromal cells.The International Society for Cellular Therapy position statement.Cytotherapy 2006;8:315-317[PMID:16923606 DOI:10.1080/14653240600855905]
21 Zanichelli F,Capasso S,Di Bernardo G,Cipollaro M,Pagnotta E,CartenìM,Casale F,Iori R,Giordano A,Galderisi U.Low concentrations of isothiocyanates protect mesenchymal stem cells from oxidative injuries,while high concentrations exacerbate DNA damage.Apoptosis 2012;17:964-974[PMID:22684843 DOI:10.1007/s10495-012-0740-3]
22 Alessio N,Bohn W,Rauchberger V,Rizzolio F,Cipollaro M,Rosemann M,Irmler M,Beckers J,Giordano A,Galderisi U.Silencing of RB1 but not of RB2/P130 induces cellular senescence and impairs the differentiation potential of human mesenchymal stem cells.Cell Mol Life Sci 2013;70:1637-1651[PMID:23370776 DOI:10.1007/s00018-012-1224-x]
23 Iacono E,Brunori L,Pirrone A,Pagliaro PP,Ricci F,Tazzari PL,Merlo B.Isolation,characterization and differentiation of mesenchymal stem cells from amniotic fluid,umbilical cord blood and Wharton's jelly in the horse.Reproduction 2012;143:455-468[PMID:22274885 DOI:10.1530/REP-10-0408]
24 Li L,Yao XL,He XL,Liu XJ,Wu WC,Kuang W,Tang M.Role of mechanical strain and estrogen in modulating osteogenic differentiation of mesenchymal stem cells(MSCs)from normal and ovariectomized rats.Cell Mol Biol(Noisy-le-grand)2013;Suppl 59:OL1889-OL1893[PMID:24209734]
25 Zhou S,Zilberman Y,Wassermann K,Bain SD,Sadovsky Y,Gazit D.Estrogen modulates estrogen receptor alpha and beta expression,osteogenic activity,and apoptosis in mesenchymal stem cells(MSCs)of osteoporotic mice.J Cell Biochem Suppl 2001;Suppl 36:144-155[PMID:11455579 DOI:10.1002/jcb.1096]
26 Kusonmano K,Netzer M,Baumgartner C,Dehmer M,Liedl KR,Graber A.Effects of pooling samples on the performance of classification algorithms:a comparative study.ScientificWorldJournal 2012;2012:278352[PMID:22654582 DOI:10.1100/2012/278352]
27 Muraglia A,Cancedda R,Quarto R.Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model.J Cell Sci 2000;113:1161-1166[PMID:10704367DOI:10.1023/A:1005568132027]
28 Kershaw EE,Hamm JK,Verhagen LA,Peroni O,Katic M,Flier JS.Adipose triglyceride lipase:function,regulation by insulin,and comparison with adiponutrin.Diabetes 2006;55:148-157[PMID:16380488DOI:10.2337/diabetes.55.01.06.db05-0982]
29 Rambold AS,Cohen S,Lippincott-Schwartz J.Fatty acid trafficking in starved cells:regulation by lipid droplet lipolysis,autophagy,and mitochondrial fusion dynamics.Dev Cell 2015;32:678-692[PMID:25752962 DOI:10.1016/j.devcel.2015.01.029]
30 Coelho M,Oliveira T,Fernandes R.Biochemistry of adipose tissue:an endocrine organ.Arch Med Sci2013;9:191-200[PMID:23671428 DOI:10.5114/aoms.2013.33181]
31 Nedergaard J,Bengtsson T,Cannon B.New powers of brown fat:fighting the metabolic syndrome.Cell Metab 2011;13:238-240[PMID:21356513 DOI:10.1016/j.cmet.2011.02.009]
32 Fruebis J,Tsao TS,Javorschi S,Ebbets-Reed D,Erickson MR,Yen FT,Bihain BE,Lodish HF.Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.Proc Natl Acad Sci USA 2001;98:2005-2010[PMID:11172066 DOI:10.1073/pnas.98.4.2005]
33 Yamauchi T,Kamon J,Waki H,Terauchi Y,Kubota N,Hara K,Mori Y,Ide T,Murakami K,Tsuboyama-Kasaoka N,Ezaki O,Akanuma Y,Gavrilova O,Vinson C,Reitman ML,Kagechika H,Shudo K,Yoda M,Nakano Y,Tobe K,Nagai R,Kimura S,Tomita M,Froguel P,Kadowaki T.The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.Nat Med2001;7:941-946[PMID:11479627 DOI:10.1038/90984]
34 Yang WS,Lee WJ,Funahashi T,Tanaka S,Matsuzawa Y,Chao CL,Chen CL,Tai TY,Chuang LM.Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein,adiponectin.JClin Endocrinol Metab 2001;86:3815-3819[PMID:11502817 DOI:10.1210/jcem.86.8.7741]
35 Petersson U,Ostgren CJ,Brudin L,Brismar K,Nilsson PM.Low levels of insulin-like growth-factorbinding protein-1(IGFBP-1)are prospectively associated with the incidence of type 2 diabetes and impaired glucose tolerance(IGT):the S?der?kra Cardiovascular Risk Factor Study.Diabetes Metab 2009;35:198-205[PMID:19297224 DOI:10.1016/j.diabet.2008.11.003]
36 Liu B,Hassan Z,Amisten S,King AJ,Bowe JE,Huang GC,Jones PM,Persaud SJ.The novel chemokine receptor,G-protein-coupled receptor 75,is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis.Diabetologia 2013;56:2467-2476[PMID:23979485 DOI:10.1007/s00125-013-3022-x]
2 Nuttall FQ.Body Mass Index:Obesity,BMI,and Health:A Critical Review.Nutr Today 2015;50:117-128[PMID:27340299 DOI:10.1097/NT.0000000000000092]
3 Lamberto M,Mantovan M,Novi RF.Essential obesity:an unresolved clinical problem.Considerations on central appetite stimulants and inhibitors.Minerva Endocrinol 1993;18:27-35[PMID:7901745]
4 GBD 2015 Obesity Collaborators;Afshin A,Forouzanfar MH,Reitsma MB,Sur P,Estep K,Lee A,Marczak L,Mokdad AH,Moradi-Lakeh M,Naghavi M,Salama JS,Vos T,Abate KH,Abbafati C,Ahmed MB,Al-Aly Z,Alkerwi A,Al-Raddadi R,Amare AT,Amberbir A,Amegah AK,Amini E,Amrock SM,Anjana RM,?rnl?v J,Asayesh H,Banerjee A,Barac A,Baye E,Bennett DA,Beyene AS,Biadgilign S,Biryukov S,Bjertness E,Boneya DJ,Campos-Nonato I,Carrero JJ,Cecilio P,Cercy K,Ciobanu LG,Cornaby L,Damtew SA,Dandona L,Dandona R,Dharmaratne SD,Duncan BB,Eshrati B,Esteghamati A,Feigin VL,Fernandes JC,Fürst T,Gebrehiwot TT,Gold A,Gona PN,Goto A,Habtewold TD,Hadush KT,Hafezi-Nejad N,Hay SI,Horino M,Islami F,Kamal R,Kasaeian A,Katikireddi SV,Kengne AP,Kesavachandran CN,Khader YS,Khang YH,Khubchandani J,Kim D,Kim YJ,Kinfu Y,Kosen S,Ku T,Defo BK,Kumar GA,Larson HJ,Leinsalu M,Liang X,Lim SS,Liu P,Lopez AD,Lozano R,Majeed A,Malekzadeh R,Malta DC,Mazidi M,McAlinden C,McGarvey ST,Mengistu DT,Mensah GA,Mensink GBM,Mezgebe HB,Mirrakhimov EM,Mueller UO,Noubiap JJ,Obermeyer CM,Ogbo FA,Owolabi MO,Patton GC,Pourmalek F,Qorbani M,Rafay A,Rai RK,Ranabhat CL,Reinig N,Safiri S,Salomon JA,Sanabria JR,Santos IS,Sartorius B,Sawhney M,Schmidhuber J,Schutte AE,Schmidt MI,Sepanlou SG,Shamsizadeh M,Sheikhbahaei S,Shin MJ,Shiri R,Shiue I,Roba HS,Silva DAS,Silverberg JI,Singh JA,Stranges S,Swaminathan S,Tabarés-Seisdedos R,Tadese F,Tedla BA,Tegegne BS,Terkawi AS,Thakur JS,Tonelli M,Topor-Madry R,Tyrovolas S,Ukwaja KN,Uthman OA,Vaezghasemi M,Vasankari T,Vlassov VV,Vollset SE,Weiderpass E,Werdecker A,Wesana J,Westerman R,Yano Y,Yonemoto N,Yonga G,Zaidi Z,Zenebe ZM,Zipkin B,Murray CJL.Health Effects of Overweight and Obesity in 195 Countries over 25 Years.N Engl J Med 2017;377:13-27[PMID:28604169 DOI:10.1056/NEJMoa1614362]
5 Guglielmi V,Sbraccia P.Obesity phenotypes:depot-differences in adipose tissue and their clinical implications.Eat Weight Disord 2018;23:3-14[PMID:29230714 DOI:10.1007/s40519-017-0467-9]
6 Wiklund P,Toss F,Weinehall L,Hallmans G,Franks PW,Nordstr?m A,Nordstr?m P.Abdominal and gynoid fat mass are associated with cardiovascular risk factors in men and women.J Clin Endocrinol Metab 2008;93:4360-4366[PMID:18728169 DOI:10.1210/jc.2008-0804]
7 Xia Q,Grant SF.The genetics of human obesity.Ann N Y Acad Sci 2013;1281:178-190[PMID:23360386 DOI:10.1111/nyas.12020]
8 Garrow JS,Blaza SE,Warwick PM,Ashwell MA.Predisposition to obesity.Lancet 1980;1:1103-1104[PMID:6103439 DOI:10.1016/S0140-6736(80)91552-4]
9 Falchi M,El-Sayed Moustafa JS,Takousis P,Pesce F,Bonnefond A,Andersson-Assarsson JC,Sudmant PH,Dorajoo R,Al-Shafai MN,Bottolo L,Ozdemir E,So HC,Davies RW,Patrice A,Dent R,Mangino M,Hysi PG,Dechaume A,Huyvaert M,Skinner J,Pigeyre M,Caiazzo R,Raverdy V,Vaillant E,Field S,Balkau B,Marre M,Visvikis-Siest S,Weill J,Poulain-Godefroy O,Jacobson P,Sjostrom L,Hammond CJ,Deloukas P,Sham PC,McPherson R,Lee J,Tai ES,Sladek R,Carlsson LM,Walley A,Eichler EE,Pattou F,Spector TD,Froguel P.Low copy number of the salivary amylase gene predisposes to obesity.Nat Genet 2014;46:492-497[PMID:24686848 DOI:10.1038/ng.2939]
10 Gavini CK,Jones WC 2nd,Novak CM.Ventromedial hypothalamic melanocortin receptor activation:regulation of activity energy expenditure and skeletal muscle thermogenesis.J Physiol 2016;594:5285-5301[PMID:27126579 DOI:10.1113/JP272352]
11 Scheja L,Heeren J.Metabolic interplay between white,beige,brown adipocytes and the liver.J Hepatol2016;64:1176-1186[PMID:26829204 DOI:10.1016/j.jhep.2016.01.025]
12 Broeders EP,Nascimento EB,Havekes B,Brans B,Roumans KH,Tailleux A,Schaart G,Kouach M,Charton J,Deprez B,Bouvy ND,Mottaghy F,Staels B,van Marken Lichtenbelt WD,Schrauwen P.The Bile Acid Chenodeoxycholic Acid Increases Human Brown Adipose Tissue Activity.Cell Metab 2015;22:418-426[PMID:26235421 DOI:10.1016/j.cmet.2015.07.002]
13 Vargovic P,Ukropec J,Laukova M,Cleary S,Manz B,Pacak K,Kvetnansky R.Adipocytes as a new source of catecholamine production.FEBS Lett 2011;585:2279-2284[PMID:21689652 DOI:10.1016/j.febslet.2011.06.001]
14 Sakellariou P,Valente A,Carrillo AE,Metsios GS,Nadolnik L,Jamurtas AZ,Koutedakis Y,Boguszewski C,Andrade CM,Svensson PA,Kawashita NH,Flouris AD.Chronic l-menthol-induced browning of white adipose tissue hypothesis:A putative therapeutic regime for combating obesity and improving metabolic health.Med Hypotheses 2016;93:21-26[PMID:27372851 DOI:10.1016/j.mehy.2016.05.006]
15 Bartelt A,Heeren J.Adipose tissue browning and metabolic health.Nat Rev Endocrinol 2014;10:24-36[PMID:24146030 DOI:10.1038/nrendo.2013.204]
16 Squillaro T,Peluso G,Galderisi U.Clinical Trials With Mesenchymal Stem Cells:An Update.Cell Transplant 2016;25:829-848[PMID:26423725 DOI:10.3727/096368915X689622]
17 Park A,Kim WK,Bae KH.Distinction of white,beige and brown adipocytes derived from mesenchymal stem cells.World J Stem Cells 2014;6:33-42[PMID:24567786 DOI:10.4252/wjsc.v6.i1.33]
18 Timmons JA,Wennmalm K,Larsson O,Walden TB,Lassmann T,Petrovic N,Hamilton DL,Gimeno RE,Wahlestedt C,Baar K,Nedergaard J,Cannon B.Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages.Proc Natl Acad Sci USA 2007;104:4401-4406[PMID:17360536 DOI:10.1073/pnas.0610615104]
19 Di Bernardo G,Messina G,Capasso S,Del Gaudio S,Cipollaro M,Peluso G,Casale F,Monda M,Galderisi U.Sera of overweight people promote in vitro adipocyte differentiation of bone marrow stromal cells.Stem Cell Res Ther 2014;5:4[PMID:24405848 DOI:10.1186/scrt393]
20 Dominici M,Le Blanc K,Mueller I,Slaper-Cortenbach I,Marini F,Krause D,Deans R,Keating A,Prockop Dj,Horwitz E.Minimal criteria for defining multipotent mesenchymal stromal cells.The International Society for Cellular Therapy position statement.Cytotherapy 2006;8:315-317[PMID:16923606 DOI:10.1080/14653240600855905]
21 Zanichelli F,Capasso S,Di Bernardo G,Cipollaro M,Pagnotta E,CartenìM,Casale F,Iori R,Giordano A,Galderisi U.Low concentrations of isothiocyanates protect mesenchymal stem cells from oxidative injuries,while high concentrations exacerbate DNA damage.Apoptosis 2012;17:964-974[PMID:22684843 DOI:10.1007/s10495-012-0740-3]
22 Alessio N,Bohn W,Rauchberger V,Rizzolio F,Cipollaro M,Rosemann M,Irmler M,Beckers J,Giordano A,Galderisi U.Silencing of RB1 but not of RB2/P130 induces cellular senescence and impairs the differentiation potential of human mesenchymal stem cells.Cell Mol Life Sci 2013;70:1637-1651[PMID:23370776 DOI:10.1007/s00018-012-1224-x]
23 Iacono E,Brunori L,Pirrone A,Pagliaro PP,Ricci F,Tazzari PL,Merlo B.Isolation,characterization and differentiation of mesenchymal stem cells from amniotic fluid,umbilical cord blood and Wharton's jelly in the horse.Reproduction 2012;143:455-468[PMID:22274885 DOI:10.1530/REP-10-0408]
24 Li L,Yao XL,He XL,Liu XJ,Wu WC,Kuang W,Tang M.Role of mechanical strain and estrogen in modulating osteogenic differentiation of mesenchymal stem cells(MSCs)from normal and ovariectomized rats.Cell Mol Biol(Noisy-le-grand)2013;Suppl 59:OL1889-OL1893[PMID:24209734]
25 Zhou S,Zilberman Y,Wassermann K,Bain SD,Sadovsky Y,Gazit D.Estrogen modulates estrogen receptor alpha and beta expression,osteogenic activity,and apoptosis in mesenchymal stem cells(MSCs)of osteoporotic mice.J Cell Biochem Suppl 2001;Suppl 36:144-155[PMID:11455579 DOI:10.1002/jcb.1096]
26 Kusonmano K,Netzer M,Baumgartner C,Dehmer M,Liedl KR,Graber A.Effects of pooling samples on the performance of classification algorithms:a comparative study.ScientificWorldJournal 2012;2012:278352[PMID:22654582 DOI:10.1100/2012/278352]
27 Muraglia A,Cancedda R,Quarto R.Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model.J Cell Sci 2000;113:1161-1166[PMID:10704367DOI:10.1023/A:1005568132027]
28 Kershaw EE,Hamm JK,Verhagen LA,Peroni O,Katic M,Flier JS.Adipose triglyceride lipase:function,regulation by insulin,and comparison with adiponutrin.Diabetes 2006;55:148-157[PMID:16380488DOI:10.2337/diabetes.55.01.06.db05-0982]
29 Rambold AS,Cohen S,Lippincott-Schwartz J.Fatty acid trafficking in starved cells:regulation by lipid droplet lipolysis,autophagy,and mitochondrial fusion dynamics.Dev Cell 2015;32:678-692[PMID:25752962 DOI:10.1016/j.devcel.2015.01.029]
30 Coelho M,Oliveira T,Fernandes R.Biochemistry of adipose tissue:an endocrine organ.Arch Med Sci2013;9:191-200[PMID:23671428 DOI:10.5114/aoms.2013.33181]
31 Nedergaard J,Bengtsson T,Cannon B.New powers of brown fat:fighting the metabolic syndrome.Cell Metab 2011;13:238-240[PMID:21356513 DOI:10.1016/j.cmet.2011.02.009]
32 Fruebis J,Tsao TS,Javorschi S,Ebbets-Reed D,Erickson MR,Yen FT,Bihain BE,Lodish HF.Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.Proc Natl Acad Sci USA 2001;98:2005-2010[PMID:11172066 DOI:10.1073/pnas.98.4.2005]
33 Yamauchi T,Kamon J,Waki H,Terauchi Y,Kubota N,Hara K,Mori Y,Ide T,Murakami K,Tsuboyama-Kasaoka N,Ezaki O,Akanuma Y,Gavrilova O,Vinson C,Reitman ML,Kagechika H,Shudo K,Yoda M,Nakano Y,Tobe K,Nagai R,Kimura S,Tomita M,Froguel P,Kadowaki T.The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.Nat Med2001;7:941-946[PMID:11479627 DOI:10.1038/90984]
34 Yang WS,Lee WJ,Funahashi T,Tanaka S,Matsuzawa Y,Chao CL,Chen CL,Tai TY,Chuang LM.Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein,adiponectin.JClin Endocrinol Metab 2001;86:3815-3819[PMID:11502817 DOI:10.1210/jcem.86.8.7741]
35 Petersson U,Ostgren CJ,Brudin L,Brismar K,Nilsson PM.Low levels of insulin-like growth-factorbinding protein-1(IGFBP-1)are prospectively associated with the incidence of type 2 diabetes and impaired glucose tolerance(IGT):the S?der?kra Cardiovascular Risk Factor Study.Diabetes Metab 2009;35:198-205[PMID:19297224 DOI:10.1016/j.diabet.2008.11.003]
36 Liu B,Hassan Z,Amisten S,King AJ,Bowe JE,Huang GC,Jones PM,Persaud SJ.The novel chemokine receptor,G-protein-coupled receptor 75,is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis.Diabetologia 2013;56:2467-2476[PMID:23979485 DOI:10.1007/s00125-013-3022-x]