Tadalafil reduces visceral adipose tissue accumulation by promoting preadipocytes differentiation towards a metabolically healthy phenotype: Studies in rabbits

Molecular and Cellular Endocrinology

Volumn 424, Issue , 2016, Pages 50-70

  Maneschi, Elena ^a   Cellai, Ilaria ^a   Aversa, Antonio ^b   Mello, Tommaso ^a   Filippi, Sandra ^c   Comeglio, Paolo ^a   Bani, Daniele ^a   Guasti, Daniele ^a   Sarchielli, Erica ^a   Salvatore, Giulia ^a   Morelli, Annamaria ^a   Mazzanti, Benedetta ^a   Corcetto, Francesca ^a   Corno, Chiara ^a   Francomano, Davide ^b   Galli, Andrea ^a   Vannelli, Gabriella Barbara ^a   Lenzi, Andrea ^b   Mannucci, Edoardo ^d   Maggi, Mario ^a   Vignozzi, Linda ^a   more..

^a UNIVERSITY OF FLORENCE   (Italy)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

^c UNIVERSITY OF FLORENCE   (Italy)

^d CAREGGI UNIVERSITY HOSPITAL   (Italy)

Author keywords

Insulin resistance; Metabolic syndrome; PDE5; Tadalafil

Indexed keywords

ASPARTATE AMINOTRANSFERASE; BONE MORPHOGENETIC PROTEIN 4; CARBONATE DEHYDRATASE IX; CARRIER PROTEIN; CD137 ANTIGEN; CYCLIC GMP DEPENDENT PROTEIN KINASE 1; FATTY ACID BINDING PROTEIN 4; GLUCOSE TRANSPORTER 4; HOMEOBOX PROTEIN HOX 9; HOMEODOMAIN PROTEIN; HORMONE SENSITIVE LIPASE; INSULIN; MEMBRANE PROTEIN; MESSENGER RNA; MITOCHONDRIAL TRANSCRIPTION FACTOR A; MITOFUSIN 1; PHOSPHODIESTERASE; PHOSPHODIESTERASE TYPE 11; PHOSPHODIESTERASE V; RETINOBLASTOMA 1; RETINOBLASTOMA PROTEIN; RHOA GUANINE NUCLEOTIDE BINDING PROTEIN; SOLUTE CARRIER FAMILY 25 MEMBER 12; SUPEROXIDE; TADALAFIL; TRANSCRIPTION FACTOR NRF1; TRANSMEMBRANE PROTEIN 26; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; UNCOUPLING PROTEIN 1;

ADIPOGENESIS; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BIOACCUMULATION; BROWN ADIPOSE TISSUE; CELL DIFFERENTIATION; CELL ISOLATION; CELL STRUCTURE; CIDEA GENE; CONTROLLED STUDY; DRUG EFFECT; DRUG MECHANISM; ENZYME INHIBITION; EXPERIMENTAL MODEL; EXPERIMENTAL RABBIT; GENE; GENE EXPRESSION REGULATION; HYPERTRIGLYCERIDEMIA; IN VITRO STUDY; IN VIVO STUDY; INSULIN SENSITIVITY; INTRAABDOMINAL FAT; LIPID DIET; LONG TERM CARE; MALE; METABOLIC REGULATION; METABOLIC SYNDROME X; MITOCHONDRIAL BIOGENESIS; MITOCHONDRIAL DYNAMICS; MITOCHONDRION; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROADIPOCYTE; PROTEIN EXPRESSION; SHORT COURSE THERAPY; TISSUE DISTRIBUTION; TREATMENT DURATION; UCP1 GENE; UPREGULATION; WHITE ADIPOSE TISSUE; ADVERSE EFFECTS; ANIMAL; CHEMICALLY INDUCED; DISEASE MODEL; DRUG EFFECTS; METABOLISM; RABBITS AND HARES;

ADIPOSE TISSUE, BROWN; ANIMALS; CELL DIFFERENTIATION; DIET, HIGH-FAT; DISEASE MODELS, ANIMAL; GENE EXPRESSION REGULATION; INTRA-ABDOMINAL FAT; MALE; METABOLIC SYNDROME X; MITOCHONDRIA; RABBITS; TADALAFIL; UNCOUPLING PROTEIN 1;

EID: 84959249536     PISSN: 03037207     EISSN: 18728057     Source Type: Journal    
DOI: 10.1016/j.mce.2016.01.015     Document Type: Article

References (73)

1. Anderson E.J., Lustig M.E., Boyle K.E., Woodlief T.L., Kane D.A., Lin C.T., Price J.W., Kang L., Rabinovitch P.S., Szeto H.H., Houmard J.A., Cortright R.N., Wasserman D.H., Neufer P.D. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J. Clin. Investig. 2009, 119(3):573-581. 10.1172/JCI37048.
2. Armani A., Marzolla V., Rosano G.M., Fabbri A., Caprio M. Phosphodiesterase type 5 (PDE5) in the adipocyte: a novel player in fat metabolism?. Trends Endocrinol. Metab. 2011, 22(10):404-411. 10.1016/j.tem.2011.05.004.
3. Aversa A., Caprio M., Antelmi A., Armani A., Brama M., Greco E.A., Francomano D., Calanchini M., Spera G., Di Luigi L., Rosano G.M., Lenzi A., Migliaccio S., Fabbri A. Exposure to phosphodiesterase type 5 inhibitors stimulates aromatase expression in human adipocytes in vitro. J. Sex. Med. 2011, 8(3):696-704. 10.1111/j.1743-6109.2010.02152.x.
4. Ayala J.E., Bracy D.P., Julien B.M., Rottman J.N., Fueger P.T., Wasserman D.H. Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice. Diabetes 2007, 56(4):1025-1033.
5. Bach D., Pich S., Soriano F.X., Vega N., Baumgartner B., Oriola J., Daugaard J.R., Lloberas J., Camps M., Zierath J.R., Rabasa-Lhoret R., Wallberg-Henriksson H., Laville M., Palacín M., Vidal H., Rivera F., Brand M., Zorzano A. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J. Biol. Chem. 2003, 278(19):17190-17197.
6. Baglioni S., Cantini G., Poli G., Francalanci M., Squecco R., Di Franco A., Borgogni E., Frontera S., Nesi G., Liotta F., Lucchese M., Perigli G., Francini F., Forti G., Serio M., Luconi M. Functional differences in visceral and subcutaneous fat pads originate from differences in the adipose stem cell. PLoS One 2012, 7(5):e36569. 10.1371/journal.pone.0036569.
7. Baglioni S., Francalanci M., Squecco R., Lombardi A., Cantini G., Angeli R., Gelmini S., Guasti D., Benvenuti S., Annunziato F., Bani D., Liotta F., Francini F., Perigli G., Serio M., Luconi M. Characterization of human adult stem-cell populations isolated from visceral and subcutaneous adipose tissue. FASEB J. 2009, 23(10):3494-3505. 10.1096/fj.08-126946.
8. Berry R., Rodeheffer M.S. Characterization of the adipocyte cellular lineage in vivo. Nat. Cell Biol. 2013, 15(3):302-308. 10.1038/ncb2696.
9. Bonnard C., Durand A., Peyrol S., Chanseaume E., Chauvin M.A., Morio B., Vidal H., Rieusset J. Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J. Clin. Investig. 2008, 118(2):789-800. 10.1172/JCI32601.
10. Bordicchia M., Liu D., Amri E.Z., Ailhaud G., Dessì-Fulgheri P., Zhang C., Takahashi N., Sarzani R., Collins S. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J. Clin. Investig. 2012, 122(3):1022-1036. 10.1172/JCI59701.
11. Boudina S., Sena S., Sloan C., Tebbi A., Han Y.H., O'Neill B.T., Cooksey R.C., Jones D., Holland W.L., McClain D.A., Abel E.D. Early mitochondrial adaptations in skeletal muscle to diet-induced obesity are strain dependent and determine oxidative stress and energy expenditure but not insulin sensitivity. Endocrinology 2012, 153(6):2677-2688. 10.1210/en.2011-2147.
12. Cederberg A., Grønning L.M., Ahrén B., Taskén K., Carlsson P., Enerbäck S. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell. 2001, 106(5):563-573.
13. Chechi K., Nedergaard J., Richard D. Brown adipose tissue as an anti-obesity tissue in humans. Obes. Rev. 2014, 15(2):92-106. 10.1111/obr.12116.
14. Comeglio P., Morelli A., Cellai I., Vignozzi L., Sarchielli E., Filippi S., Maneschi E., Corcetto F., Corno C., Gacci M., Vannelli G.B., Maggi M. Opposite effects of tamoxifen on metabolic syndrome-induced bladder and prostate alterations: a role for GPR30/GPER?. Prostate 2014, 74(1):10-28. 10.1002/pros.22723.
15. Cummings D.E., Brandon E.P., Planas J.V., Motamed K., Idzerda R.L., McKnight G.S. Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A. Nature 1996, 382(6592):622-626.
16. Cusi K. The role of adipose tissue and lipotoxicity in the pathogenesis of type 2 diabetes. Curr. Diabetes Rep. 2010, 10(4):306-315. 10.1007/s11892-010-0122-6.
17. De Arcangelis V., Strimpakos G., Gabanella F., Corbi N., Luvisetto S., Magrelli A., Onori A., Passananti C., Pisani C., Rome S., Severini C., Naro F., Mattei E., Di Certo M.G., Monaco L. Pathways implicated in tadalafil amelioration of duchenne muscular dystrophy. J. Cell. Physiol. 2016, 231(1):224-232. 10.1002/jcp.25075.
18. DeFronzo R.A. Dysfunctional fat cells, lipotoxicity and type 2 diabetes. Int. J. Clin. Pract. 2004, 143(Suppl. l.):9-21.
19. De Lean A., Munson P.J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am. J. Physiol. 1978, 235:E97-E102.
20. Detmer S.A., Chan D.C. Functions and dysfunctions of mitochondrial dynamics. Nat. Rev. Mol. Cell Biol. 2007, 8(11):870-879.
21. Filippi S., Vignozzi L., Morelli A., Chavalmane A.K., Sarchielli E., Fibbi B., Saad F., Sandner P., Ruggiano P., Vannelli G.B., Mannucci E., Maggi M. Testosterone partially ameliorates metabolic profile and erectile responsiveness to PDE5inhibitors in an animal model of male metabolic syndrome. J. Sex. Med. 2009, 6(12):3274-3288. 10.1111/j.1743-6109.2009.01467.x.
22. Frezza C., Cipolat S., Martins de Brito O., Micaroni M., Beznoussenko G.V., Rudka T., Bartoli D., Polishuck R.S., Danial N.N., De Strooper B., Scorrano L. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 2006, 126(1):177-189.
23. Gnanasegaran N., Govindasamy V., Musa S., Kasim N.H. Different isolation methods alter the gene expression profiling of adipose derived stem cells. Int. J. Med. Sci. 2014, 11(4):391-403. 10.7150/ijms.7697.
24. Haas B., Mayer P., Jennissen K., Scholz D., Berriel Diaz M., Bloch W., Herzig S., Fässler R., Pfeifer A. Protein kinase G controls brown fat cell differentiation and mitochondrial biogenesis. Sci. Signal. 2009, 2(99):ra78. 10.1126/scisignal.2000511.
25. Harms M., Seale P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 2013, 19(10):1252-1263. 10.1038/nm.3361.
26. Hellström L., Langin D., Reynisdottir S., Dauzats M., Arner P. Adipocyte lipolysis in normal weight subjects with obesity among first-degree relatives. Diabetologia 1996, 39(8):921-928.
27. Hoffmann L.S., Etzrodt J., Willkomm L., Sanyal A., Scheja L., Fischer A.W., Stasch J.P., Bloch W., Friebe A., Heeren J., Pfeifer A. Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue. Nat. Commun. 2015, 6:7235. 10.1038/ncomms8235.
28. Ishibashi J., Seale P. Medicine. Beige can be slimming. Science. 2010, 328(5982):1113-1114. 28. 10.1126/science.1190816.
29. Jocken J.W., Goossens G.H., Popeijus H., Essers Y., Hoebers N., Blaak E.E. Contribution of lipase deficiency to mitochondrial dysfunction and insulin resistance in hMADS adipocytes. Int. J. Obes. Lond 2015, 10.1038/ijo.2015.211.
30. Joe A.W., Yi L., Even Y., Vogl A.W., Rossi F.M. Depot-specific differences in adipogenic progenitor abundance and proliferative response to high-fat diet. Stem Cells 2009, 27(10):2563-2570. 10.1002/stem.190.
31. Kelley D.E., He J., Menshikova E.V., Ritov V.B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002, 51(10):2944-2950.
32. Kiefer F.W., Vernochet C., O'Brien P., Spoerl S., Brown J.D., Nallamshetty S., Zeyda M., Stulnig T.M., Cohen D.E., Kahn C.R., Plutzky J. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat. Med. 2012, 18(6):918-925. 10.1038/nm.2757.
33. Kim D.S., Lee M.W., Yoo K.H., Lee T.H., Kim H.J., Jang I.K., Chun Y.H., Kim H.J., Park S.J., Lee S.H., Son M.H., Jung H.L., Sung K.W., Koo H.H. Gene expression profiles of human adipose tissue-derived mesenchymal stem cells are modified by cell culture density. PLoS One 2014, 9(1):e83363. 10.1371/journal.pone.0083363.
34. Koka S., Aluri H.S., Xi L., Lesnefsky E.J., Kukreja R.C. Chronic inhibition of phosphodiesterase 5 with tadalafil attenuates mitochondrial dysfunction in type 2 diabetic hearts: potential role of NO/SIRT1/PGC-1α signaling. Am. J. Physiol. Heart Circ. Physiol. 2014, 306(11):H1558-H1568. 10.1152/ajpheart.00865.2013.
35. Kozak L.P. Brown fat and the myth of diet-induced thermogenesis. Cell Metab. 2010, 11(4):263-267. 10.1016/j.cmet.2010.03.009.
36. Lee K.H., Kwon S.J., Woo J.S., Lee G.J., Lee S.R., Jang H.H., Kim H.S., Kim J.W., Park H.K., Cho K.S., Kim W. Effects of sildenafil on nanostructural and nanomechanical changes in mitochondria in an ischaemia-reperfusion rat model. Clin. Exp. Pharmacol. Physiol. 2014, 41(10):763-768. 10.1111/1440-1681.12290.
37. Liesa M., Shirihai O.S. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 2013, 17(4):491-506. 10.1016/j.cmet.2013.03.002.
38. Maneschi E., Morelli A., Filippi S., Cellai I., Comeglio P., Mazzanti B., Mello T., Calcagno A., Sarchielli E., Vignozzi L., Saad F., Vettor R., Vannelli G.B., Maggi M. Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements. J. Endocrinol. 2012, 215(3):347-362. 10.1530/JOE-12-0333.
39. Maneschi E., Vignozzi L., Morelli A., Mello T., Filippi S., Cellai I., Comeglio P,Sarchielli E., Calcagno A., Mazzanti B., Vettor R., Vannelli G.B., Adorini L., Maggi M. FXR activation normalizes insulin sensitivity in visceral preadipocytes of a rabbit model of MetS. J. Endocrinol. 2013, 218(2):215-231. 10.1530/JOE-13-0109.
40. Marchiani S., Vignozzi L., Filippi S., Gurrieri B., Comeglio P., Morelli A., Danza G., Bartolucci G., Maggi M., Baldi E. Metabolic syndrome-associated sperm alterations in an experimental rabbit model: relation with metabolic profile, testis and epididymis gene expression and effect of tamoxifen treatment. Mol. Cell. Endocrinol. 2015, 401:12-24. 10.1016/j.mce.2014.11.005.
41. Martin S.D., Morrison S., Konstantopoulos N., McGee S.L. Mitochondrial dysfunction has divergent, cell type-dependent effects on insulin action. Mol. Metab. 2014, 3(4):408-418. 2014. 10.1016/j.molmet.2014.02.001.
42. Mitschke M.M., Hoffmann L.S., Gnad T., Scholz D., Kruithoff K., Mayer P., Haas B., Sassmann A., Pfeifer A., Kilic A. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J. 2013, 27(4):1621-1630. 10.1096/fj.12-221580.
43. Morelli A., Comeglio P., Filippi S., Sarchielli E., Cellai I., Vignozzi L., Yehiely-Cohen R., Maneschi E., Gacci M., Carini M., Adorini L., Vannelli G.B., Maggi M. Testosterone and farnesoid X receptor agonist INT-747 counteract high fat diet-induced bladder alterations in a rabbit model of metabolic syndrome. J. Steroid Biochem. Mol. Biol. 2012, 132(1-2):80-92. 10.1016/j.jsbmb.2012.02.007.
44. Morelli A., Comeglio P., Filippi S., Sarchielli E., Vignozzi L., Maneschi E., Cellai I., Gacci M., Lenzi A., Vannelli G.B., Maggi M. Mechanism of action of phosphodiesterase type 5 inhibition in metabolic syndrome-associated prostate alterations: an experimental study in the rabbit. Prostate 2013, 73(4):428-441. 10.1002/pros.22584.
45. Morelli A., Filippi S., Zhang X.H., Luconi M., Vignozzi L., Mancina R., Maggi M. Peripheral regulatory mechanisms in erection. Int. J. Androl. 2005, 28(Suppl. 2):23-27.
46. Morelli A., Sarchielli E., Comeglio P., Filippi S., Vignozzi L., Marini M., Rastrelli G., Maneschi E., Cellai I., Persani L., Adorini L., Vannelli G.B., Maggi M. Metabolic syndrome induces inflammation and impairs gonadotropin-releasing hormone neurons in the preoptic area of the hypothalamus in rabbits. Mol. Cell. Endocrinol. 2014, 382(1):107-119. 10.1016/j.mce.2013.09.017.
47. Morelli A., Vignozzi L., Maggi M., Adorini L. Farnesoid X receptor activation improves erectile dysfunction in models of metabolic syndrome and diabetes. Biochim. Biophys. Acta 2011, 1812(8):859-866. Review. 10.1016/j.bbadis.2010.10.013.
48. Newmeyer D.D., Ferguson-Miller S. Mitochondria: releasing power for life and unleashing the machineries of death. Cell 2003, 112(4):481-490.
49. Nincheri P., Luciani P., Squecco R., Donati C., Bernacchioni C., Borgognoni L., Luciani G., Benvenuti S., Francini F., Bruni P. Sphingosine 1-phosphate induces differentiation of adipose tissue-derived mesenchymal stem cells towards smooth muscle cells. Cell. Mol. Life Sci. 2009, 66(10):1741-1754. 2009 May. 10.1007/s00018-009-9181-8.
50. Nisoli E., Clementi E., Paolucci C., Cozzi V., Tonello C., Sciorati C., Bracale R., Valerio A., Francolini M., Moncada S., Carruba M.O. Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 2003, 299(5608):896-899.
51. Petrovic N., Walden T.B., Shabalina I.G., Timmons J.A., Cannon B., Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J. Biol. Chem. 2010, 285(10):7153-7164. 10.1074/jbc.M109.053942.
52. Porst H., Burnett A., Brock G., Ghanem H., Giuliano F., Glina S., Hellstrom W., Martin-Morales A., Salonia A., Sharlip I. SOP conservative (medical and mechanical) treatment of erectile dysfunction. J. Sex. Med. 2013, 10(1):130-171. ISSM Standards Committee for Sexual Medicine. 10.1111/jsm.12023.
53. Rodeheffer M.S., Birsoy K., Friedman J.M. Identification of white adipocyte progenitor cells in vivo. Cell. 2008, 135(2):240-249. 10.1016/j.cell.2008.09.036.
54. Rousset S., Alves-Guerra M.C., Mozo J., Miroux B., Cassard-Doulcier A.M., Bouillaud F., Ricquier D. The biology of mitochondrial uncoupling proteins. Diabetes 2004, 53(Suppl. 1):S130-S135.
55. Schindelin J., Arganda-Carreras I., Frise E., Kaynig V., Longair M., Pietzsch T., Preibisch S., Rueden C., Saalfeld S., Schmid B., Tinevez J.Y., White D.J., Hartenstein V., Eliceiri K., Tomancak P., Cardona A. Fiji: an open-source platform for biological-image analysis. Nat. Methods 2012, 9(7):676-682. Jun 28. 10.1038/nmeth.2019.
56. Schulz T.J., Huang P., Huang T.L., Xue R., McDougall L.E., Townsend K.L., Cypess A.M., Mishina Y., Gussoni E., Tseng Y.H. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 2013, 495(7441):379-383. 10.1038/nature11943.
57. Seale P., Conroe H.M., Estall J., Kajimura S., Frontini A., Ishibashi J., Cohen P., Cinti S., Spiegelman B.M. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Investig. 2011, 121(1):96-105. 10.1172/JCI44271.
58. Student A.K., Hsu R.Y., Lane M.D. Induction of fatty acid synthetase synthesis in differentiating 3T3-L1 preadipocytes. J. Biol. Chem. 1980, 255:4745-4750.
59. Tchernof A., Després J.P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 2013, 93(1):359-404. 10.1152/physrev.00033.2011.
60. Toledo F.G., Watkins S., Kelley D.E. Changes induced by physical activity and weight loss in the morphology of intermyofibrillar mitochondria in obese men and women. J. Clin. Endocrinol. Metab. 2006, 91(8):3224-3227.
61. Vignozzi L., Filippi S., Comeglio P., Cellai I., Morelli A., Maneschi E., Sarchielli E., Gacci M., Carini M., Vannelli G.B., Maggi M. Tadalafil effect on metabolic syndrome-associated bladder alterations: an experimental study in a rabbit model. J. Sex. Med. 2014, 11(5):1159-1172. 10.1111/jsm.12478.
62. Vignozzi L., Filippi S., Comeglio P., Cellai I., Morelli A., Marchetta M., Maggi M. Estrogen mediates metabolic syndrome-induced erectile dysfunction: a study in the rabbit. J. Sex. Med. 2014, 11(12):2890-2902. 10.1111/jsm.12695.
63. Vignozzi L., Filippi S., Comeglio P., Cellai I., Morelli A., Rastrelli G., Maneschi E., Mannucci E., Maggi M. Metformin in vitro and in vivo increases adenosine signaling in rabbit corpora cavernosa. J. Sex. Med. 2014, 11(7):1694-1708. 10.1111/jsm.12572.
64. Vignozzi L., Filippi S., Comeglio P., Cellai I., Sarchielli E., Morelli A., Rastrelli G., Maneschi E., Galli A., Vannelli G.B., Saad F., Mannucci E., Adorini L., Maggi M. Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit. Mol. Cell. Endocrinol. 2014, 384(1-2):143-154. 10.1016/j.mce.2014.01.014.
65. Vignozzi L., Gacci M., Cellai I., Morelli A., Maneschi E., Comeglio P., Santi R., Filippi S., Sebastianelli A., Nesi G., Serni S., Carini M., Maggi M. PDE5 inhibitors blunt inflammation in human BPH: a potential mechanism of action for PDE5, inhibitors in LUTS. Prostate 2013, 73(13):1391-1402. 10.1002/pros.22686.
66. Vignozzi L., Morelli A., Filippi S., Comeglio P., Chavalmane A.K., Marchetta M., Toce M., Yehiely-Cohen R., Vannelli G.B., Adorini L., Maggi M. Farnesoid X receptor activation improves erectile function in animal models of metabolic syndrome and diabetes. J. Sex. Med. 2011, 8(1):57-77. 10.1111/j.1743-6109.2010.02073.x.
67. Vignozzi L., Morelli A., Sarchielli E., Comeglio P., Filippi S., Cellai I., Maneschi E., Serni S., Gacci M., Carini M., Piccinni M.P., Saad F., Adorini L., Vannelli G.B., Maggi M. Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit. J. Endocrinol. 2012, 212(1):71-84. 10.1530/JOE-11-0289.
68. Waldén T.B., Hansen I.R., Timmons J.A., Cannon B., Nedergaard J. Recruited vs. nonrecruited molecular signatures of brown, "brite," and white adipose tissues. Am. J. Physiol. Endocrinol. Metab. 2012, 302(1):E19-E31. 10.1152/ajpendo.00249.2011.
69. Wu J., Boström P., Sparks L.M., Ye L., Choi J.H., Giang A.H., Khandekar M., Virtanen K.A., Nuutila P., Schaart G., Huang K., Tu H., van Marken Lichtenbelt W.D., Hoeks J., Enerbäck S., Schrauwen P., Spiegelman B.M. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012, 150(2):366-376. 10.1016/j.cell.2012.05.016.
70. Yu T., Robotham J.L., Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc. Natl. Acad. Sci. U. S. A. 2006, 103(8):2653-2658. Epub 2006 Feb 13.
71. Zhang X., Ji J., Yan G., Wu J., Sun X., Shen J., Jiang H., Wang H. Sildenafil promotes adipogenesis through a PKG pathway. Biochem. Biophys. Res. Commun. 2010, 396(4):1054-1059. 10.1016/j.bbrc.2010.05.064.
72. Zuk P.A., Zhu M., Ashjian P., De Ugarte D.A., Huang J.I., Mizuno H., Alfonso Z.C., Fraser J.K., Benhaim P., Hedrick M.H. Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell. 2002, 13(12):4279-4295.
73. Zuk P.A., Zhu M., Mizuno H., Huang J., Futrell J.W., Katz A.J., Benhaim P., Lorenz H.P., Hedrick M.H. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001, 7(2):211-228.