Urolithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice

PLoS Biology

Volumn 18, Issue 3, 2020, Pages

  Xia, Bo ^a   Shi, Xiao Chen ^a   Xie, Bao Cai ^a   Zhu, Meng Qing ^a   Chen, Yan ^a   Chu, Xin Yi ^a   Cai, Guo He ^a   Liu, Min ^a   Yang, Shi Zhen ^a   Mitchell, Grant A ^b   Pang, Wei Jun ^a   Wu, Jiang Wei ^a  

^a NORTHWEST A F UNIVERSITY   (China)

^b UNIVERSITY OF MONTREAL   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIOBESITY AGENT; LIOTHYRONINE; PROPYLTHIOURACIL; TETRAHYDROLIPSTATIN; THYROID HORMONE; THYROXINE; UNCLASSIFIED DRUG; UROLITHIN A; 3,8-DIHYDROXY-6H-DIBENZO(B,D)PYRAN-6-ONE; COUMARIN DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIOBESITY ACTIVITY; ARTICLE; BODY WEIGHT CONTROL; BODY WEIGHT GAIN; BROWN ADIPOSE TISSUE; CELL ACTIVATION; CONTROLLED STUDY; DIET-INDUCED OBESITY; ENERGY EXPENDITURE; GLUCOSE HOMEOSTASIS; HORMONAL REGULATION; INGUINAL FAT PAD; LIPID DIET; MALE; METABOLIC DISORDER; MOUSE; NONHUMAN; THERMOGENESIS; THYROID HORMONE SYNTHESIS; TISSUE LEVEL; WHITE ADIPOSE TISSUE; ANIMAL; BROWN ADIPOCYTE; C57BL MOUSE; DRUG EFFECT; ENERGY METABOLISM; FATTY LIVER; GLUCOSE INTOLERANCE; GLYCATION; INSULIN RESISTANCE; METABOLISM; MOUSE MUTANT; OBESITY; WHITE ADIPOCYTE;

ADIPOCYTES, BROWN; ADIPOCYTES, WHITE; ADIPOSE TISSUE, BROWN; ADIPOSE TISSUE, WHITE; ANIMALS; ANTI-OBESITY AGENTS; COUMARINS; DIET, HIGH-FAT; ENERGY METABOLISM; FATTY LIVER; GLUCOSE INTOLERANCE; INSULIN RESISTANCE; MAILLARD REACTION; MALE; MICE; MICE, INBRED C57BL; MICE, OBESE; OBESITY; PROPYLTHIOURACIL; THERMOGENESIS; TRIIODOTHYRONINE; WEIGHT GAIN;

EID: 85083083898     PISSN: 15449173     EISSN: 15457885     Source Type: Journal    
DOI: 10.1371/journal.pbio.3000688     Document Type: Article

References (94)

1. Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, et al. Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnol Adv. 2015; 33(8):1582-614. https://doi.org/10.1016/j.biotechadv.2015.08.001 PMID: 26281720; PubMed Central PMCID: PMC4748402.
2. Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. Journal of natural products. 2016; 79(3):629-61. https://doi.org/10.1021/acs.jnatprod.5b01055 PMID: 26852623
3. Meena P. Development of various functional food components in health aspects. The Pharma Innovation. 2017; 6(7, Part D):265.
4. Miguel MG, Neves MA, Antunes MD. Pomegranate (Punica granatum L.): A medicinal plant with myriad biological properties-A short review. Journal of Medicinal Plants Research. 2010; 4(25):2836-47.
5. Giampieri F, Alvarez-Suarez JM, Mazzoni L, Forbes-Hernandez TY, Gasparrini M, Gonzalez-Paramas AM, et al. An anthocyanin-rich strawberry extract protects against oxidative stress damage and improves mitochondrial functionality in human dermal fibroblasts exposed to an oxidizing agent. Food Funct. 2014; 5(8):1939-48. https://doi.org/10.1039/c4fo00048j PMID: 24956972.
6. Bazylko A, Piwowarski JP, Filipek A, Bonarewicz J, Tomczyk M. In vitro antioxidant and anti-inflammatory activities of extracts from Potentilla recta and its main ellagitannin, agrimoniin. J Ethnopharmacol. 2013; 149(1):222-7. https://doi.org/10.1016/j.jep.2013.06.026 PMID: 23811215.
7. Bors W, Foo LY, Hertkorn N, Michel C, Stettmaier K. Chemical studies of proanthocyanidins and hydrolyzable tannins. Antioxid Redox Signal. 2001; 3(6):995-1008. https://doi.org/10.1089/ 152308601317203530 PMID: 11813994.
8. Gimenez-Bastida JA, Gonzalez-Sarrias A, Larrosa M, Tomas-Barberan F, Espin JC, Garcia-Conesa MT. Ellagitannin metabolites, urolithin A glucuronide and its aglycone urolithin A, ameliorate TNF-alpha-induced inflammation and associated molecular markers in human aortic endothelial cells. Mol Nutr Food Res. 2012; 56(5):784-96. https://doi.org/10.1002/mnfr.201100677 PMID: 22648625.
9. Piwowarski JP, Granica S, Zwierzynska M, Stefanska J, Schopohl P, Melzig MF, et al. Role of human gut microbiota metabolism in the anti-inflammatory effect of traditionally used ellagitannin-rich plant materials. J Ethnopharmacol. 2014; 155(1):801-9. https://doi.org/10.1016/j.jep.2014.06.032 PMID: 24969824.
10. Heber D. Multitargeted therapy of cancer by ellagitannins. Cancer Lett. 2008; 269(2):262-8. https://doi.org/10.1016/j.canlet.2008.03.043 PMID: 18468784.
11. Li Z, Henning SM, Lee RP, Lu QY, Summanen PH, Thames G, et al. Pomegranate extract induces ellagitannin metabolite formation and changes stool microbiota in healthy volunteers. Food Funct. 2015; 6 (8):2487-95. https://doi.org/10.1039/c5fo00669d PMID: 26189645.
12. Puupponen-Pimia R, Seppanen-Laakso T, Kankainen M, Maukonen J, Torronen R, Kolehmainen M, et al. Effects of ellagitannin-rich berries on blood lipids, gut microbiota, and urolithin production in human subjects with symptoms of metabolic syndrome. Mol Nutr Food Res. 2013; 57(12):2258-63. https://doi.org/10.1002/mnfr.201300280 PMID: 23934737.
13. Tomas-Barberan FA, Gonzalez-Sarrias A, Garcia-Villalba R, Nunez-Sanchez MA, Selma MV, Garcia-Conesa MT, et al. Urolithins, the rescue of "old" metabolites to understand a "new" concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status. Mol Nutr Food Res. 2017; 61(1):1500901. Epub 2016 Jun 20. https://doi.org/10.1002/mnfr.201500901 PMID: 27158799.
14. Espin JC, Larrosa M, Garcia-Conesa MT, Tomas-Barberan F. Biological significance of urolithins, the gut microbial ellagic Acid-derived metabolites: the evidence so far. Evid Based Complement Alternat Med. 2013; 2013:270418. https://doi.org/10.1155/2013/270418 PMID: 23781257; PubMed Central PMCID: PMC3679724.
15. Selma MV, Gonzalez-Sarrias A, Salas-Salvado J, Andres-Lacueva C, Alasalvar C, Orem A, et al. The gut microbiota metabolism of pomegranate or walnut ellagitannins yields two urolithin-metabotypes that correlate with cardiometabolic risk biomarkers: Comparison between normoweight, overweight-obesity and metabolic syndrome. Clin Nutr. 2018; 37(3):897-905. https://doi.org/10.1016/j.clnu.2017.03.012 PMID: 28347564.
16. Selma MV, Romo-Vaquero M, Garcia-Villalba R, Gonzalez-Sarrias A, Tomas-Barberan FA, Espin JC. The human gut microbial ecology associated with overweight and obesity determines ellagic acid metabolism. Food Funct. 2016; 7(4):1769-74. https://doi.org/10.1039/c5fo01100k PMID: 26597167.
17. Cortes-Martin A, Garcia-Villalba R, Gonzalez-Sarrias A, Romo-Vaquero M, Loria-Kohen V, Ramirezde-Molina A, et al. The gut microbiota urolithin metabotypes revisited: the human metabolism of ellagic acid is mainly determined by aging. Food Funct. 2018; 9(8):4100-6. https://doi.org/10.1039/ c8fo00956b PMID: 30004553.
18. Ishimoto H, Shibata M, Myojin Y, Ito H, Sugimoto Y, Tai A, et al. In vivo anti-inflammatory and antioxidant properties of ellagitannin metabolite urolithin A. Bioorganic & Medicinal Chemistry Letters. 2011; 21(19):5901-4. https://doi.org/10.1016/j.bmcl.2011.07.086 WOS:000294714400052. PMID: 21843938
19. Cerdá B, Periago P, Espín JC, Tomás-Barberán FA. Identification of urolithin A as a metabolite produced by human colon microflora from ellagic acid and related compounds. Journal of agricultural and food chemistry. 2005; 53(14):5571-6. https://doi.org/10.1021/jf050384i PMID: 15998116
20. Singh R, Chandrashekharappa S, Bodduluri SR, Baby BV, Hegde B, Kotla NG, et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat Commun. 2019; 10 (1):89. https://doi.org/10.1038/s41467-018-07859-7 PMID: 30626868; PubMed Central PMCID: PMC6327034.
21. Seeram NP, Aronson WJ, Zhang Y, Henning SM, Moro A, Lee RP, et al. Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland. J Agric Food Chem. 2007; 55(19):7732-7. https://doi.org/10.1021/jf071303g PMID: 17722872.
22. Zhao W, Shi F, Guo Z, Zhao J, Song X, Yang H. Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells. Mol Carcinog. 2018; 57(2):193-200. https://doi.org/10.1002/mc.22746 PMID: 28976622; PubMed Central PMCID: PMC5814919.
23. Wang ST, Chang WC, Hsu C, Su NW. Antimelanogenic Effect of Urolithin A and Urolithin B, the Colonic Metabolites of Ellagic Acid, in B16 Melanoma Cells. J Agric Food Chem. 2017; 65(32):6870-6. https://doi.org/10.1021/acs.jafc.7b02442 PMID: 28726389.
24. Piwowarski JP, Kiss AK, Granica S, Moeslinger T. Urolithins, gut microbiota-derived metabolites of ellagitannins, inhibit LPS-induced inflammation in RAW 264.7 murine macrophages. Mol Nutr Food Res. 2015; 59(11):2168-77. https://doi.org/10.1002/mnfr.201500264 PMID: 26202092.
25. Boakye YD, Groyer L, Heiss EH. An increased autophagic flux contributes to the anti-inflammatory potential of urolithin A in macrophages. Biochim Biophys Acta Gen Subj. 2018; 1862(1):61-70. https://doi.org/10.1016/j.bbagen.2017.10.006 PMID: 29031765; PubMed Central PMCID: PMC5823236.
26. Savi M, Bocchi L, Mena P, Dall'Asta M, Crozier A, Brighenti F, et al. In vivo administration of urolithin A and B prevents the occurrence of cardiac dysfunction in streptozotocin-induced diabetic rats. Cardiovasc Diabetol. 2017; 16(1):80. https://doi.org/10.1186/s12933-017-0561-3 PMID: 28683791; PubMed Central PMCID: PMC5501434.
27. Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Felix AA, et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016; 22(8):879-88. https://doi.org/10.1038/nm.4132 PMID: 27400265.
28. Andreux PA, Blanco-Bose W, Ryu D, Burdet F, Ibberson M, Aebischer P, et al. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nature Metabolism. 2019; 1(6):595.
29. Kang I, Kim Y, Tomas-Barberan FA, Espin JC, Chung S. Urolithin A, C, and D, but not iso-urolithin A and urolithin B, attenuate triglyceride accumulation in human cultures of adipocytes and hepatocytes. Mol Nutr Food Res. 2016; 60(5):1129-38. https://doi.org/10.1002/mnfr.201500796 PMID: 26872561.
30. Les F, Arbones-Mainar JM, Valero MS, Lopez V. Pomegranate polyphenols and urolithin A inhibit alpha-glucosidase, dipeptidyl peptidase-4, lipase, triglyceride accumulation and adipogenesis related genes in 3T3-L1 adipocyte-like cells. J Ethnopharmacol. 2018; 220:67-74. https://doi.org/10.1016/j.jep.2018.03.029 PMID: 29604377.
31. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995; 269(5223):540-3. Epub 1995/07/28. https://doi.org/10.1126/science.7624776 PMID: 7624776.
32. Heymsfield SB, Wadden TA. Mechanisms, Pathophysiology, and Management of Obesity. N Engl J Med. 2017; 376(3):254-66. https://doi.org/10.1056/NEJMra1514009 PMID: 28099824.
33. Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2010; 51(2):679-89. Epub 2009 Sept 9. https://doi.org/10.1002/hep.23280 PMID: 20041406; PubMed Central PMCID: PMC3575093.
34. Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elia E, Kessler SH, Kahn PA, et al. Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist. Cell Metab. 2015; 21(1):33-8. https://doi.org/10.1016/j.cmet.2014.12.009 PMID: 25565203; PubMed Central PMCID: PMC4298351.
35. Robidoux J, Martin TL, Collins S. Beta-adrenergic receptors and regulation of energy expenditure: a family affair. Annu Rev Pharmacol Toxicol. 2004; 44:297-323. https://doi.org/10.1146/annurev.pharmtox.44.101802.121659 PMID: 14744248.
36. Song NJ, Chang SH, Li DY, Villanueva CJ, Park KW. Induction of thermogenic adipocytes: molecular targets and thermogenic small molecules. Exp Mol Med. 2017; 49(7):e353. https://doi.org/10.1038/emm.2017.70 PMID: 28684864; PubMed Central PMCID: PMC5565954.
37. Lin JZ, Martagon AJ, Cimini SL, Gonzalez DD, Tinkey DW, Biter A, et al. Pharmacological Activation of Thyroid Hormone Receptors Elicits a Functional Conversion of White to Brown Fat. Cell Rep. 2015; 13 (8):1528-37. https://doi.org/10.1016/j.celrep.2015.10.022 PMID: 26586443; PubMed Central PMCID: PMC4662916.
38. Martinez-Sanchez N, Moreno-Navarrete JM, Contreras C, Rial-Pensado E, Ferno J, Nogueiras R, et al. Thyroid hormones induce browning of white fat. J Endocrinol. 2017; 232(2):351-62. https://doi.org/10.1530/JOE-16-0425 PMID: 27913573; PubMed Central PMCID: PMC5292977.
39. Bianco AC, McAninch EA. The role of thyroid hormone and brown adipose tissue in energy homoeostasis. Lancet Diabetes Endocrinol. 2013; 1(3):250-8. https://doi.org/10.1016/S2213-8587(13)70069-X PMID: 24622373; PubMed Central PMCID: PMC4976626.
40. Weiner J, Hankir M, Heiker JT, Fenske W, Krause K. Thyroid hormones and browning of adipose tissue. Mol Cell Endocrinol. 2017; 458:156-9. https://doi.org/10.1016/j.mce.2017.01.011 PMID: 28089823.
41. Braverman LE, Ingbar SH, Sterling K. Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects. J Clin Invest. 1970; 49(5):855-64. https://doi.org/10.1172/JCI106304 PMID: 4986007; PubMed Central PMCID: PMC535757.
42. Obregon MJ. Adipose tissues and thyroid hormones. Front Physiol. 2014; 5:479. https://doi.org/10.3389/fphys.2014.00479 PMID: 25566082; PubMed Central PMCID: PMC4263094.
43. Geffner DL, Azukizawa M, Hershman JM. Propylthiouracil blocks extrathyroidal conversion of thyroxine to triiodothyronine and augments thyrotropin secretion in man. The Journal of clinical investigation. 1975; 55(2):224-9. https://doi.org/10.1172/JCI107925 PMID: 805160
44. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. Jama. 2006; 295(13):1549-55. https://doi.org/10.1001/jama.295.13.1549 PMID: 16595758
45. WHO. Global report on diabetes. Geneva, Switzerland: World Health Organization; 2016. https://doi.org/10.2337/db15-0956
46. Chooi YC, Ding C, Magkos F. The epidemiology of obesity. Metabolism. 2019; 92:6-10. Epub 2018 Sept 22. https://doi.org/10.1016/j.metabol.2018.09.005 PMID: 30253139
47. Global Burden of Disease Study 2015. Global Burden of Disease Study 2015 (GBD 2015) Obesity and Overweight Prevalence 1980-2015. Seattle: United States: Institute for Health Metrics and Evaluation (IHME); 2017.
48. Montesi L, El Ghoch M, Brodosi L, Calugi S, Marchesini G, Dalle Grave R. Long-term weight loss maintenance for obesity: a multidisciplinary approach. Diabetes, metabolic syndrome and obesity: targets and therapy. 2016; 9:37.
49. MacLean PS, Wing RR, Davidson T, Epstein L, Goodpaster B, Hall KD, et al. NIH working group report: innovative research to improve maintenance of weight loss. Obesity. 2015; 23(1):7-15. https://doi.org/10.1002/oby.20967 PMID: 25469998
50. Kotseva K, Wood D, De Bacquer D, De Backer G, Rydén L, Jennings C, et al. EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries. European journal of preventive cardiology. 2016; 23(6):636-48. https://doi.org/10.1177/2047487315569401 PMID: 25687109
51. Soleymani T, Daniel S, Garvey WT. Weight maintenance: challenges, tools and strategies for primary care physicians. Obesity Reviews. 2016; 17(1):81-93. https://doi.org/10.1111/obr.12322 PMID: 26490059
52. Konstantinos L, Karavis M, Mastorakos G, Valsamakis G. New Molecular Targets for the Pharmacotherapy of Obesity. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, et al., editors. Endotext. South Dartmouth, MA: MDText.com, Inc.; 2000.
53. Conn PM. Animal models for the study of human disease. Cambridge, MA: Academic Press; 2017.
54. Contreras C, Nogueiras R, Diéguez C, Medina-Gómez G, López M. Hypothalamus and thermogenesis: heating the BAT, browning the WAT. Molecular and cellular endocrinology. 2016; 438:107-15. https://doi.org/10.1016/j.mce.2016.08.002 PMID: 27498420
55. Contreras C, Gonzalez F, Fernø J, Diéguez C, Rahmouni K, Nogueiras R, et al. The brain and brown fat. Annals of medicine. 2015; 47(2):150-68. https://doi.org/10.3109/07853890.2014.919727 PMID: 24915455
56. Morrison SF, Madden CJ, Tupone D. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell metabolism. 2014; 19(5):741-56. https://doi.org/10.1016/j.cmet.2014.02. 007 PMID: 24630813
57. Villarroya F, Vidal-Puig A. Beyond the sympathetic tone: the new brown fat activators. Cell metabolism. 2013; 17(5):638-43. https://doi.org/10.1016/j.cmet.2013.02.020 PMID: 23583169
58. Alvarez-Crespo M, Csikasz RI, Martínez-Sánchez N, Diéguez C, Cannon B, Nedergaard J, et al. Essential role of UCP1 modulating the central effects of thyroid hormones on energy balance. Molecular metabolism. 2016; 5(4):271-82. https://doi.org/10.1016/j.molmet.2016.01.008 PMID: 27069867
59. López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nature medicine. 2010; 16(9):1001. https://doi.org/10.1038/nm.2207 PMID: 20802499
60. Mottillo EP, Ramseyer VD, Granneman JG. SERCA2b Cycles Its Way to UCP1-Independent Thermogenesis in Beige Fat. Cell Metab. 2018; 27(1):7-9. https://doi.org/10.1016/j.cmet.2017.12.015 PMID: 29320712.
61. Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K, Cohen P, et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell. 2015; 163(3):643-55. https://doi.org/10.1016/j.cell.2015.09.035 PMID: 26496606; PubMed Central PMCID: PMC4656041.
62. Bartelt A, Widenmaier SB, Schlein C, Johann K, Goncalves RLS, Eguchi K, et al. Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity. Nat Med. 2018; 24(3):292-303. https://doi.org/10.1038/nm.4481 PMID: 29400713; PubMed Central PMCID: PMC5839993.
63. Zhang Z, Zhang H, Li B, Meng X, Wang J, Zhang Y, et al. Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun. 2014; 5:5493. https://doi.org/10.1038/ncomms6493 PMID: 25423280.
64. Liu J, Lee J, Salazar Hernandez MA, Mazitschek R, Ozcan U. Treatment of obesity with celastrol. Cell. 2015; 161(5):999-1011. https://doi.org/10.1016/j.cell.2015.05.011 PMID: 26000480; PubMed Central PMCID: PMC4768733.
65. Li MD, Vera NB, Yang Y, Zhang B, Ni W, Ziso-Qejvanaj E, et al. Adipocyte OGT governs diet-induced hyperphagia and obesity. Nat Commun. 2018; 9(1):5103. https://doi.org/10.1038/s41467-018-07461-x PMID: 30504766; PubMed Central PMCID: PMC6269424.
66. Shu L, Hoo RL, Wu X, Pan Y, Lee IP, Cheong LY, et al. A-FABP mediates adaptive thermogenesis by promoting intracellular activation of thyroid hormones in brown adipocytes. Nat Commun. 2017; 8:14147. https://doi.org/10.1038/ncomms14147 PMID: 28128199; PubMed Central PMCID: PMC5290165.
67. Mullican SE, Lin-Schmidt X, Chin CN, Chavez JA, Furman JL, Armstrong AA, et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med. 2017; 23 (10):1150-7. https://doi.org/10.1038/nm.4392 PMID: 28846097.
68. Patel S, Alvarez-Guaita A, Melvin A, Rimmington D, Dattilo A, Miedzybrodzka EL, et al. GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans. Cell Metab. 2019; 29(3):707-18 e8. https://doi.org/10.1016/j.cmet.2018.12.016 PMID: 30639358; PubMed Central PMCID: PMC6408327.
69. Mills EL, Pierce KA, Jedrychowski MP, Garrity R, Winther S, Vidoni S, et al. Accumulation of succinate controls activation of adipose tissue thermogenesis. Nature. 2018; 560(7716):102-6. https://doi.org/10.1038/s41586-018-0353-2 PMID: 30022159.
70. Dietz WH, Baur LA, Hall K, Puhl RM, Taveras EM, Uauy R, et al. Management of obesity: improvement of health-care training and systems for prevention and care. The Lancet. 2015; 385(9986):2521-33.
71. Bessesen DH, Van Gaal LF. Progress and challenges in anti-obesity pharmacotherapy. The Lancet Diabetes & Endocrinology. 2018; 6(3):237-48.
72. Kusminski CM, Bickel PE, Scherer PE. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nature reviews Drug discovery. 2016; 15(9):639. https://doi.org/10.1038/nrd.2016.75 PMID: 27256476
73. Igel LI, Kumar RB, Saunders KH, Aronne LJ. Practical use of pharmacotherapy for obesity. Gastroenterology. 2017; 152(7):1765-79. https://doi.org/10.1053/j.gastro.2016.12.049 PMID: 28192104
74. Hussain H, Parker J, Sharma A. Clinical trial success rates of anti-obesity agents: the importance of combination therapies. Obesity reviews. 2015; 16(9):707-14. https://doi.org/10.1111/obr.12299 PMID: 26222385
75. Heilman J, Andreux P, Tran N, Rinsch C, Blanco-Bose W. Safety assessment of Urolithin A, a metabolite produced by the human gut microbiota upon dietary intake of plant derived ellagitannins and ellagic acid. Food Chem Toxicol. 2017; 108(Pt A):289-97. https://doi.org/10.1016/j.fct.2017.07.050 PMID: 28757461.
76. Singh A, Andreux P, Blanco-Bose W, Ryu D, Aebischer P, Auwerx J, et al. ORALLY ADMINISTERED UROLITHIN A IS SAFE AND MODULATES MUSCLE AND MITOCHONDRIAL BIOMARKERS IN ELDERLY. Innovation in Aging. 2017; 1(suppl_1):1223-4.
77. Ebner N, von Haehling S. Silver linings on the horizon: highlights from the 10th Cachexia Conference. J Cachexia Sarcopenia Muscle. 2018; 9(1):176-82. https://doi.org/10.1002/jcsm.12290 PMID: 29417752; PubMed Central PMCID: PMC5803612.
78. Cavaliere H, Floriano I, Medeiros-Neto G. Gastrointestinal side effects of orlistat may be prevented by concomitant prescription of natural fibers (psyllium mucilloid). Int J Obes Relat Metab Disord. 2001; 25 (7):1095-9. https://doi.org/10.1038/sj.ijo.0801645 PMID: 11443512.
79. Ringman JM, Mozaffar T. Myopathy associated with chronic orlistat consumption: a case report. Neuromuscul Disord. 2008; 18(5):410-2. https://doi.org/10.1016/j.nmd.2008.03.005 PMID: 18430571.
80. Camporez JP, Wang Y, Faarkrog K, Chukijrungroat N, Petersen KF, Shulman GI. Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice. Proc Natl Acad Sci U S A. 2017; 114(52):E11285-E92. https://doi.org/10.1073/pnas.1716990115 PMID: 29237750; PubMed Central PMCID: PMC5748223.
81. Wu JW, Wang SP, Casavant S, Moreau A, Yang GS, Mitchell GA. Fasting energy homeostasis in mice with adipose deficiency of desnutrin/adipose triglyceride lipase. Endocrinology. 2012; 153(5):2198-207. https://doi.org/10.1210/en.2011-1518 PMID: 22374972.
82. Cannon B, Nedergaard J. Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol. 2011; 214(Pt 2):242-53. https://doi.org/10.1242/jeb.050989 PMID: 21177944.
83. Matesanz N, Bernardo E, Acin-Perez R, Manieri E, Perez-Sieira S, Hernandez-Cosido L, et al. MKK6 controls T3-mediated browning of white adipose tissue. Nat Commun. 2017; 8(1):856. https://doi.org/10.1038/s41467-017-00948-z PMID: 29021624; PubMed Central PMCID: PMC5636784.
84. Warner A, Rahman A, Solsjo P, Gottschling K, Davis B, Vennstrom B, et al. Inappropriate heat dissipation ignites brown fat thermogenesis in mice with a mutant thyroid hormone receptor alpha1. Proc Natl Acad Sci U S A. 2013; 110(40):16241-6. https://doi.org/10.1073/pnas.1310300110 PMID: 24046370; PubMed Central PMCID: PMC3791708.
85. Tseng YH, Kriauciunas KM, Kokkotou E, Kahn CR. Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol Cell Biol. 2004; 24(5):1918-29. https://doi.org/10.1128/MCB.24.5.1918-1929.2004 PMID: 14966273; PubMed Central PMCID: PMC350563.
86. Soukas A, Socci ND, Saatkamp BD, Novelli S, Friedman JM. Distinct transcriptional profiles of adipogenesis in vivo and in vitro. J Biol Chem. 2001; 276(36):34167-74. https://doi.org/10.1074/jbc. M104421200 PMID: 11445576.
87. Klein J, Fasshauer M, Ito M, Lowell BB, Benito M, Kahn CR. beta(3)-adrenergic stimulation differentially inhibits insulin signaling and decreases insulin-induced glucose uptake in brown adipocytes. J Biol Chem. 1999; 274(49):34795-802. https://doi.org/10.1074/jbc.274.49.34795 PMID: 10574950.
88. Xia B, Cai GH, Yang H, Wang SP, Mitchell GA, Wu JW. Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice. PLoS Genet. 2017; 13(12):e1007110. https://doi.org/10.1371/journal.pgen.1007110 PMID: 29232702; PubMed Central PMCID: PMC5741266.
89. Kong X, Banks A, Liu T, Kazak L, Rao RR, Cohen P, et al. IRF4 is a key thermogenic transcriptional partner of PGC-1alpha. Cell. 2014; 158(1):69-83. https://doi.org/10.1016/j.cell.2014.04.049 PMID: 24995979; PubMed Central PMCID: PMC4116691.
90. Leonard JL, Rosenberg IN. Iodothyronine 5'-deiodinase from rat kidney: substrate specificity and the 5'-deiodination of reverse triiodothyronine. Endocrinology. 1980; 107(5):1376-83. https://doi.org/10.1210/ endo-107-5-1376 PMID: 7428675.
91. Hoefig CS, Wuensch T, Rijntjes E, Lehmphul I, Daniel H, Schweizer U, et al. Biosynthesis of 3-Iodothyr-onamine From T4 in Murine Intestinal Tissue. Endocrinology. 2015; 156(11):4356-64. https://doi.org/10.1210/en.2014-1499 PMID: 26348473.
92. Deacon RM. Measuring the strength of mice. Journal of visualized experiments: JoVE. 2013;(76): e2610.
93. Ferraro E, Pin F, Gorini S, Pontecorvo L, Ferri A, Mollace V, et al. Improvement of skeletal muscle performance in ageing by the metabolic modulator Trimetazidine. Journal of cachexia, sarcopenia and muscle. 2016; 7(4):449-57. https://doi.org/10.1002/jcsm.12097 PMID: 27239426
94. Wei W, Li Z-P, Zhu T, Fung H-Y, Wong T-L, Wen X, et al. Anti-fatigue effects of the unique polysaccharide marker of Dendrobium officinale on BALB/c mice. Molecules. 2017; 22(1):155.