From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy.

adipose transplantation cell therapy gene therapy leptin replacement therapy lipodystrophy lipolysis rare disorders

Journal

Diabetic medicine : a journal of the British Diabetic Association
ISSN: 1464-5491
Titre abrégé: Diabet Med
Pays: England
ID NLM: 8500858

Informations de publication

Date de publication:
12 2023
Historique:
revised: 19 08 2023
received: 26 06 2023
accepted: 22 08 2023
medline: 13 11 2023
pubmed: 28 8 2023
entrez: 28 8 2023
Statut: ppublish

Résumé

Lipodystrophy is a rare disorder characterised by abnormal or deficient adipose tissue formation and distribution. It poses significant challenges to affected individuals, including the development of severe metabolic complications like diabetes and fatty liver disease. These conditions are often chronic, debilitating and life-threatening, with limited treatment options and a lack of specialised expertise. This review aims to raise awareness of lipodystrophy disorders and highlights therapeutic strategies to restore adipose tissue functionality. Extensive research has been conducted, including both historical and recent advances. We have examined and summarised the literature to provide an overview of potential strategies to restore adipose tissue functionality and treat/reverse metabolic complications in lipodystrophy disorders. A wealth of basic and clinical research has investigated various therapeutic approaches for lipodystrophy. These include ground-breaking methods such as adipose tissue transplantation, innovative leptin replacement therapy, targeted inhibition of lipolysis and cutting-edge gene and cell therapies. Each approach shows great potential in addressing the complex challenges posed by lipodystrophy. Lipodystrophy disorders require urgent attention and innovative treatments. Through rigorous basic and clinical research, several promising therapeutic strategies have emerged that could restore adipose tissue functionality and reverse the severe metabolic complications associated with this condition. However, further research and collaboration between academics, clinicians, patient advocacy groups and pharmaceutical companies will be crucial in transforming these scientific breakthroughs into effective and viable treatment options for individuals and families affected by lipodystrophy. Fostering such interdisciplinary partnerships could pave the way for a brighter future for those battling this debilitating disorder.

Identifiants

pubmed: 37638531
doi: 10.1111/dme.15214
doi:

Substances chimiques

Leptin 0

Types de publication

Journal Article Review Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e15214

Informations de copyright

© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

Références

Moliner AM, Waligora J. The European Union policy in the field of rare diseases. Adv Exp Med Biol. 2017;1031:561-587. doi:10.1007/978-3-319-67144-4_30
Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28(2):165-173. doi:10.1038/s41431-019-0508-0
Kolkhir P, Grad DA, Charalampous P, et al. An EU task force to assess the burden of rare diseases. Nat Med. 2023;29(3):516-517. doi:10.1038/s41591-023-02207-9
Lim K, Haider A, Adams C, Sleigh A, Savage DB. Lipodistrophy: a paradigm for understanding the consequences of “overloading” adipose tissue. Physiol Rev. 2021;101(3):907-993. doi:10.1152/physrev.00032.2020
Gonzaga-Jauregui C, Ge W, Staples J, et al. Clinical and molecular prevalence of lipodystrophy in an unascertained large clinical care cohort. Diabetes. 2020;69(2):249-258.
Akinci B, Onay H, Demir T, et al. Natural history of congenital generalized lipodystrophy: a nationwide study from Turkey. J Clin Endocrinol Metab. 2016;101(7):2759-2767.
Agarwal AK, Arioglu E, De Almeida S, et al. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet. 2002;31(1):21-23.
Magre J, Delepine M, Khallouf E, et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet. 2001;28(4):365-370.
Kim CA, Delepine M, Boutet E, et al. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab. 2008;93(4):1129-1134.
Hayashi YK, Matsuda C, Ogawa M, et al. Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest. 2009;119(9):2623-2633.
Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell. 2014;156(1-2):20-44.
Cawthorn WP. Bone marrow adipose tissue. In: Zaidi M, ed. Encyclopedia of Bone Biology. Academic Press; 2020:156-177.
Gavrilova O, Marcus-Samuels B, Graham D, et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest. 2000;105(3):271-278.
Herrero L, Shapiro H, Nayer A, Lee J, Shoelson SE. Inflammation and adipose tissue macrophages in lipodystrophic mice. Proc Natl Acad Sci U S A. 2010;107(1):240-245. doi:10.1073/pnas.0905310107
Zhang Z, Turer E, Li X, et al. Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice. Proc Natl Acad Sci U S A. 2016;113(42):E6418-E6426. doi:10.1073/pnas.1614467113
Liu Z, Jin L, Yang J, et al. The dysfunctional MDM2-p53 axis in adipocytes contributes to aging-related metabolic complications by induction of lipodystrophy. Diabetes. 2018;67(11):2397-2409. doi:10.2337/db18-0684
Yeh Y, Jheng H, Iwase M, et al. The mevalonate pathway is indispensable for adipocyte survival. iScience. 2018;9:175-191. doi:10.1016/j.isci.2018.10.019
Zou W, Rohatgi N, Brestoff JR, et al. Ablation of fat cells in adult mice induces massive bone gain. Cell Metab. 2020;32(5):801-813.e6. doi:10.1016/j.cmet.2020.09.011
Liu XJ, Wu XY, Wang H, et al. Renal injury in seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue-kidney crosstalk. FASEB J. 2018;32(10):5550-5562.
Wang H, Xu PF, Li JY, et al. Adipose tissue transplantation ameliorates lipodystrophy-associated metabolic disorders in seipin-deficient mice. Am J Physiol Endocrinol Metab. 2019;316(1):E54-E62.
Lima JG, Nobrega LHC, Lima NN, et al. Causes of death in patients with Berardinelli-Seip congenital generalized lipodystrophy. PLoS One. 2018;13(6):e0199052.
Davis S, Hocking S, Watt MJ, Gunton JE. Metabolic effects of lipectomy and of adipose tissue transplantation. Obesity (Silver Spring). 2023;31(1):7-19. doi:10.1002/oby.23601
Colombo C, Cutson JJ, Yamauchi T, et al. Transplantation of adipose tissue lacking leptin is unable to reverse the metabolic abnormalities associated with lipoatrophy. Diabetes. 2002;51(9):2727-2733. doi:10.2337/diabetes.51.9.2727
Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature. 1999;401(6748):73-76.
Gavrilova O, Marcus-Samuels B, Leon LR, Vinson C, Reitman ML. Leptin and diabetes in lipoatrophic mice. Nature. 2000;403(6772):850; discussion 850-851. doi:10.1038/35002663
Ebihara K, Ogawa Y, Masuzaki H, et al. Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes. Diabetes. 2001;50(6):1440-1448. doi:10.2337/diabetes.50.6.1440
Cortés VA, Cautivo KM, Rong S, Garg A, Horton JD, Agarwal AK. Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2−/− lipodystrophic mice independent of hepatocyte leptin receptors. J Lipid Res. 2014;55(2):276-288. doi:10.1194/jlr.M045799
Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346(8):570-578. doi:10.1056/NEJMoa012437
Petersen KF, Oral EA, Dufour S, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest. 2002;109(10):1345-1350. doi:10.1172/JCI15001
Chong AY, Lupsa BC, Cochran EK, Gorden P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia. 2010;53(1):27-35. doi:10.1007/s00125-009-1502-9
Brown RJ, Valencia A, Startzell M, et al. Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy. J Clin Invest. 2018;128(8):3504-3516. doi:10.1172/JCI95476
Metz M, Beghini M, Wolf P, et al. Leptin increases hepatic triglyceride export via a vagal mechanism in humans. Cell Metab. 2022;34(11):1719-1731.e5. doi:10.1016/j.cmet.2022.09.020
Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7(8):941-946. doi:10.1038/90984
Akinci B, Meral R, Oral EA. Update on therapeutic options in lipodystrophy. Curr Diab Rep. 2018;18(12):139. doi:10.1007/s11892-018-1100-7
Chan JL, Koda J, Heilig JS, et al. Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy. Clin Endocrinol (Oxf). 2016;85(1):137-149. doi:10.1111/cen.12980
Chen W, Chang B, Saha P, et al. Berardinelli-seip congenital lipodystrophy 2/seipin is a cell-autonomous regulator of lipolysis essential for adipocyte differentiation. Mol Cell Biol. 2012;32(6):1099-1111.
Prieur X, Dollet L, Takahashi M, et al. Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice. Diabetologia. 2013;56(8):1813-1825.
Zhou H, Lei X, Benson T, et al. Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals. J Lipid Res. 2015;56(10):1912-1925.
Zhou H, Lei X, Yan Y, et al. Targeting ATGL to rescue BSCL2 lFipodystrophy and its associated cardiomyopathy. JCI Insight. 2019;4(14):e129781. doi:10.1172/jci.insight.129781
Liao C, Anderson SS, Chicoine NH, et al. Rapamycin reverses metabolic deficits in lamin A/C-deficient mice. Cell Rep. 2016;17(10):2542-2552. doi:10.1016/j.celrep.2016.10.040
Martinez-Botas J, Anderson JB, Tessier D, et al. Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice. Nat Genet. 2000;26(4):474-479. doi:10.1038/82630
Nishino N, Tamori Y, Tateya S, et al. FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. J Clin Invest. 2008;118(8):2808-2821. doi:10.1172/JCI34090
Peinado JR, Quirós PM, Pulido MR, et al. Proteomic profiling of adipose tissue from Zmpste24−/− mice, a model of lipodystrophy and premature aging, reveals major changes in mitochondrial function and vimentin processing. Mol Cell Proteomics. 2011;10(11):M111.008094. doi:10.1074/mcp.M111.008094
Ding S, Lee M, Summer R, Liu L, Fried SK, Pilch PF. Pleiotropic effects of cavin-1 deficiency on lipid metabolism. J Biol Chem. 2014;289(12):8473-8483. doi:10.1074/jbc.M113.546242
Dunbar CE, High KA, Joung JK, Kohn DB, Ozawa K, Sadelain M. Gene therapy comes of age. Science. 2018;359(6372):eaan4672. doi:10.1126/science.aan4672
Bates R, Huang W, Cao L. Adipose tissue: an emerging target for adeno-associated viral vectors. Mol Ther Methods Clin Dev. 2020;19:236-249.
O'Neill SM, Hinkle C, Chen SJ, et al. Targeting adipose tissue via systemic gene therapy. Gene Ther. 2014;21(7):653-661.
Huang W, Liu X, Queen NJ, Cao L. Targeting visceral fat by intraperitoneal delivery of novel AAV serotype vector restricting off-target transduction in liver. Mol Ther Methods Clin Dev. 2017;6:68-78.
Uhrig-Schmidt S, Geiger M, Luippold G, et al. Gene delivery to adipose tissue using transcriptionally targeted rAAV8 vectors. PLoS One. 2014;9(12):e116288.
Sommer N, Roumane A, Han W, Delibegović M, Rochford JJ, Mcilroy GD. Gene therapy restores adipose tissue and metabolic health in a pre-clinical mouse model of lipodystrophy. Mol Ther Methods Clin Dev. 2022;27:206-216. doi:10.1016/j.omtm.2022.09.014
Jimenez V, Muñoz S, Casana E, et al. In vivo adeno-associated viral vector-mediated genetic engineering of white and brown adipose tissue in adult mice. Diabetes. 2013;62(12):4012-4022.
Rodeheffer MS, Birsoy K, Friedman JM. Identification of white adipocyte progenitor cells in vivo. Cell. 2008;135(2):240-249.
Ambrosi TH, Scialdone A, Graja A, et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell. 2017;20(6):771-784.e6. doi:10.1016/j.stem.2017.02.009
Suzuki K, Akita S, Yoshimoto H, Ohtsuru A, Hirano A, Yamashita S. Biological features implies potential use of autologous adipose-derived stem/progenitor cells in wound repair and regenerations for the patients with lipodystrophy. Int J Mol Sci. 2019;20(21):5505. doi:10.3390/ijms20215505

Auteurs

Mansi Tiwari (M)

The Rowett Institute, University of Aberdeen, Aberdeen, UK.
Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK.

George D Mcilroy (GD)

The Rowett Institute, University of Aberdeen, Aberdeen, UK.
Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK.

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