@article{e58c08ee045648da91c2cd49c2323e4c,
title = "CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice",
abstract = "Brown and brown-like beige/brite adipocytes dissipate energy and have been proposed as therapeutic targets to combat metabolic disorders. However, the therapeutic effects of cell-based therapy in humans remain unclear. Here, we created human brown-like (HUMBLE) cells by engineering human white preadipocytes using CRISPR-Cas9–SAM–gRNA to activate endogenous uncoupling protein 1 expression. Obese mice that received HUMBLE cell transplants showed a sustained improvement in glucose tolerance and insulin sensitivity, as well as increased energy expenditure. Mechanistically, increased arginine/nitric oxide (NO) metabolism in HUMBLE adipocytes promoted the production of NO that was carried by S-nitrosothiols and nitrite in red blood cells to activate endogenous brown fat and improved glucose homeostasis in recipient animals. Together, these data demonstrate the utility of using CRISPR-Cas9 technology to engineer human white adipocytes to display brown fat-like phenotypes and may open up cell-based therapeutic opportunities to combat obesity and diabetes.",
author = "Wang, {Chih Hao} and Morten Lundh and Accalia Fu and R{\'o}kus Kriszt and Huang, {Tian Lian} and Lynes, {Matthew D.} and Leiria, {Luiz O.} and Farnaz Shamsi and Justin Darcy and Greenwood, {Bennett P.} and Narain, {Niven R.} and Vladimir Tolstikov and Smith, {Kyle L.} and Brice Emanuelli and Chang, {Young Tae} and Susan Hagen and Danial, {Nika N.} and Kiebish, {Michael A.} and Tseng, {Yu Hua}",
note = "Funding Information: We thank A. Dean and A. Clermont of the Joslin Diabetes Center Animal Physiology core and C. Hill at BERG for expert technical assistance. We appreciate M. Suzuki at Osaka University and S. Arai at Waseda University for suggestions regarding optimization of the thermodye experimental protocol. We thank E. Chouchani at Dana-Farber Cancer Institute for providing the protocol for detection of S-nitrosylation using in gel Cy5-labeling method. This work was supported in part by U.S. NIH grants R01DK077097 and R01DK102898 (to Y.-H.T.), R01DK078081 (to N.N.D.), P30DK036836 (to Joslin Diabetes Center{\textquoteright}s Diabetes Research Center) from the National Institute of Diabetes and Digestive and Kidney Diseases, and by U.S. Army Medical Research grant W81XWH-17-1-0428 (to Y.-H.T.). C.-H.W. was supported by a Postdoctoral Research Abroad Program (PRAP) from the Ministry of Science and Technology, Taiwan (106-2917-I-564-069). M.L. was supported by the Danish Council for Independent Research and Sapere Aude Research Talent (DFF 5053-00112). M.D.L. was supported by NIH grants F32DK102320 and K01DK111714. L.O.L. was supported by an American Diabetes Association Postdoctoral Fellowship (1-16-PDF-063) and by the S{\~a}o Paulo Research Foundation (FAPESP) grant 2017/02684. F.S. was supported by postdoctoral fellowships from the American Diabetes Association (1-18-PDF-169). J.D. was supported by an NIH grant (T32DK007260) and American Heart Association fellowship (20POST35210497). A.F. was supported by a postdoctoral fellowship from the Juvenile Diabetes Research foundation (JDRF). Publisher Copyright: {\textcopyright} 2020 The Authors, some rights reserved",
year = "2020",
month = aug,
doi = "10.1126/SCITRANSLMED.AAZ8664",
language = "English (US)",
volume = "12",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "558",
}