PT  - JOURNAL ARTICLE
AU  - Wang, Chih-Hao
AU  - Lundh, Morten
AU  - Fu, Accalia
AU  - Kriszt, Rókus
AU  - Huang, Tian Lian
AU  - Lynes, Matthew D.
AU  - Leiria, Luiz O.
AU  - Shamsi, Farnaz
AU  - Darcy, Justin
AU  - Greenwood, Bennett P.
AU  - Narain, Niven R.
AU  - Tolstikov, Vladimir
AU  - Smith, Kyle L.
AU  - Emanuelli, Brice
AU  - Chang, Young-Tae
AU  - Hagen, Susan
AU  - Danial, Nika N.
AU  - Kiebish, Michael A.
AU  - Tseng, Yu-Hua
TI  - CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice
AID  - 10.1126/scitranslmed.aaz8664
DP  - 2020 Aug 26
TA  - Science Translational Medicine
PG  - eaaz8664
VI  - 12
IP  - 558
4099  - http://stm.sciencemag.org/content/12/558/eaaz8664.short
4100  - http://stm.sciencemag.org/content/12/558/eaaz8664.full
AB  - Uncoupling protein 1 (UCP1) is the major player in the energy-siphoning thermogenesis that primarily occurs in brown adipose tissue (BAT). Wang et al. generated UCP1-overexpressing human white adipocytes so that they more resembled their brown counterparts. Transplantation of the modified white adipocytes prevented diet-induced obesity and glucose intolerance and increased energy expenditure in the recipient mice. These metabolic benefits resulted from increased nitric oxide signaling in the transplanted human cells, which activated endogenous murine BAT. Future work will need to examine whether this cell-based strategy can activate BAT thermogenesis in humans.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.