CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice

Chih Hao Wang, Morten Lundh, Accalia Fu, Rókus Kriszt, Tian Lian Huang, Matthew D. Lynes, Luiz O. Leiria, Farnaz Shamsi, Justin Darcy, Bennett P. Greenwood, Niven R. Narain, Vladimir Tolstikov, Kyle L. Smith, Brice Emanuelli, Young Tae Chang, Susan Hagen, Nika N. Danial, Michael A. Kiebish, Yu Hua Tseng

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbereaaz8664
JournalScience Translational Medicine
Volume12
Issue number558
DOIs
StatePublished - Aug 2020

ASJC Scopus subject areas

  • Medicine(all)

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