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

Research output: Contribution to journalJournal articlepeer-review

  • 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
  • Emanuelli, Brice
  • Young-Tae Chang
  • Susan Hagen
  • Nika N Danial
  • Michael A Kiebish
  • Yu-Hua Tseng

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
Article numbereaaz8664
JournalScience Translational Medicine
Issue number558
Number of pages15
Publication statusPublished - 2020

ID: 247540881