Research ArticleMetabolism

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

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Science Translational Medicine  26 Aug 2020:
Vol. 12, Issue 558, eaaz8664
DOI: 10.1126/scitranslmed.aaz8664

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Turning up the heat

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.

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.

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