CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice
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CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice. / Wang, Chih-Hao; Lundh, Morten; Fu, Accalia; Kriszt, Rókus; Huang, Tian Lian; Lynes, Matthew D; Leiria, Luiz O; Shamsi, Farnaz; Darcy, Justin; Greenwood, Bennett P; Narain, Niven R; Tolstikov, Vladimir; Smith, Kyle L; Emanuelli, Brice; Chang, Young-Tae; Hagen, Susan; Danial, Nika N; Kiebish, Michael A; Tseng, Yu-Hua.
In: Science Translational Medicine, Vol. 12, No. 558, eaaz8664, 2020.Research output: Contribution to journal › Journal article › peer-review
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TY - JOUR
T1 - CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice
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
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.1126/scitranslmed.aaz8664
DO - 10.1126/scitranslmed.aaz8664
M3 - Journal article
C2 - 32848096
VL - 12
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 558
M1 - eaaz8664
ER -
ID: 247540881