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

Autor:	Wang CH; Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan., Lundh M; Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200, Denmark.; Gubra Aps, Hørsholm, DK-2970, Denmark., Fu A; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA., Kriszt R; Department of Biomedical Engineering, National University of Singapore, Singapore, 117583.; Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, Singapore 119077, Singapore., Huang TL; Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA., Lynes MD; Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA., Leiria LO; Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Ribeirão Preto, 14049-900, Brazil.; Center of Research of Inflammatory Diseases, Ribeirao Preto Medical School, University of São Paulo, Ribeirão Preto, 14049-900, Brazil., Shamsi F; Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA., Darcy J; Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA., Greenwood BP; BERG, Framingham, MA 01701, USA., Narain NR; BERG, Framingham, MA 01701, USA., Tolstikov V; BERG, Framingham, MA 01701, USA., Smith KL; Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA., Emanuelli B; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200, Denmark., Chang YT; Center for Self-assembly and Complexity, Institute for Basic Science (IBS), Pohang 34126, Republic of Korea.; Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea., Hagen S; Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA., Danial NN; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Kiebish MA; BERG, Framingham, MA 01701, USA., Tseng YH; Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA. yu-hua.tseng@joslin.harvard.edu.; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2020 Aug 26; Vol. 12 (558).
DOI:	10.1126/scitranslmed.aaz8664
Abstrakt:	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. (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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