Journal:
Nature Medicine
Publication Date:
Tue, 2015-04-21
Institutions:
11] Diabetes Center, University of California, San Francisco (UCSF), San Francisco, California, USA. [2] Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA. [3] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA.
21] Diabetes Center, University of California, San Francisco (UCSF), San Francisco, California, USA. [2] Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA. [3] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA. [4] Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
31] Joslin Diabetes Center, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA.
41] Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas, USA. [2] Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA. [3] Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA. [4] Department of Nutrition and Metabolism, University of Texas Medical Branch, Galveston, Texas, USA.
5Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Abstract:
Brown adipose tissue (BAT) acts in mammals as a natural defense system against hypothermia, and its activation to a state of increased energy expenditure is believed to protect against the development of obesity. Even though the existence of BAT in adult humans has been widely appreciated, its cellular origin and molecular identity remain elusive largely because of high cellular heterogeneity within various adipose tissue depots. To understand the nature of adult human brown adipocytes at single cell resolution, we isolated clonally derived adipocytes from stromal vascular fractions of adult human BAT from two individuals and globally analyzed their molecular signatures. We used RNA sequencing followed by unbiased genome-wide expression analyses and found that a population of uncoupling protein 1 (UCP1)-positive human adipocytes possessed molecular signatures resembling those of a recruitable form of thermogenic adipocytes (that is, beige adipocytes). In addition, we identified molecular markers that were highly enriched in UCP1-positive human adipocytes, a set that included potassium channel K3 (KCNK3) and mitochondrial tumor suppressor 1 (MTUS1). Further, we functionally characterized these two markers using a loss-of-function approach and found that KCNK3 and MTUS1 were required for beige adipocyte differentiation and thermogenic function. The results of this study present new opportunities for human BAT research, such as facilitating cell-based disease modeling and unbiased screens for thermogenic regulators.
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