Journal:
PLOS Genetics
Publication Date:
Wed, 2017-08-30
Institutions:
1 Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan, 2 Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Maebashi, Gunma, Japan, 3 AMED-JST-CREST Program, Tokyo, Japan, 4 Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan, 5 Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo, Japan, 6 RIKEN Center for Integrative Medical Sciences, Yokohama, Japan, 7 Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands, 8 Graduate School of Health and Sports Science, Juntendo University, Inzai, Chiba, Japan, 9 Department of Tropical Medicine and Parasitology, Graduate School of Medicine, Juntendo University, Tokyo, Japan, 10 Laboratory of Metabolic Signaling, Institute for Molecular & Cellular Regulation, Gunma University, Maebashi, Gunma, Japan, 11 Laboratory of Epigenetics and Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Maebashi, Gunma, Japan, 12 UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California–San Francisco, San Francisco, United States of America, 13 PRESTO-JST, Tokyo, Japan,
14 Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo, Japan, 15 Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan, 16 Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo, Japan
Abstract:
Given the relevance of beige adipocytes in adult humans, a better understanding of the molecular circuits involved in beige adipocyte biogenesis has provided new insight into human brown adipocyte biology. Genetic mutations in SLC39A13/ZIP13, a member of zinc transporter family, are known to reduce adipose tissue mass in humans; however, the underlying mechanisms remains unknown. Here, we demonstrate that the Zip13-deficient mouse shows enhanced beige adipocyte biogenesis and energy expenditure, and shows ameliorated diet-induced obesity and insulin resistance. Both gain- and loss-of-function studies showed that an accumulation of the CCAAT/enhancer binding protein-β (C/EBP-β) protein, which cooperates with dominant transcriptional co-regulator PR domain containing 16 (PRDM16) to determine brown/beige adipocyte lineage, is essential for the enhanced adipocyte browning caused by the loss of ZIP13. Furthermore, ZIP13-mediated zinc transport is a prerequisite for degrading the C/EBP-β protein to inhibit adipocyte browning. Thus, our data reveal an unexpected association between zinc homeostasis and beige adipocyte biogenesis, which may contribute significantly to the development of new therapies for obesity and metabolic syndrome.
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