Zinc transporter ZIP13 suppresses beige adipocyte biogenesis and energy expenditure by regulating C/EBP-β expression.

Ayako Fukunaka,Yoshio Fujitani,Hisashi Naito,Takeshi Inagaki,Tsutomu Sasaki,Yuri Takamine,Hirotaka Watada,Tadahiro Kitamura,Bum-Ho Bin,Takeshi Miyatsuka,Toshinori Yoshihara,Luka Suzuki,Takamasa Tsuzuki,Shingo Kajimura,Shinzaburo Takamiya,Toshiyuki Fukada,Noriko Ichinoseki-Sekine,Jinhyuk Bhin,Gregory S Barsh

doi:10.1371/journal.pgen.1006950

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.

Highlights

Obesity and its associated metabolic diseases are caused by a long-term imbalance between energy intake and energy expenditure
Inducible brown fat-like cells, named beige adipocytes have recently been a topic of great interest, mainly because they are induced in response to external cues, and are closely associated with adult human brown adipocyte
We show that zinc homeostasis, which is controlled by ZIP13, a protein associated with human disease, is essential for the accurate regulation of beige adipocyte differentiation

Summary

Introduction

Obesity and its associated metabolic diseases are caused by a long-term imbalance between energy intake and energy expenditure. Inducible brown fat-like cells, named beige adipocytes, have been identified in white adipose tissue (WAT). The presence and activity of thermogenic adipocytes (brown and beige adipocytes) are associated with improved global metabolic fitness, such as improvements in insulin resistance and glucose homeostasis [2,4,5]; thermogenic adipocytes decrease with age and obesity in mice and humans [6,7]. Recent studies indicate that adult human brown adipose tissue (BAT) in the supraclavicular region has beige-like characteristics [8,9,10,11]. These findings indicate the potential importance of beige fats in human obesity and metabolic disease. Identifying a selective molecular pathway that regulates the acquisition of beige adipocyte properties will enable us to selectively and preferentially promote beige adipocyte biogenesis and thermogenesis as a therapy for obese or older subjects who do not have active BAT depots [1]

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Conclusion