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

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.
Author summary 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. Therefore, the identification of selective molecular circuits involved in beige adipocyte biogenesis and thermogenesis will enable the selective induction of white adipocyte browning as a therapy for obesity. Here, 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. Inhibition of ZIP13 function enhances beige adipocyte biogenesis and thermogenesis, highlighting the potential of ZIP13 as a therapeutic target for obesity and metabolic syndrome.