Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity.
Zinc is a signaling molecule in numerous metabolic pathways, the coordination of which occurs through activity of zinc transporters. The expression of zinc transporter Zip14 (Slc39a14), a zinc importer of the solute carrier 39 family, is stimulated under proinflammatory conditions. Adipose tissue upregulates Zip14 during lipopolysaccharide-induced endotoxemia. A null mutation of Zip14 (KO) revealed that phenotypic changes in adipose include increased cytokine production, increased plasma leptin, hypertrophied adipocytes, and dampened insulin signaling. Adipose tissue from KO mice had increased levels of preadipocyte markers, lower expression of the differentiation marker (PPARγ), and activation of NF-κB and STAT3 pathways. Our overall hypothesis was that ZIP14 would play a role in adipocyte differentiation and inflammatory obesity. Global Zip14 KO causes systemic endotoxemia. The observed metabolic changes in adipose metabolism were reversed when oral antibiotics were administrated, indicating that circulating levels of endotoxin were in part responsible for the adipose phenotype. To evaluate a mechanism, 3T3-L1 cells were differentiated into adipocytes and treated with siRNA to knock down Zip14. These cells had an impaired ability to mobilize zinc, which caused dysregulation of inflammatory pathways (JAK2/STAT3 and NF-κB). The Zip14 deletion may limit the availability of intracellular zinc, yielding the unique phenotype of inflammation coupled with hypertrophy. Taken together, these results suggest that aberrant zinc distribution observed with Zip14 ablation impacts adipose cytokine production and metabolism, ultimately increasing fat deposition when exposed to endotoxin. To our knowledge, this is the first investigation into the mechanistic role of ZIP14 in adipose tissue regulation and metabolism.
['Troche|Catalina|C|', 'Aydemir|Tolunay Beker|TB|', 'Cousins|Robert J|RJ|']
D041721:3T3-L1 Cells D017667:Adipocytes D000273:Adipose Tissue D052436:Adipose Tissue, White D050154:Adiposity D000818:Animals D015153:Blotting, Western D027682:Cation Transport Proteins D002454:Cell Differentiation D016207:Cytokines D019446:Endotoxemia D055785:Gene Knockdown Techniques D006984:Hypertrophy D007249:Inflammation D053614:Janus Kinase 2 D020738:Leptin D008070:Lipopolysaccharides D051379:Mice D018345:Mice, Knockout D018613:Microscopy, Confocal D016328:NF-kappa B D047495:PPAR gamma D050796:STAT3 Transcription Factor D015398:Signal Transduction
adipose endotoxemia hypertrophy inflammation zinc signaling