title: Zinc deficiency augments leptin production and exacerbates macrophage infiltration into adipose tissue in mice fed a high-fat diet.
abstract: Zinc (Zn) deficiency and obesity are global public health problems. Zn deficiency is associated with obesity and comorbid conditions that include insulin resistance and type 2 diabetes. However, the function of Zn in obesity remains unclear. Using a mouse model of combined high-fat and low-Zn intake (0.5-1.5 mg/kg), we investigated whether Zn deficiency exacerbates the extent of adiposity as well as perturbations in metabolic and immune function. C57BL/6 mice were randomly assigned to receive either a high-fat diet (HFD) or a control (C) diet for 6 wk, followed by further subdivision into 2 additional groups fed Zn-deficient diets (C-Zn, HFD-Zn), along with a C diet and an HFD, for 3 wk (n = 8-9 mice/group). The extent of visceral fat, insulin resistance, or systemic inflammation was unaffected by Zn deficiency. Strikingly, Zn deficiency significantly augmented circulating leptin concentrations (HFD-Zn vs. HFD: 3.15 ± 0.16 vs. 2.59 ± 0.12 μg/L, respectively) and leptin signaling in the liver of obese mice. Furthermore, gene expression of macrophage-specific markers ADAM8 (A disintegrin and metalloproteinase domain-containing protein 8) and CD68 (cluster of differentiation 68) was significantly greater in adipose tissue in the HFD-Zn group than in the HFD group, as confirmed by CD68 protein analysis, indicative of increased macrophage infiltration. Inspection of Zn content and mRNA profiles of all Zn transporters in the adipose tissue revealed alterations of Zn metabolism to obesity and Zn deficiency. Our results demonstrate that Zn deficiency increases leptin production and exacerbates macrophage infiltration into adipose tissue in obese mice, indicating the importance of Zn in metabolic and immune dysregulation in obesity.
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
authors.forename: Ming-Jie
authors.initials: MJ
authors.lastname: Liu
authors.forename: Shengying
authors.initials: S
authors.lastname: Bao
authors.forename: Eric R
authors.initials: ER
authors.lastname: Bolin
authors.forename: Dara L
authors.initials: DL
authors.lastname: Burris
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xu
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.forename: David W
authors.initials: DW
authors.lastname: Killilea
authors.forename: Qiwen
authors.initials: Q
authors.lastname: Shen
authors.forename: Ouliana
authors.initials: O
authors.lastname: Ziouzenkova
authors.forename: Martha A
authors.initials: MA
authors.lastname: Belury
authors.forename: Mark L
authors.initials: ML
authors.lastname: Failla
authors.forename: Daren L
authors.initials: DL
authors.lastname: Knoell
mesh_terms: D054392:Adipokines / Q000097:blood; D050154:Adiposity; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D016207:Cytokines / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D059305:Diet, High-Fat; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D020738:Leptin / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D009765:Obesity / Q000503:physiopathology; D047495:PPAR gamma / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D015032:Zinc / Q000097:blood* / Q000172:deficiency*; D000097382:CD68 Molecule
chemical_list: D054392:Adipokines; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D016207:Cytokines; D020738:Leptin; D016328:NF-kappa B; D047495:PPAR gamma; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D015032:Zinc; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C494087:Stat3 protein, mouse