Zinc Deficiency Augments Leptin Production and Exacerbates Macrophage Infiltration into Adipose Tissue in Mice Fed a High-Fat Diet1–3

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.

RETRACTED ARTICLE: The Effect of Zinc Supplementation on Expressed Levels of Peroxisome Proliferator-Activated Receptor Gamma and Glucose Transporter Type 1 Genes in Newborns of Women with Gestational Diabetes Mellitus

“…Previous studies have shown that zinc deficiency induces PPAR-γ signaling, pro-inflammatory phenotype and atherosclerosis in vascular endothelial cells and LDL-receptor knockout mice [7,19]. However, no significant difference was observed for PPAR-γ activity after low-zinc intake (0.5-1.5 mg/kg) in mice fed with a high-fat diet [20]. PPAR-γ is a member of the nuclear receptor superfamily and regulates the expression of several genes encoding proteins involved in adipocyte differentiation, fatty acid storage and glucose metabolism [21].…”

Decreased adipose tissue zinc content is associated with metabolic parameters in high fat fed Wistar rats

“…In particular, it has been shown that high fat feeding results in decreased epidydimal adipose tissue zinc content in C57BL/6J mice (Tallman and Taylor, 2003). Similar data were obtained later by Liu et al (2013). It is also notable, that epidydimal but not retroperitoneal and subcutaneous adipose tissue in Diabetic Sand Rat is also characterized by signifi cantly lower zinc content (Maxel et al, 2015).…”

Impact of Resolvin E1 on Murine Neutrophil Phagocytosis in Type 2 Diabetes

“…Accumulation of cutaneous fat and marked infiltration of the adipose tissue with active macrophages are characteristics of T2D thought to contribute to elevation of systemic inflammation, particularly as a source of the proinflammatory adipokine TNF-␣ (44)(45)(46). Interestingly, overexpression of ERV1 reduces fat accumulation and markedly reduces macrophages in the adipose tissue of diabetic animals.…”

“…Accumulation of macrophage-laden fat in cutaneous tissue is a well-known characteristic of diabetic mice (44)(45)(46). In order to determine the impact of overexpression of ERV1, we compared the dorsal air pouch linings of db/db and db/ERV1 mice (Fig.…”

“…Accumulation of fat containing activated macrophages in db/db animals is thought to be a source of increased TNF-␣ and a potential contributor to the enhanced inflammatory phenotype of T2D (44,45). In order to evaluate the tissue lining, the air pouches were excised, soaked in 10% formalin solution for 72 h, and embedded in paraffin.…”