Znt7-null Mice Are More Susceptible to Diet-induced Glucose Intolerance and Insulin Resistance

• Published in: The Journal of biological chemistry 2012-09, Vol.287 (40), p.33883-33896
• Main Authors: Huang, Liping, Kirschke, Catherine P., Lay, Yu-An E., Levy, Lauren B., Lamirande, Danielle E., Zhang, Patrick H.
• Format: Article
• Language: English
• Subjects: Akt; Animal Feed; Animals; Body Composition; Cation Transport Proteins - genetics; Cation Transport Proteins - physiology; Diabetes; Diabetes Mellitus, Experimental - metabolism; Diet; Diet-induced Obesity; Female; Gene Expression Regulation; Glucose - metabolism; Glucose Intolerance; High Fat Diet; Homeostasis; Insulin - metabolism; Insulin Resistance; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Muscle Cells - cytology; Signal Transduction; Slc30a7; Transport Metals; Zinc; Zinc - metabolism; ZnT7
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.309666

The Znt7 gene encodes a ubiquitously expressed zinc transporter that is involved in transporting cytoplasmic zinc into the Golgi apparatus and a ZnT7-containing vesicular compartment. Overexpression of ZnT7 in the pancreatic β-cell stimulates insulin synthesis and secretion through regulation of insulin gene transcription. In this study, we demonstrate that ZnT7 is expressed in the mouse skeletal muscle. The activity of the insulin signaling pathway was down-regulated in myocytes isolated from the femoral muscle of Znt7 knock-out (KO) mice. High fat diet consumption (45% kcal) induced weight gain in male Znt7 KO mice but not female Znt7 KO mice. Male Znt7 KO mice fed the high fat diet at 5 weeks of age for 10 weeks exhibited hyperglycemia in the non-fasting state. Oral glucose tolerance tests revealed that male Znt7 KO mice fed the high fat diet had severe glucose intolerance. Insulin tolerance tests showed that male Znt7 KO mice were insulin-resistant. Diet-induced insulin resistance in male Znt7 KO mice was paralleled by a reduction in mRNA expression of Insr, Irs2, and Akt1 in the primary skeletal myotubes isolated from the KO mice. Overexpression of ZnT7 in a rat skeletal muscle cell line (L6) increased Irs2 mRNA expression, Irs2 and Akt phosphorylation, and glucose uptake. We conclude that a combination of decreased insulin secretion and increased insulin resistance accounts for the glucose intolerance observed in Znt7 KO mice. Background: Zinc transporter 7 (ZnT7) influences insulin synthesis/secretion in β-cells. Results:Znt7-null mice have impaired glucose tolerance and are insulin-resistant. Conclusion: A combination of decreased insulin secretion and increased insulin resistance accounts for the glucose intolerance in Znt7-null mice. Significance: The study provides direct evidence that zinc homeostasis is crucial for glucose/insulin metabolism.