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.