title: Znt7-null mice are more susceptible to diet-induced glucose intolerance and insulin resistance.
abstract: 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.
authors.affiliation: United States Department of Agriculture/Agricultural Research Service/Western Human Nutrition Research Center, Obesity and Metabolism Research Unit, Davis, California 95616, USA. liping.huang@ars.usda.gov
authors.forename: Liping
authors.initials: L
authors.lastname: Huang
authors.forename: Catherine P
authors.initials: CP
authors.lastname: Kirschke
authors.forename: Yu-An E
authors.initials: YA
authors.lastname: Lay
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Levy
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Lamirande
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Zhang
mesh_terms: D000821:Animal Feed; D000818:Animals; D001823:Body Composition; D027682:Cation Transport Proteins / Q000235:genetics* / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004032:Diet; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D032342:Muscle Cells / Q000166:cytology; D015398:Signal Transduction; D015032:Zinc / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D007328:Insulin; C472293:ZnT7 protein, mouse; D005947:Glucose; D015032:Zinc