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Nutrient-Gene Interactions

Mice Heterozygous for Atp10c, a Putative Amphipath, Represent a Novel Model of Obesity and Type 2 Diabetes^1,2

Madhu S. Dhar³, Carla S. Sommardahl^*, Tanisa Kirkland, Sarah Nelson^**, Robert Donnell^*, Dabney K. Johnson^** and Lawrence W. Castellani

Department of Nutrition, University of Tennessee, Knoxville, TN 37996; ^* University of Tennessee College of Veterinary Medicine, Knoxville, TN 37996; Office of Biological and Environmental Research and ^** Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831; and University of California, Los Angeles, CA 90095

³To whom correspondence and reprint requests should be addressed. E-mail: mdhar{at}utk.edu.

Atp10c is a novel type IV P-type ATPase and is a putative phospholipid transporter. The purpose of this study was to assess the overall effect of the heterozygous deletion of Atp10c on obesity-related phenotypes and metabolic abnormalities in mice fed a high-fat diet. Heterozygous mice with maternal inheritance of Atp10c were compared with heterozygous mice with paternal inheritance of Atp10c and wild-type controls. Body weight, adiposity index, and plasma insulin, leptin and triglyceride concentrations were significantly greater in the mutants inheriting the deletion maternally compared with their sex- and age-matched control male mice fed a 10% fat (% energy) diet and female mice fed a 45% fat (% energy) diet. Glucose and insulin tolerance tests were performed after mice consumed the diets for 4 and 8 wk. Mutants had altered glucose tolerance and insulin response compared with controls, suggesting insulin resistance in both sexes. Mice were killed at 12 wk and routine gross and histological evaluations of the liver, pancreas, adipose tissue, and heart were performed. Histological evaluation showed micro- and macrovesicular lipid deposition within the hepatocytes that was more severe in the mutant mice than in age-matched controls. Although sex differences were observed, our data suggest that heterozygous deletion along with an unusual pattern of maternal inheritance of the chromosomal region containing the single gene, Atp10c, causes obesity, type 2 diabetes, and nonalcoholic fatty liver disease in these mice.

KEY WORDS: • mouse chromosome 7 • Atp10c, type IV P-type ATPase • insulin resistance

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