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

Abstract

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.

Phospholipid Flippases

“…Angelman syndrome, which is characterized by neurologic abnormalities, including mental retardation, ataxia, and epilepsy (70), and behavioral disorders, such as autism (71), have been linked to ATP10C. A mouse homolog of ATP10C (pfatp) has been associated with obesity and may be a new model for Type 2 diabetes (72). How the putative role of the P 4 -ATPases in membrane structure and function influences these diseases remains to be determined.…”

Yeast P4-ATPases Drs2p and Dnf1p Are Essential Cargos of the NPFXD/Sla1p Endocytic Pathway

“…Mammalian homologues of Drs2p include the chromaffin granule ATPase II (now called ATP8A1) (Tang et al, 1996), which is likely responsible for a PS translocase activity observed with these exocytic vesicles (Zachowski et al, 1989), and FIC1 (ATP8B1), for which mutations in humans cause an impairment of bile flow through the liver (cholestasis) (Bull et al, 1998;Klomp et al, 2004). In addition, deletions removing the mouse Atp10c gene cause diet-induced obesity and type 2 diabetes phenotypes (Dhar et al, 2004). P4-ATPases are also agriculturally important, because they are required for pathogenesis of the rice blast fungus Magneporthe griseus (Balhadere and Talbot, 2001;Gilbert et al, 2006) and growth of plants at cold temperatures (Gomes et al, 2000).…”

The Essential Neo1 Protein from Budding Yeast Plays a Role in Establishing Aminophospholipid Asymmetry of the Plasma Membrane

“…There are 14 mammalian P4-ATPases that are associated with intellectual disability (24), neurodegeneration (25), liver disease (26,27), hearing loss (28), diabetes (29), immune deficiency (30,31), anemia (32), and reduced male fertility (33). Budding yeast express the following five members of this subgroup: Dnf1, Dnf2, Dnf3, Drs2, and Neo1.…”