Abstract 20013: The Alpha-Arrestin Arrdc3 Regulates Obesity in Mice and Humans
Obesity, a major contributor to cardiovascular disease, has a significant genetic component, yet few genes are known to contribute to the risk of obesity. A genome-wide linkage scan for high body mass index (BMI) in 3893 males and 4445 females identified a linkage peak on chromosome 5q13-15. Positional cloning revealed an association of a rare haplotype to high BMI in males (P=0.000006) but not females, with an odds ratio of 3.8. The risk locus contains a single gene named “arrestin domain containing 3” (ARRDC3), an uncharacterized alpha-arrestin. Alpha-arrestins are related to the visual and beta-arrestins that regulate receptor signaling, but little is known about alpha-arrestin function. We investigated ARRDC3 expression by Northern analysis and detected prominent expression in non-neural tissues, especially adipose and muscle. Analysis of gene expression in human omental fat biopsies showed significant correlation of ARRDC3 mRNA with BMI in males but not females, supporting the male-specific linkage to obesity. In addition, Arrdc3 expression was increased by fasting in both human and mouse adipose tissue, suggesting that Arrdc3 functions to conserve energy when food is not available. To test whether Arrdc3 causally regulates obesity, we generated Arrdc3-null mice. We observed striking resistance to age-induced obesity, with total body mass of male Arrdc3-null mice smaller than wild-type mice from weaning through 20 weeks of age. The effect of Arrdc3 was dose-dependent, as body mass of male heterozygous mice was also smaller than wild-type mice by 12 weeks of age. Consistent with the human linkage data, loss of Arrdc3 had less effect on female mice: Arrdc3-null females had lower body mass only after 12 weeks of age, and body mass of heterozygous females was not significantly different than wild-type females. Fat pad mass as a percentage of total body mass was also reduced in male and female Arrdc3-null mice. Furthermore, Arrdc3-null mice were resistant to the metabolic complications of obesity, maintaining a stronger response to intraperitoneal insulin, enhanced clearance of a glucose load, and lower lipid content of liver and brown fat. These results implicate a novel family of arrestins in the control of metabolism and development of obesity.
- © 2010 by American Heart Association, Inc.