Ablation of the evolutionarily acquired functions of the Atp1b4 gene in mice protects against obesity and increases metabolic capacity

The co-option of vertebrate orthologous ATP1B4 genes in placental mammals has radically altered the properties of the encoded BetaM proteins, which are genuine {beta}-subunits of Na,K-ATPases in lower vertebrates. Eutherian BetaM acquired an extended Glu-rich N-terminal domain resulting in complete loss of its ancestral function and became skeletal and cardiac muscle-specific component of the inner nuclear membrane. BetaM is expressed at the highest level during perinatal development and is implicated in gene regulation (Pestov et al., Proc Natl Acad Sci U S A. 2007). Here we report the long-term consequences of the Atp1b4 ablation on metabolic parameters in adult mice. BetaM deficient (Atp1b4-/Y) mice have significantly lower body weight and remarkably low adiposity. They exhibit lower fasting blood glucose, enhanced insulin sensitivity, and improved glucose tolerance as compared to their wild type littermates. Knockout mice display higher heat production, increased food intake, elevated oxygen consumption especially in darkness, and higher locomotor activity. The lower respiratory exchange ratio of knockout mice indicates that fat from the diet is metabolized rather than deposited as storage. These robust changes in mouse metabolic parameters induced by Atp1b4 disruption clearly demonstrate that eutherian BetaM plays an important role in the regulation of adult mouse metabolism. Ablation of Atp1b4, leading to the loss of evolutionarily acquired BetaM functions, serves as a model for a potential alternative pathway in mammalian evolution. Essentially, Atp1b4 ablation simulates a scenario where a specific stage in mammalian evolution is bypassed. Our results suggest that bypassing the co-option of Atp1b4 potentially reduces susceptibility to obesity.