Ablation of the Evolutionarily Acquired Functions of the Atp1b4 Gene Increases Metabolic Capacity and Reduces Obesity

In placental mammals, the co-option of vertebrate orthologous <i>ATP1B4</i> genes has profoundly altered the properties of the encoded BetaM proteins, which function as bona fide β-subunits of Na,K-ATPases in lower vertebrates. Eutherian BetaM acquired an extended Glu-rich N-terminal domain resulting in the complete loss of its ancestral function and became a 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. Here we report the long-term consequences of <i>Atp1b4</i> ablation on metabolic parameters in adult mice. Male BetaM-deficient (<i>Atp1b4-/Y</i>) mice have remarkably lower body weight and adiposity than their wild-type littermates, despite higher food intake. Indirect calorimetry shows higher energy expenditure (heat production and oxygen consumption) with a greater spontaneous locomotor activity in <i>Atp1b4-/Y</i> males. Their lower respiratory exchange ratio suggests a greater reliance on fat metabolism compared to their wild-type counterparts. Consistently, <i>Atp1b4-/Y</i> KO mice exhibit enhanced β-oxidation in skeletal muscle, along with improved glucose and insulin tolerance. These robust metabolic changes induced by <i>Atp1b4</i> disruption demonstrate that eutherian BetaM plays an important role in regulating adult mouse metabolism. This demonstrates that bypassing the co-option of <i>Atp1b4</i> potentially reduces susceptibility to obesity. Thus, <i>Atp1b4</i> ablation leading to the loss of evolutionarily acquired BetaM functions serves as a model for a potential alternative pathway in mammalian evolution.