Loss of Evolutionarily Acquired Functions of Atp1b4 leads to Increase Energy Expenditure and Protection Against Diet‐Induced Obesity of Adult Mice

Co‐option of vertebrate orthologous ATP1B4 genes in placental mammals radically changed properties of the encoded BetaM‐proteins. These proteins in lower vertebrates are authentic Na, K‐ATPase β‐subunits which in complex with a‐subunits function as ion pumps in the plasma membrane. In placental mammals BetaM proteins gained entirely different properties through structural changes of N‐terminal domains. As a result of these evolutionary alterations, eutherian BetaM completely lost its ancestral role and became the only currently known skeletal and atrial cardiac muscle‐specific protein of the inner nuclear membrane, which is expressed at highest level during perinatal development and is implicated in gene expression regulation. Loss of BetaM the Atp1b4 knockout mouse model results in significantly lower body size and weight, growth retardation and high mortality of neonates. Transcriptome analysis by mRNA sequencing of skeletal muscle from neonatal wild type and knockout littermates revealed broad changes in expression of genes regulating lipid metabolism. These results imply that BetaM plays an essential role during a critical period of perinatal and neonatal development of placental mammals and its damage or malfunction can cause birth and growth defects in humans. Most importantly, Atp1b4 disruption exhibits a somewhat unexpected and profound beneficial effect of on metabolic parameters in adult male 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 and are resistant to high‐fat diet‐induced obesity as compared to their wild type littermates. Knockout mice display higher heat production associated with increased food intake, elevated oxygen consumption especially in darkness and higher locomotor activity. Lower respiratory exchange ratio of knockout mice indicates that fat from high‐fat 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 the important role in development of pathways regulating metabolism of adult mice. Finally, ablation of the evolutionarily acquired functions of Atp1b4 gene in mice is in fact a simulation of the alternative pathway of mammalian evolution. Support or Funding Information This work was supported by College of Medicine and Life Sciences, Center for Diabetes and Endocrine Research and Department of Physiology & Pharmacology, University of Toledo