Ablation of the Evolutionarily Acquired Functions of the <i>Atp1b4</i> 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 dom...
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2025-07-01
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| author | Nikolai N. Modyanov Lucia Russo Sumona Ghosh Lester Tamara R. Castañeda Himangi G. Marathe Larisa V. Fedorova Raymond E. Bourey Sonia M. Najjar Ivana L. de la Serna |
| author_facet | Nikolai N. Modyanov Lucia Russo Sumona Ghosh Lester Tamara R. Castañeda Himangi G. Marathe Larisa V. Fedorova Raymond E. Bourey Sonia M. Najjar Ivana L. de la Serna |
| author_sort | Nikolai N. Modyanov |
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| description | 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. |
| format | Article |
| id | doaj-art-c985fcaafc124cb18b2bb2c5daff59f3 |
| institution | DOAJ |
| issn | 2075-1729 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
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| series | Life |
| spelling | doaj-art-c985fcaafc124cb18b2bb2c5daff59f32025-08-20T02:45:46ZengMDPI AGLife2075-17292025-07-01157110310.3390/life15071103Ablation of the Evolutionarily Acquired Functions of the <i>Atp1b4</i> Gene Increases Metabolic Capacity and Reduces ObesityNikolai N. Modyanov0Lucia Russo1Sumona Ghosh Lester2Tamara R. Castañeda3Himangi G. Marathe4Larisa V. Fedorova5Raymond E. Bourey6Sonia M. Najjar7Ivana L. de la Serna8Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, Health Science Campus, University of Toledo, 3000 Arlington Avenue, Mail Stop1009 Toledo, Toledo, OH 43614, USACenter for Diabetes and Endocrine Research, College of Medicine and Life Sciences, Health Science Campus, University of Toledo, 3000 Arlington Avenue, Mail Stop1009 Toledo, Toledo, OH 43614, USACenter for Diabetes and Endocrine Research, College of Medicine and Life Sciences, Health Science Campus, University of Toledo, 3000 Arlington Avenue, Mail Stop1009 Toledo, Toledo, OH 43614, USACenter for Diabetes and Endocrine Research, College of Medicine and Life Sciences, Health Science Campus, University of Toledo, 3000 Arlington Avenue, Mail Stop1009 Toledo, Toledo, OH 43614, USADepartment of Cell and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USACenter for Diabetes and Endocrine Research, College of Medicine and Life Sciences, Health Science Campus, University of Toledo, 3000 Arlington Avenue, Mail Stop1009 Toledo, Toledo, OH 43614, USACenter for Diabetes and Endocrine Research, College of Medicine and Life Sciences, Health Science Campus, University of Toledo, 3000 Arlington Avenue, Mail Stop1009 Toledo, Toledo, OH 43614, USACenter for Diabetes and Endocrine Research, College of Medicine and Life Sciences, Health Science Campus, University of Toledo, 3000 Arlington Avenue, Mail Stop1009 Toledo, Toledo, OH 43614, USACenter for Diabetes and Endocrine Research, College of Medicine and Life Sciences, Health Science Campus, University of Toledo, 3000 Arlington Avenue, Mail Stop1009 Toledo, Toledo, OH 43614, USAIn 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.https://www.mdpi.com/2075-1729/15/7/1103<i>ATP1B4</i>gene co-optionplacental mammal evolutionmusclemetabolismobesity |
| spellingShingle | Nikolai N. Modyanov Lucia Russo Sumona Ghosh Lester Tamara R. Castañeda Himangi G. Marathe Larisa V. Fedorova Raymond E. Bourey Sonia M. Najjar Ivana L. de la Serna Ablation of the Evolutionarily Acquired Functions of the <i>Atp1b4</i> Gene Increases Metabolic Capacity and Reduces Obesity Life <i>ATP1B4</i> gene co-option placental mammal evolution muscle metabolism obesity |
| title | Ablation of the Evolutionarily Acquired Functions of the <i>Atp1b4</i> Gene Increases Metabolic Capacity and Reduces Obesity |
| title_full | Ablation of the Evolutionarily Acquired Functions of the <i>Atp1b4</i> Gene Increases Metabolic Capacity and Reduces Obesity |
| title_fullStr | Ablation of the Evolutionarily Acquired Functions of the <i>Atp1b4</i> Gene Increases Metabolic Capacity and Reduces Obesity |
| title_full_unstemmed | Ablation of the Evolutionarily Acquired Functions of the <i>Atp1b4</i> Gene Increases Metabolic Capacity and Reduces Obesity |
| title_short | Ablation of the Evolutionarily Acquired Functions of the <i>Atp1b4</i> Gene Increases Metabolic Capacity and Reduces Obesity |
| title_sort | ablation of the evolutionarily acquired functions of the i atp1b4 i gene increases metabolic capacity and reduces obesity |
| topic | <i>ATP1B4</i> gene co-option placental mammal evolution muscle metabolism obesity |
| url | https://www.mdpi.com/2075-1729/15/7/1103 |
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