Loss of the alternative calcineurin variant CnAβ1 enhances brown adipocyte differentiation and drives metabolic overactivation through FoxO1 activation

Bello-Arroyo, E.; Rubio, B.; Mora, A.; Lopez-Olaneta, M.; Gomez-Salinero, J. M.; Ramos, L.; Sanchez-Cabezudo, C. G.; Camafeita, E.; Cusso, L.; Desco, M.; Joffin, N.; Le Coq, J.; Boskovic, J.; McGurk, K. A.; Ware, J. S.; Barton, P. J.; Vazquez, J.; Scherer, P. E.; Sabio, G.; Gomez-Gaviro, M. V.; Lara-Pezzi, E.

doi:10.1101/2025.05.09.653054

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bioRxiv · 10.1101/2025.05.09.653054

Loss of the alternative calcineurin variant CnAβ1 enhances brown adipocyte differentiation and drives metabolic overactivation through FoxO1 activation

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Abstract

The alternative calcineurin A variant CnA{beta}1 has a unique C-terminal domain that provides it with distinct subcellular localization and mechanism of action different from other calcineurin isoforms. Here, we used mice lacking CnA{beta}1s C-terminal domain (CnA{beta}1{Delta}i12) to show that the absence of this specific isoform strongly reprograms metabolism. CnA{beta}1{Delta}i12 mice on a high-fat diet showed reduced body weight, white adipose tissue (WAT) mass, and circulating triglycerides, together with enhanced insulin sensitivity. In brown adipose tissue (BAT), CnA{beta}1 deficiency increased mitochondrial content and upregulated fatty acid oxidation and thermogenic proteins, improving cold resistance. Conversely, under starvation, CnA{beta}1{Delta}i12 mice experienced rapid fat depletion and hypothermia. Importantly, BAT-specific FoxO1 knockout in CnA{beta}1{Delta}i12 mice reduced catabolism-related gene expression and partially reversed the metabolic phenotypes, increasing body weight and WAT mass. Our findings reveal a relevant role for CnA{beta}1 in orchestrating BAT metabolism, highlighting its potential as a therapeutic target for obesity and metabolic syndrome.

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Bello-Arroyo, E., Rubio, B., Mora, A., Lopez-Olaneta, M., Gomez-Salinero, J. M., Ramos, L., Sanchez-Cabezudo, C. G., Camafeita, E., Cusso, L., Desco, M., Joffin, N., Le Coq, J., Boskovic, J., McGurk, K. A., Ware, J. S., Barton, P. J., Vazquez, J., Scherer, P. E., Sabio, G., Gomez-Gaviro, M. V., Lara-Pezzi, E.. 2025-05-11. Loss of the alternative calcineurin variant CnAβ1 enhances brown adipocyte differentiation and drives metabolic overactivation through FoxO1 activation. https://doi.org/10.1101/2025.05.09.653054

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