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

The alternative calcineurin A variant CnAβ1 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 CnAβ1’s C-terminal domain (CnAβ1 ^Δi12 ) to show that the absence of this specific isoform strongly reprograms metabolism. CnAβ1 ^Δi12 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), CnAβ1 deficiency increased mitochondrial content and upregulated fatty acid oxidation and thermogenic proteins, improving cold resistance. Conversely, under starvation, CnAβ1 ^Δi12 mice experienced rapid fat depletion and hypothermia. Importantly, BAT-specific FoxO1 knockout in CnAβ1 ^Δi12 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 CnAβ1 in orchestrating BAT metabolism, highlighting its potential as a therapeutic target for obesity and metabolic syndrome.