Adipocyte-specific MICU1 deficiency impairs memory and compromises hippocampal integrity in adult male mice

Peripheral metabolic stress is increasingly implicated in cognitive decline, but whether adipocyte-specific perturbation of mitochondrial calcium regulation is associated with hippocampal vulnerability remains unclear. Here, we used adipocyte-specific mitochondrial calcium uptake 1 knockout mice (aMICU1 KO) to examine whether adipocyte MICU1 deficiency is accompanied by memory-related behavioral changes and hippocampal pathology. aMICU1 KO mice showed no significant changes in body weight or adipose tissue mass but exhibited impaired spontaneous alternation in the Y-maze and reduced novel object recognition, whereas locomotor activity, anxiety-like behavior, impulsivity, and rotarod performance were not significantly altered. Histological and molecular analyses revealed reduced Nissl-positive cell counts in the dentate gyrus and CA regions, increased TUNEL staining, elevated cleaved caspase-3, and reduced BrdU+ and BrdU+/DCX+ cell populations. Hippocampal MICU1 expression was unchanged, supporting a non-cell-autonomous association rather than direct brain MICU1 loss. Adipose tissue and plasma analyses identified increased GDF15 as a prominent stress-associated circulating factor; however, hippocampal GFRAL/RET expression and downstream AKT/ERK phosphorylation were not robustly activated. Thus, GDF15 should be interpreted as a systemic stress-associated marker rather than a proven causal mediator. Together, these findings identify adipocyte MICU1 deficiency as a peripheral perturbation associated with hippocampal vulnerability and memory impairment, and they provide a foundation for future studies testing the adipocyte mitochondrial mechanisms and peripheral mediators that link adipose dysfunction to brain pathology.