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

AI Summary

Adipocyte-specific MICU1 deficiency impairs memory, reducing Y-maze spontaneous alternation and novel object recognition without altering body weight or adipose mass.
Hippocampal integrity compromised with fewer Nissl positive cells in dentate gyrus and CA regions, increased apoptosis, and reduced BrdU+ and BrdU+/DCX+ neurogenesis.
Circulating GDF15 markedly elevated as a systemic stress marker; hippocampal GFRAL/RET signalling and AKT/ERK phosphorylation not robustly activated, arguing against proven causality.

AI Summary

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.

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.

Basic summary

Biomed J. 2026 Aug 22:101034. doi: 10.1016/j.bj.2026.101034. Online ahead of print.

ABSTRACT

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.

PMID:42632565 | DOI:10.1016/j.bj.2026.101034

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