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bioRxiv · 10.1101/2025.02.26.640035

Mid-aged mice rapidly normalize dysglycemia but aggravate obesity-induced hypothalamic and microglial changes upon dietary obesity reversal

Zemer, A.·Haim, Y.·Tsitrina, A.·Chalifa-Caspi, V.·Muallem, H.·Pincu, Y.·Yoel, U.·Monsonego, A.·Rudich, A.
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Abstract

ObjectiveObesity-induced-dysglycemia and hypothalamic-microgliosis coincide, but whether they remain linked upon obesity reversal, and what is the effect of age, remain unclear. Here we hypothesized that rapid normalization of dysglycemia upon obesity-reversal remains linked to microgliosis resolution, but differs between young and mid-aged mice. MethodsYoung (7w) and mid-aged (1y) mice were fed normal chow (NC) or high-fat diet (HFD,8w), then switched to NC (Rev,2w). ResultsCompared to young mice, NC-fed mid-aged mice were heavier and weight-stable, gained weight with HFD comparably, and lost less weight in Rev. HFD-induced dysglycemia was less severe in mid-aged compared to young mice, but similarly normalized by obesity-reversal. However, whole-hypothalamus RNA sequencing revealed 2,419 differentially expressed genes (DEGs) in mid-aged mice, [~]4-times more than in young mice, and in both age-groups [~]80% of DEGs obesity-induced changes were aggravated in Rev. Furthermore, compared with young mice, middle-aged mice showed greater obesity-induced microglial cyto-morphological changes in the arcuate nucleus (ARC), which associated with increased p-NF{kappa}B-(p-p65) nuclear staining. Only in middle-aged mice obesity-induced microglial changes were aggravated by obesity reversal, with cell volume correlating (Rho({rho})=0.691, p=0.001) with adipose tissue crown-like-structures. ConclusionsIn conclusion, rapid dysglycemia normalization is uncoupled to the resolution of hypothalamic microgliosis, more-so in mid-age.

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Zemer, A., Haim, Y., Tsitrina, A., Chalifa-Caspi, V., Muallem, H., Pincu, Y., Yoel, U., Monsonego, A., Rudich, A.. 2025-02-27. Mid-aged mice rapidly normalize dysglycemia but aggravate obesity-induced hypothalamic and microglial changes upon dietary obesity reversal. https://doi.org/10.1101/2025.02.26.640035

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