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Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation
Keerthana Chithanathan1, Monika Jürgenson1, Katrina Ducena2
1Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
Immunity & Ageing : I & A
|November 23, 2024
Summary
Elocalcitol (Elo) treatment prevents obesity-induced brain senescence by upregulating microRNA-146a (miR-146a), which protects against inflammation and cognitive decline. This highlights Elo and miR-146a as potential therapies for obesity-related neuroinflammation.
Area of Science:
- Neuroscience
- Molecular Biology
- Endocrinology
Background:
- MicroRNAs (miRNAs) are key regulators of inflammation and cellular senescence.
- miR-146a is a known inflammation modulator, but its role in obesity-induced senescence is unclear.
- This study explores miR-146a's involvement in high-fat diet (HFD)-induced hypothalamic senescence and elocalcitol's (Elo) protective effects.
Purpose of the Study:
- Investigate the role of miR-146a in HFD-induced hypothalamic senescence.
- Determine the protective mechanisms of elocalcitol (Elo) against HFD-induced senescence.
- Assess the therapeutic potential of Elo and miR-146a in obesity-related neuroinflammation.
Main Methods:
- Utilized wild-type (WT) and miR-146a knockout (Mir146a-/-) mice fed a high-fat diet (HFD).
- Assessed senescence markers (p16, p21, β-gal), senescence-associated secretory phenotype (SASP) cytokines, and miR-146a expression in the hypothalamus and liver.
- Administered elocalcitol (Elo) to HFD-fed mice and evaluated its effects on senescence, cognitive function, and miR-146a expression.
Main Results:
- HFD induced hypothalamic senescence, cognitive decline, and downregulated miR-146a in WT mice.
- Mir146a-/- mice exhibited exacerbated HFD-induced hypothalamic senescence.
- Elo treatment upregulated miR-146a, reduced senescence, and improved cognitive function in WT HFD mice, but not in Mir146a-/- mice.
- Elo's efficacy was dependent on miR-146a, likely through the TGF/Smad4 pathway.
Conclusions:
- Elocalcitol (Elo) mitigates microglia senescence in the hypothalamus via miR-146a modulation.
- miR-146a protects against HFD-induced hypothalamic senescence, potentially by inhibiting the TGF/Smad4 pathway.
- Elo and miR-146a show promise for treating obesity-related neuroinflammation and senescence.
