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bioRxiv · 10.64898/2026.04.09.716665

Galectin-8 regulates primary cilium in hypothalamic neurons through anL-type calcium channel/Aurora kinaseA/HDAC6 pathway impacting body energy balance

Herrera-Cid, C. R.·Hernandez, M. P.·Pinto, D.·Aranguiz, A.·Perez-Molina, F.·Vivero, A.·Cortes-Diaz, D.·Jara, C.·Espinoza, S.·Soza, A.·Tapia-Rojas, C.·Kerr, B.·Morselli, E.·Gonzalez, A.
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Abstract

OBJETIVEFood intake, energy expenditure, and metabolic homeostasis depend on hypothalamic neurons responses to peripheral signals, such as leptin, involving the primary cilium (PC). The PC is crucial for signal transduction and is dynamically regulated by assembly/disassembly or reabsorption of its microtubules-based axoneme. Absence or reduction in the length of PC is associated with obesity and type-2 diabetes (T2D). In other cellular systems, PC reabsorption is primarily regulated by calcium-mediated activation of the Aurora kinase A (AurkA)/histone deacetylase C6 (HDAC6) axis, which promotes axonemal disassembly. Here, we explore the role of Galectin-8 (Gal-8), a glycan-binding protein, in regulating PC structure and signaling related to metabolic parameters in hypothalamic neurons. METHODSGal-8 effects were assessed in hypothalamic Clu-177 cells by analyzing the PC presence and length by immunofluorescence, PC dynamics, and intracellular calcium changes by in vivo cell imaging, activation of FAK, Src, AurkA, HDAC6 and STAT3 by immunoblot, and Gal-8 interactions with {beta}1-integrins by pull-down assays. Gal-8-KO mice were used to evaluate PC length in hypothalamic neurons, metabolic phenotype, and responses to Gal-8 intranasal administration. RESULTSIn Clu-177 cells, Gal-8 induced PC reabsorption and reduced responsiveness to leptin signaling towards STAT3 activation. PC reabsorption involves glycan-mediated Gal-8 interactions with a5b1 and a3b1 integrins, activation of FAK and Src leading to calcium influx through L-type calcium channels (LTCC), and subsequent AurkA/HDAC6 axis activation. Gal-8-KO mice showed longer PC in hypothalamic neurons, higher STAT3 activation, decreased body weight and food intake, improved glucose tolerance, higher locomotor activity, and a glycolytic respiratory exchange rate (RER). Daily intranasal Gal-8 administration for 4 days restored hypothalamic PC length and STAT3 signaling, as well as RER in Gal-8-KO mice to the level of WT mice. CONCLUSIONSEndogenous Gal-8 is required to maintain PC structure and leptin signaling in hypothalamic neurons, impacting body weight, energy balance, and glucose homeostasis. The mechanism involves calcium influx via LTCC downstream of b1-integrin/FAK/Src signaling and subsequent AurkA/HDAC6 axis activation. Both Gal-8 and the AurkA/HDAC6 axis may offer new therapeutic opportunities for treating metabolic diseases characterized by ciliogenesis impairment, including obesity and type-2 diabetes.

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Herrera-Cid, C. R., Hernandez, M. P., Pinto, D., Aranguiz, A., Perez-Molina, F., Vivero, A., Cortes-Diaz, D., Jara, C., Espinoza, S., Soza, A., Tapia-Rojas, C., Kerr, B., Morselli, E., Gonzalez, A.. 2026-04-11. Galectin-8 regulates primary cilium in hypothalamic neurons through anL-type calcium channel/Aurora kinaseA/HDAC6 pathway impacting body energy balance. https://doi.org/10.64898/2026.04.09.716665

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