Astrocytic insulin receptor controls circadian behavior via dopamine signaling in a sexually dimorphic manner

Antía González-Vila, María Luengo-Mateos, María Silveira-Loureiro, Pablo Garrido-Gil, Nataliia Ohinska, Marco González-Domínguez, Jose Luis Labandeira-García, Cristina García-Cáceres, Miguel López () and Olga Barca-Mayo ()
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Antía González-Vila: University of Santiago de Compostela
María Luengo-Mateos: University of Santiago de Compostela
María Silveira-Loureiro: University of Santiago de Compostela
Pablo Garrido-Gil: University of Santiago de Compostela
Nataliia Ohinska: University of Santiago de Compostela
Marco González-Domínguez: University of Santiago de Compostela
Jose Luis Labandeira-García: University of Santiago de Compostela
Cristina García-Cáceres: Helmholtz Munich & German Center for Diabetes Research (DZD)
Miguel López: University of Santiago de Compostela
Olga Barca-Mayo: University of Santiago de Compostela

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Mammalian circadian clocks respond to feeding and light cues, adjusting internal rhythms with day/night cycles. Astrocytes serve as circadian timekeepers, driving daily physiological rhythms; however, it’s unknown how they ensure precise cycle-to-cycle rhythmicity. This is critical for understanding why mistimed or erratic feeding, as in shift work, disrupts circadian physiology- a condition linked to type 2 diabetes and obesity. Here, we show that astrocytic insulin signaling sets the free-running period of locomotor activity in female mice and food entrainment in male mice. Additionally, ablating the insulin receptor in hypothalamic astrocytes alters cyclic energy homeostasis differently in male and female mice. Remarkably, the mutants exhibit altered dopamine metabolism, and the pharmacological modulation of dopaminergic signaling partially restores distinct circadian traits in both male and female mutant mice. Our findings highlight the role of astrocytic insulin-dopaminergic signaling in conveying time-of-feeding or lighting cues to the astrocyte clock, thus governing circadian behavior in a sex-specific manner.

Date: 2023
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DOI: 10.1038/s41467-023-44039-8

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