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Hypothalamic REV-ERB nuclear receptors control diurnal leptin sensitivity and circadian period: implications for diet-induced obesity

Résumé de la présentation :

Circadian disruption, as occurs in shift work, is associated with metabolic diseases often attributed to a discordance between internal clocks and environmental timekeepers. REV-ERB nuclear receptors are key components of the molecular clock, but their specific role in hypothalamus was unknown. We explored the relationship between temporal and homeostatic control of energy balance by focusing on mice that lacked the genes encoding the clock repressor elements REV-ERBα and -β, specifically in the tuberal hypothalamus or in the suprachiasmatic nucleus (SCN) master clock. Both mice lacking circadian nuclear receptors REV-ERBα and -β in the tuberal hypothalamus (HDKO mice) or in the SCN (SCN-DKO) gained excessive weight on an obesogenic high-fat diet when housed under a 24-hour light:dark period. However, integrative transcriptomic and cistromic analyses as well as mouse phenotyping revealed different mechanisms. In tuberal hypothalamus, REV-ERBs are necessary for maintaining circadian leptin responsiveness and metabolic homeostasis. In the SNC master clock, REV-ERBs are not required for rhythmicity but determine the free-running period length. Metabolic disturbances, observed when SCN-DKO mice were housed under a 24-hour light:dark period, were corrected by matching environmental lighting to their shortened endogenous 21-hour clock period. Altogether, these results lay the foundation to explore how transcriptional changes may link energy-sensing cell types with day/night rhythms and support the concept that dissonance between environmental conditions and endogenous time periods causes metabolic disruption.

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I2MC (INSERM U1297), Equipe 9, TOULOUSE