Restricting feeding to dark phase fails to entrain circadian activity and energy expenditure oscillations in Pitx3-mutant Aphakia mice

• Published in: Cell reports (Cambridge) 2022-01, Vol.38 (2), p.110241-110241, Article 110241
• Main Authors: Fernández-Pérez, Antonio, Sanz-Magro, Adrián, Moratalla, Rosario, Vallejo, Mario
• Format: Article
• Language: English
• Subjects: Animals; Aphakia; calorie restriction; circadian clock; Dopamine; Energy Metabolism; Mice; Photoperiod; Pitx3ak; retinohypothalamic tract; striatum; Suprachiasmatic Nucleus; time-restricted feeding; ventral tegmental area
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.110241

Metabolic homeostasis is under circadian regulation to adapt energy requirements to light-dark cycles. Feeding cycles are regulated by photic stimuli reaching the suprachiasmatic nucleus via retinohypothalamic axons and by nutritional information involving dopaminergic neurotransmission. Previously, we reported that Pitx3-mutant Aphakia mice with altered development of the retinohypothalamic tract and the dopaminergic neurons projecting to the striatum, are resistant to locomotor and metabolic entrainment by time-restricted feeding. In their Matters Arising article, Scarpa et al. (2022) challenge this conclusion using mice from the same strain but following a different experimental paradigm involving calorie restriction. Here, we address their concerns by extending the analyses of our previous data, by identifying important differences in the experimental design between both studies and by presenting additional results on the dopaminergic deficit in the brain of Aphakia mice. This Matters Arising Response article addresses the Matters Arising article by Scarpa et al. (2022), published concurrently in Cell Reports. •Oscillating activity and energy outputs cycle out of phase in Pitx3ak mice•Dopamine innervation of specific brain areas is altered in Pitx3ak mice•Time-restricted feeding does not entrain activity and metabolic cycles•Pitx3 deficiency irreversibly alters cyclic metabolic homeostasis Fernández-Pérez et al. respond to the Matters Arising article by Scarpa et al., published concurrently in Cell Reports, and report defective dopamine innervation in Pitx3ak mice and confirm resistance of cyclic behavioral and metabolic outputs to entrainment by time-restricted feeding. Differences including the introduction of calorie restriction and exercise may account for discrepant results between both studies.